research for type 2 diabetes

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Type 2 diabetes articles from across Nature Portfolio

Type 2 diabetes mellitus, the most frequent subtype of diabetes, is a disease characterized by high levels of blood glucose (hyperglycaemia). It arises from a resistance to and relative deficiency of the pancreatic β-cell hormone insulin.

Metformin induces a Lac-Phe gut–brain signalling axis

The mechanism by which metformin affects food intake remains controversial. Now, two studies link metformin treatment with the induction of the appetite-suppressing metabolite N -lactoyl-phenylalanine, which is produced by the intestine.

• Tara TeSlaa

Latest Research and Reviews

Leveraging continuous glucose monitoring for personalized modeling of insulin-regulated glucose metabolism

• Balázs Erdős
• Shauna D. O’Donovan
• Ilja C. W. Arts

Effectiveness of glucose-lowering medications on cardiovascular outcomes in patients with type 2 diabetes at moderate cardiovascular risk

In a retrospective cohort study examining the comparative effectiveness of diabetes drugs in adults at moderate risk for cardiovascular disease, GLP-1 receptor agonists and SGLT2 inhibitors reduced the risk of cardiovascular events compared to DPP4 inhibitors, whereas sulfonylureas increased the risk.

• Rozalina G. McCoy
• Jeph Herrin
• Eric C. Polley

Visit to visit transition in TXNIP gene methylation and the risk of type 2 diabetes mellitus: a nested case-control study

• Weiling Chen
• Dongsheng Hu

Is phase angle associated with visceral adiposity and cardiometabolic risk in cardiology outpatients?

• Victoria Domingues Ferraz
• Jarson Pedro da Costa Pereira
• Ilma Kruze Grande de Arruda

Metformin and feeding increase levels of the appetite-suppressing metabolite Lac-Phe in humans

Metformin treatment was found to be associated with acute increases in the appetite-suppressing metabolite Lac-Phe in several human observational and interventional studies.

• Barry Scott
• Emily A. Day
• Lydia Lynch

Sex differences in adipose insulin resistance are linked to obesity, lipolysis and insulin receptor substrate 1

• Peter Arner
• Nathalie Viguerie
• Daniel Peter Andersson

News and Comment

Metformin acts through appetite-suppressing metabolite: Lac-Phe

• Shimona Starling

Slowly progressive insulin-dependent diabetes mellitus in type 1 diabetes endotype 2

• Tetsuro Kobayashi
• Takashi Kadowaki

Low-calorie diets for people with isolated impaired fasting glucose

Thirunavukkarasu et al. discuss how standard lifestyle interventions prove ineffective in preventing type 2 diabetes in individuals with isolated impaired fasting glucose, a highly prevalent prediabetes phenotype globally. They propose low-calorie diets as a promising strategy for diabetes prevention in this high-risk population.

• Sathish Thirunavukkarasu
• Jonathan E. Shaw

Functionally heterogeneous β cells regulate biphasic insulin secretion

Here, we reveal functional heterogeneity among β cells and discover that readily releasable β cells (RRβs) are a subpopulation that disproportionally contributes to biphasic glucose-stimulated insulin secretion. We further show that the dysfunction of RRβs has a crucial role in the progression of diabetes.

A second step towards precision medicine in diabetes

Dwibedi et al. carry out a randomized controlled trial to evaluate whether subgroups of patients with diabetes could receive the greatest metabolic benefit from novel anti-diabetic drugs.

• Xiantong Zou

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Type 2 Diabetes

Healthy eating is your recipe for managing diabetes.

About 38 million Americans have diabetes (about 1 in 10), and approximately 90-95% of them have type 2 diabetes. Type 2 diabetes most often develops in people over age 45, but more and more children, teens , and young adults are also developing it.

What Causes Type 2 Diabetes?

Insulin is a hormone made by your pancreas that acts like a key to let blood sugar into the cells in your body for use as energy. If you have type 2 diabetes, cells don’t respond normally to insulin; this is called insulin resistance . Your pancreas makes more insulin to try to get cells to respond. Eventually your pancreas can’t keep up, and your blood sugar rises, setting the stage for prediabetes and type 2 diabetes. High blood sugar is damaging to the body and can cause other serious health problems, such as heart disease ,  vision loss , and kidney disease .

Symptoms and Risk Factors

Type 2 diabetes  symptoms often develop over several years and can go on for a long time without being noticed (sometimes there aren’t any noticeable symptoms at all). Because symptoms can be hard to spot, it’s important to know the  risk factors and to see your doctor to get your blood sugar tested if you have any of them.

Testing for Type 2 Diabetes

A simple blood test will let you know if you have diabetes. If you’ve gotten your blood sugar tested at a health fair or pharmacy, follow up at a clinic or doctor’s office to make sure the results are accurate.

Managing Diabetes

Unlike many health conditions, diabetes is managed mostly by you, with support from your health care team (including your primary care doctor, foot doctor, dentist, eye doctor, registered dietitian nutritionist, diabetes educator, and pharmacist), family, and other important people in your life. Managing diabetes can be challenging, but everything you do to improve your health is worth it!

You may be able to manage your diabetes with healthy eating and being active, or your doctor may prescribe insulin, other injectable medications, or oral diabetes medicines to help manage your blood sugar and avoid complications . You’ll still need to eat healthy and be active if you take insulin or other medicines. It’s also important to keep your blood pressure and cholesterol close to the targets your doctor sets for you and get necessary screening tests.

You’ll need to check your blood sugar  regularly. Ask your doctor how often you should check it and what your target blood sugar levels should be. Keeping your blood sugar levels as close to target as possible will help you prevent or delay diabetes-related complications.

Stress is a part of life, but it can make managing diabetes harder, including managing your blood sugar levels and dealing with daily diabetes care. Regular physical activity, getting enough sleep, and relaxation exercises can help. Talk to your doctor and diabetes educator about these and other ways you can manage stress.

Make regular appointments with your health care team to be sure you’re on track with your treatment plan and to get help with new ideas and strategies if needed.

Whether you were just diagnosed with diabetes or have had it for some time, meeting with a diabetes educator is a great way to get support and guidance, including how to:

• Develop a healthy eating and activity plan
• Test your blood sugar and keep a record of the results
• Recognize the signs of high or low blood sugar and what to do about it
• If needed, give yourself insulin by syringe, pen, or pump
• Monitor your feet, skin, and eyes to catch problems early
• Buy diabetes supplies and store them properly
• Manage stress and deal with daily diabetes care

Ask your doctor about diabetes self-management education and support services and to recommend a diabetes educator, or search the Association of Diabetes Care & Education Specialists’ (ADCES) nationwide directory  for a list of programs in your community.

Type 2 Diabetes in Children and Teens

Childhood obesity rates are rising, and so are the rates of type 2 diabetes in youth. More than 75% of children with type 2 diabetes have a close relative who has it, too. But it’s not always because family members are related; it can also be because they share certain habits that can increase their risk. Parents can help prevent or delay type 2 diabetes by developing a plan for the whole family:

• Drinking more water and fewer sugary drinks
• Eating more fruits and vegetables
• Making favorite foods healthier
• Making physical activity more fun

Healthy changes become habits more easily when everyone makes them together. Find out how to take charge family style with these healthy tips .

Get Support

Tap into online diabetes communities for encouragement, insights, and support. The American Diabetes Association’s Community page and ADCES’s Peer Support Resources  are great ways to connect with others who share your experience.

• Living With Diabetes
• Managing Diabetes: Medicare Coverage and Resources [PDF - 1 MB]
• Diabetes: What Is It? Your Health with Joan Lunden and CDC
• Diabetes and Prediabetes Articles
• Infographics

To receive updates about diabetes topics, enter your email address:

• Diabetes Home
• State, Local, and National Partner Diabetes Programs
• National Diabetes Prevention Program
• Native Diabetes Wellness Program
• Chronic Kidney Disease
• Vision Health Initiative
• Heart Disease and Stroke
• Overweight & Obesity

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Clinical Trials

Type 2 diabetes.

Displaying 96 studies

The purpose of this study is to identify changes to the metabolome (range of chemicals produced in the body) and microbiome (intestine microbe environment) that are unique to Roux-en-Y gastric bypass surgery and assess the associated effect on the metabolism of patients with type 2 diabetes.

The purpose of this study is to evaluate the impact of a digital storytelling intervention derived through a community-based participatory research (CBPR) approach on type 2 diabetes mellitus (T2D) outcomes among Hispanic adults with poorly controlled type 2 diabetes mellitus (T2D) in primary care settings through a randomized clinical trial.

The purpose of  this study is to learn more about if the medication, Entresto, could help the function of the heart and kidneys.

The purpose of this study is to assess the impact of a whole food plant-based diet on blood sugar control in diabetic patients versus a control group on the American Diabetics Association diet before having a total hip, knee, or shoulder replacement surgery.

The primary aim of this study is to compare the outcome measures of adult ECH type 2 diabetes patients who were referred to onsite pharmacist services for management of their diabetes to similar patients who were not referred for pharmacy service management of their diabetes. A secondary aim of the study is to assess the Kasson providers’ satisfaction level and estimated pharmacy service referral frequency to their patients. A tertiary aim of the study is to compare the hospitalization rates of type 2 diabetes rates who were referred to onsite pharmacist services for management of their diabetes to similar patients ...

To explore the feasibility of conducting a family centered wellness coaching program for patients at high risk for developing diabetes, in a primary care setting.

To determine engagement patterns.

To describe characteristics of families who are likely to participate.

To identify barriers/limitations to family centered wellness coaching.

To assess whether a family centered 8 week wellness coaching intervention for primary care patients at high risk for diabetes will improve self-care behaviors as measured by self-reported changes in physical activity level and food choices.

This study is being done to understand metformin's mechanisms of action regarding glucose production, protein metabolism, and mitochondrial function.

The purpose of this study is to assess the effectiveness of Revita® DMR for improving HbA1c to ≤ 7% without the need of insulin in subjects with T2D compared to sham and to assess the effectiveness of DMR versus Sham on improvement in Glycemic, Hepatic and Cardiovascular endpoints.

The purpose of this study is to evaluate 6 weeks of home use of the Control-IQ automated insulin delivery system in individuals with type 2 diabetes.

This study will evaluate whether bile acids are able to increase insulin sensitivity and enhance glycemic control in T2DM patients, as well as exploring the mechanisms that enhance glycemic control. These observations will provide the preliminary data for proposing future therapeutic as well as further mechanistic studies of the role of bile acids in the control of glycemia in T2DM.

The purpose of this study is to determine if Inpatient Stress Hyperglycemia is an indicator of future risk of developing type 2 Diabetes Mellitus.

The purpose of this study is to assess the effectiveness of a digital storytelling intervention derived through a community based participatory research (CBPR) approach on self-management of type 2 diabetes (T2D) among Somali adults. 

The GRADE Study is a pragmatic, unmasked clinical trial that will compare commonly used diabetes medications, when combined with metformin, on glycemia-lowering effectiveness and patient-centered outcomes.

The overall goal of this proposal is to determine the effects of acute hyperglycemia and its modulation by Glucagon-like Peptide-1 (GLP-1) on myocardial perfusion in type 2 diabetes (DM). This study plan utilizes myocardial contrast echocardiography (MCE) to explore a) the effects of acute hyperglycemia on myocardial perfusion and coronary flow reserve in individuals with and without DM; and b) the effects of GLP-1 on myocardial perfusion and coronary flow reserve during euglycemia and hyperglycemia in DM. The investigators will recruit individuals with and without DM matched for age, gender and degree of obesity. The investigators will measure myocardial perfusion ...

The purpose of this study is to test the hypothesis that patients with T2DM will have greater deterioration in BMSi and in cortical porosity over 3 yrs as compared to sex- and age-matched non-diabetic controls; and identify the circulating hormonal (e.g., estradiol [E2], testosterone [T]) and biochemical (e.g., bone turnover markers, AGEs) determinants of changes in these key parameters of bone quality, and evaluate the possible relationship between existing diabetic complications and skeletal deterioration over time in the T2DM patients.

The purpose of this study is to determine the effect of endogenous GLP-1 secretion on islet function in people with Typr 2 Diabetes Mellitus (T2DM).

GLP-1 is a hormone made by the body that promotes the production of insulin in response to eating. However, there is increasing evidence that this hormone might help support the body’s ability to produce insulin when diabetes develops. 

The purpose of this study is to assess whether psyllium is more effective in lowering fasting blood sugar and HbA1c, and to evaluate the effect of psyllium compared to wheat dextrin on the following laboratory markers:  LDL-C, inflammatory markers such as ceramides and hsCRP, and branch chain amino acids which predict Diabetes Mellitus (DM).

This trial is a multi-center, adaptive, randomized, double-blind, placebo- and active- controlled, parallel group, phase 2 study in subjects with Type 2 Diabetes Mellitus to evaluate the effect of TTP399 on HbA1c following administration for 6 months.

The purpose of this study is to find the inheritable changes in genetic makeup that are related to the development of type 2 diabetes in Latino families.

The objective of this early feasibility study is to assess the feasibility and preliminary safety of the Endogenex Divice for endoscopic duodenal mucosal regeneration in patients with type 2 diabetes (T2D) inadequately controlled on 2-3 non-insulin glucose-lowering medications. 

This mixed methods study aims to answer the question: "What is the work of being a patient with type 2 diabetes mellitus?" .

The purpose of this study is to assess penile length pre- and post-completion of RestoreX® traction therapy compared to control groups (no treatment) among men with type II diabetes.

This observational study is conducted to determine how the duodenal layer thicknesses (mucosa, submucosa, and muscularis) vary with several factors in patients with and without type 2 diabetes.

The purpose of this study is to evaluate if breathing pure oxygen overnight affects insulin sensitivity in participants with diabetes.   

The purpose of this study is to determine the impact of patient decision aids compared to usual care on measures of patient involvement in decision-making, diabetes care processes, medication adherence, glycemic and cardiovascular risk factor control, and use of resources in nonurban practices in the Midwestern United States.

The study is being undertaken to understand how a gastric bypass can affect a subject's diabetes even prior to their losing significant amounts of weight. The hypothesis of this study is that increased glucagon-like peptide-1 (GLP-1) secretion explains the amelioration in insulin secretion after Roux-en-Y Gastric Bypass (RYGB) surgery.

The purpose of this study is to estimate the risk of diabetes related complications after total pancreatectomy.  We will contact long term survivors after total pancreatectomy to obtain data regarding diabetes related end organ complications.

The purpose of this study is to understand nighttime glucose regulation in humans and find if the pattern is different in people with Type 2 diabetes

The study purpose is to understand patients’ with the diagnosis of Diabetes Mellitus type 1 or 2 perception of the care they receive in the Diabetes clinic or Diabetes technology clinic at Mayo Clinic and to explore and to identify the healthcare system components patients consider important to be part of the comprehensive regenerative care in the clinical setting.

However, before we can implement structural changes or design interventions to promote comprehensive regenerative care in clinical practice, we first need to characterize those regenerative practices occurring today, patients expectations, perceptions and experiences about comprehensive regenerative care and determine the ...

It is unknown how patient preferences and values impact the comparative effectiveness of second-line medications for Type 2 diabetes (T2D). The purpose of this study is to elicit patient preferences toward various treatment outcomes (e.g., hospitalization, kidney disease) using a participatory ranking exercise, use these rankings to generate individually weighted composite outcomes, and estimate patient-centered treatment effects of four different second-line T2D medications that reflect the patient's value for each outcome. 

The purpose of this mixed-methods study is to deploy the tenets of Health and Wellness Coaching (HWC) through a program called BeWell360 model , tailored to the needs of Healthcare Workers (HCWs) as patients living with poorly-controlled Type 2 Diabetes (T2D). The objective of this study is to pilot-test this novel, scalable, and sustainable BeWell360 model that is embedded and integrated as part of primary care for Mayo Clinic Employees within Mayo Clinic Florida who are identified as patients li)ving with poorly-controlled T2D. 

The investigators will determine whether people with high muscle mitochondrial capacity produce higher amount of reactive oxygen species (ROS) on consuming high fat /high glycemic diet and thus exhibit elevated cellular oxidative damage. The investigators previously found that Asian Indian immigrants have high mitochondrial capacity in spite of severe insulin resistance. Somalians are another new immigrant population with rapidly increasing prevalence of diabetes. Both of these groups traditionally consume low caloric density diets, and the investigators hypothesize that when these groups are exposed to high-calorie Western diets, they exhibit increased oxidative stress, oxidative damage, and insulin resistance. The investigators will ...

The purpose of this research is to find out how genetic variations in GLP1R, alters insulin secretion, in the fasting state and when blood sugars levels are elevated. Results from this study may help us identify therapies to prevent or reverse type 2 diabetes mellitus.

Can QBSAfe be implemented in a clinical practice setting and improve quality of life, reduce treatment burden and hypoglycemia among older, complex patients with type 2 diabetes?

Questionnaire administered to diabetic patients in primary care practice (La Crosse Mayo Family Medicine Residency /Family Health Clinic) to assess patient’s diabetic knowledge. Retrospective chart review will also be done to assess objective diabetic control based on most recent hemoglobin A1c.    

To determine if the EndoBarrier safely and effectively improves glycemic control in obese subjects with type 2 diabetes.

The purpose of this study is to assess key characteristics of bone quality, specifically material strength and porosity, in patients who have type 2 diabetes. These patients are at an unexplained increased risk for fractures and there is an urgent need to refine clinical assessment for this risk.

Muscle insulin resistance is a hallmark of upper body obesity (UBO) and Type 2 diabetes (T2DM). It is unknown whether muscle free fatty acid (FFA) availability or intramyocellular fatty acid trafficking is responsible for muscle insulin resistance, although it has been shown that raising FFA with Intralipid can cause muscle insulin resistance within 4 hours. We do not understand to what extent the incorporation of FFA into ceramides or diacylglycerols (DG) affect insulin signaling and muscle glucose uptake. We propose to alter the profile and concentrations of FFA of healthy, non-obese adults using an overnight, intra-duodenal palm oil infusion vs. ...

The objectives of this study are to identify circulating extracellular vesicle (EV)-derived protein and RNA signatures associated with Type 2 Diabetes (T2D), and to identify changes in circulating EV cargo in patients whose T2D resolves after sleeve gastrectomy (SG) or Roux-en-Y gastric bypass (RYGB).

This research study is being done to develop educational materials that will help patients and clinicians talk about diabetes treatment and management options.

The purpose of this study evaluates a subset of people with isolated Impaired Fasting Glucose with Normal Glucose Tolerance (i.e., IFG/NGT) believed to have normal β-cell function in response to a glucose challenge, suggesting that – at least in this subset of prediabetes – fasting glucose is regulated independently of glucose in the postprandial period. To some extent this is borne out by genetic association studies which have identified loci that affect fasting glucose but not glucose tolerance and vice-versa.

Assessment of glucose metabolism and liver fat after 12 week dietary intervention in pre diabetes subjects. Subjects will be randomized to either high fat (olive oil supplemented),high carb/high fiber (beans supplemented) and high carb/low fiber diets. Glucose metabolism will be assessed by labeled oral glucose tolerance test and liver fat by magnetic resonance spectroscopy pre randomization and at 8 and 12 week after starting dietary intervention.

To study the effect of an ileocolonic formulation of ox bile extract on insulin sensitivity, postprandial glycemia and incretin levels, gastric emptying, body weight and fasting serum FGF-19 (fibroblast growth factor) levels in overweight or obese type 2 diabetic subjects on therapy with DPP4 (dipeptidyl peptidase-4) inhibitors (e.g. sitagliptin) alone or in combination with metformin.

The purpose of this study is to evaluate whether or not a 6 month supply (1 meal//day) of healthy food choices readily available in the patient's home and self management training including understanding of how foods impact diabetes, improved food choices and how to prepare those foods, improve glucose control.  In addition, it will evaluate whether or not there will be lasting behavior change modification after the program.

The purpose of this study is to compare the rate of progression from prediabetes at 4 months to frank diabetes at 12 months (as defined by increase in HbA1C or fasting BS to diabetic range based on the ADA criteria) after transplantation in kidney transplant recipients on Exenatide SR + SOC vs. standard-of-care alone.

The purpose of this study is to learn more about how the body stores dietary fat. Medical research has shown that fat stored in different parts of the body can affect the risk for diabetes, heart disease and other major health conditions.

The purpose of this study is to see why the ability of fat cells to respond to insulin is different depending on body shape and how fat tissue inflammation is involved.

The purpose of this study is to determine the mechanism(s) by which common bariatric surgical procedures alter carbohydrate metabolism. Understanding these mechanisms may ultimately lead to the development of new interventions for the prevention and treatment of type 2 diabetes and obesity.

The purpose of this study is to evaluate the effects of improving glycemic control, and/or reducing glycemic variability on gastric emptying, intestinal barrier function, autonomic nerve functions, and epigenetic changes in subjects with type 1 diabetes mellitus (T1DM) and  type 2 diabetes mellitus (T2DM) who are switched to intensive insulin therapy as part of clinical practice.

This study is designed to compare an intensive lifestyle and activity coaching program ("Sessions") to usual care for diabetic patients who are sedentary. The question to be answered is whether the Sessions program improves clinical or patient centric outcomes. Recruitment is through invitiation only.

A research study to enhance clinical discussion between patients and pharmacists using a shared decision making tool for type 2 diabetes or usual care.

While the potential clinical uses of pulsed electromagnetic field therapy (PEMF) are extensive, we are focusing on the potential benefits of PEMF on vascular health. We are targeting, the pre diabetic - metabolic syndrome population, a group with high prevalence in the American population. This population tends to be overweight, low fitness, high blood pressure, high triglycerides and borderline high blood glucose.

This is a study to evaluate a new Point of Care test for blood glucose monitoring.

This protocol is being conducted to determine the mechanisms responsible for insulin resistance, obesity and type 2 diabetes.

The purpose of this study is to assess the effects of a nighttime rise in cortisol on the body's glucose production in type 2 diabetes.

The goal of this study is to evaluate a new format for delivery of a culturally tailored digital storytelling intervention by incorporating a facilitated group discussion following the videos, for management of type II diabetes in Latino communities.

The purpose of this study is to determine the metabolic effects of Colesevelam, particularly for the ability to lower blood sugar after a meal in type 2 diabetics, in order to develop a better understanding of it's potential role in the treatment of obesity.

The purpose of this study is to test whether markers of cellular aging and the SASP are elevated in subjects with obesity and further increased in patients with obesity and Type 2 Diabetes Mellitus (T2DM) and to relate markers of cellular aging (senescence) and the SASP to skeletal parameters (DXA, HRpQCT, bone turnover markers) in each of these groups.

Integration of Diabetes Prevention Program (DPP) and Diabetes Self Management Program (DSMP) into WellConnect.

Muscle insulin resistance is a hallmark of upper body obesity (UBO) and Type 2 diabetes (T2DM). It is unknown whether muscle free fatty acid (FFA) availability or intramyocellular fatty acid trafficking is responsible for the abnormal response to insulin. Likewise, we do not understand to what extent the incorporation of FFA into ceramides or diacylglycerols (DG) affect insulin signaling and muscle glucose uptake. We will measure muscle FFA storage into intramyocellular triglyceride, intramyocellular fatty acid trafficking, activation of the insulin signaling pathway and glucose disposal rates under both saline control (high overnight FFA) and after an overnight infusion of intravenous ...

The purpose of this study is to improve our understanding of why gastrointestinal symptoms occur in diabetes mellitus patients and identify new treatment(s) in the future.  

These symptoms are often distressing and may impair glycemic control. We do not understand how diabetes mellitus affects the GI tracy. In 45 patients undergoing sleeve gastrectomy, we plan to compare the cellular composition of circulating peripheral mononuclear cells, stomach immune cells, and interstitial cells of Cajal in the stomach. 

Muscle insulin resistance is a hallmark of upper body obesity (UBO) and Type 2 diabetes (T2DM), whereas lower body obesity (LBO) is characterized by near-normal insulin sensitivity. It is unknown whether muscle free fatty acid (FFA) availability or intramyocellular fatty acid trafficking differs between different obesity phenotypes. Likewise, we do not understand to what extent the incorporation of FFA into ceramides or diacylglycerols (DG) affect insulin signaling and muscle glucose uptake. By measuring muscle FFA storage into intramyocellular triglyceride, intramyocellular fatty acid trafficking, activation of the insulin signaling pathway and glucose disposal rates we will provide the first integrated examination ...

The goal of this study is to evaluate the presence of podocytes (special cells in the kidney that prevent protein loss) in the urine in patients with diabetes or glomerulonephritis (inflammation in the kidneys). Loss of podocyte in the urine may be an earlier sign of kidney injury (before protein loss) and the goal of this study is to evaluate the association between protein in the urine and podocytes in the urine.

Using stem cell derived intestinal epithelial cultures (enteroids) derived from obese (BMI> 30) patients and non-obese and metabolically normal patients (either post-bariatric surgery (BS) or BS-naïve with BMI < 25), dietary glucose absorption was measured. We identified that enteroids from obese patients were characterized by glucose hyper-absorption (~ 5 fold) compared to non-obese patients. Significant upregulation of major intestinal sugar transporters, including SGLT1, GLU2 and GLUT5 was responsible for hyper-absorptive phenotype and their pharmacologic inhibition significantly decreased glucose absorption. Importantly, we observed that enteroids from post-BS non-obese patients exhibited low dietary glucose absorption, indicating that altered glucose absorption ...

The purpose of this study is to evaluate the effects of multiple dose regimens of RM-131 on vomiting episodes, stomach emptying and stomach paralysis symptoms in patients with Type 1 and Type 2 diabetes and gastroparesis.

The purpose of this study is to create a prospective cohort of subjects with increased probability of being diagnosed with pancreatic cancer and then screen this cohort for pancreatic cancer

The purpose of this study is assess the feasibility, effectiveness, and acceptability of Diabetes-REM (Rescue, Engagement, and Management), a comprehensive community paramedic (CP) program to improve diabetes self-management among adults in Southeast Minnesota (SEMN) treated for servere hypoglycemia by the Mayo Clinic Ambulance Services (MCAS).

The purpose of this study is to determine if a blood test called "pancreatic polypeptide" can help distinguish between patients with diabetes mellitus with and without pancreatic cancer.

The purpose of this study is to evaluate the effectiveness and safety of brolucizumab vs. aflibercept in the treatment of patients with visual impairment due to diabetic macular edema (DME).

Women with gestational diabetes mellitus (GDM) are likely to have insulin resistance that persists long after pregnancy, resulting in greater risk of developing type 2 diabetes mellitus (T2DM). The study will compare women with and without a previous diagnosis of GDM to determine if women with a history of GDM have abnormal fatty acid metabolism, specifically impaired adipose tissue lipolysis. The study will aim to determine whether women with a history of GDM have impaired pancreatic β-cell function. The study will determine whether women with a history of GDM have tissue specific defects in insulin action, and also identify the effect of a ...

Although vitreous hemorrhage (VH) from proliferative diabetic retinopathy (PDR) can cause acute and dramatic vision loss for patients with diabetes, there is no current, evidence-based clinical guidance as to what treatment method is most likely to provide the best visual outcomes once intervention is desired. Intravitreous anti-vascular endothelial growth factor (anti-VEGF) therapy alone or vitrectomy combined with intraoperative PRP each provide the opportunity to stabilize or regress retinal neovascularization. However, clinical trials are lacking to elucidate the relative time frame of visual recovery or final visual outcome in prompt vitrectomy compared with initial anti-VEGF treatment. The Diabetic Retinopathy Clinical Research ...

The purpose of this study is to demonstrate feasibility of dynamic 11C-ER176 PET imaging to identify macrophage-driven immune dysregulation in gastric muscle of patients with DG. Non-invasive quantitative assessment with PET can significantly add to our diagnostic armamentarium for patients with diabetic gastroenteropathy.

The purpose of this study is to assess the safety and tolerability of intra-arterially delivered mesenchymal stem/stromal cells (MSC) to a single kidney in one of two fixed doses at two time points in patients with progressive diabetic kidney disease. 

Diabetic kidney disease, also known as diabetic nephropathy, is the most common cause of chronic kidney disease and end-stage kidney failure requiring dialysis or kidney transplantation.  Regenerative, cell-based therapy applying MSCs holds promise to delay the progression of kidney disease in individuals with diabetes mellitus.  Our clinical trial will use MSCs processed from each study participant to test the ...

The purpose of this study is to evaluate whether or not semaglutide can slow down the growth and worsening of chronic kidney disease in people with type 2 diabetes. Participants will receive semaglutide (active medicine) or placebo ('dummy medicine'). This is known as participants' study medicine - which treatment participants get is decided by chance. Semaglutide is a medicine, doctors can prescribe in some countries for the treatment of type 2 diabetes. Participants will get the study medicine in a pen. Participants will use the pen to inject the medicine in a skin fold once a week. The study will close when ...

This study aims to measure the percentage of time spent in hyperglycemia in patients on insulin therapy and evaluate diabetes related patient reported outcomes in kidney transplant recipients with type 2 diabetes. It also aimes to evaluate immunosuppression related patient reported outcomes in kidney transplant recipients with type 2 diabetes.

The purpose of this study is to look at how participants' daily life is affected by their heart failure. The study will also look at the change in participants' body weight. This study will compare the effect of semaglutide (a new medicine) compared to "dummy" medicine on body weight and heart failure symptoms. Participants will either get semaglutide or "dummy" medicine, which treatment participants get is decided by chance. Participants will need to take 1 injection once a week. 

The objectives of this study are to evaluate the safety of IW-9179 in patients with diabetic gastroparesis (DGP) and the effect of treatment on the cardinal symptoms of DGP.

The purpose of this study is to understand why patients with indigestion, with or without diabetes, have gastrointestinal symptoms and, in particular, to understand where the symptoms are related to increased sensitivity to nutrients.Subsequently, look at the effects of Ondansetron on these patients' symptoms.

The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics, and exploratory effectiveness of nimacimab in patients with diabetic gastroparesis.

The purpose of this study is to prospectively assemble a cohort of subjects >50 and ≤85 years of age with New-onset Diabetes (NOD):

• Estimate the probability of pancreatic ductal adenocarcinoma (PDAC) in the NOD Cohort;
• Establish a biobank of clinically annotated biospecimens including a reference set of biospecimens from pre-symptomatic PDAC and control new-onset type 2 diabetes mellitus (DM) subjects;
• Facilitate validation of emerging tests for identifying NOD subjects at high risk for having PDAC using the reference set; and
• Provide a platform for development of an interventional protocol for early detection of sporadic PDAC ...

The primary purpose of this study is to evaluate the impact of dapagliflozin, as compared with placebo, on heart failure, disease specific biomarkers, symptoms, health status and quality of life in patients with type 2 diabetes or prediabetes and chronic heart failure with preserved systolic function.

The purpose of this study is to look at the relationship of patient-centered education, the Electronic Medical Record (patient portal) and the use of digital photography to improve the practice of routine foot care and reduce the number of foot ulcers/wounds in patients with diabetes.

Diabetes mellitus is a common condition which is defined by persistently high blood sugar levels. This is a frequent problem that is most commonly due to type 2 diabetes. However, it is now recognized that a small portion of the population with diabetes have an underlying problem with their pancreas, such as chronic pancreatitis or pancreatic cancer, as the cause of their diabetes. Currently, there is no test to identify the small number of patients who have diabetes caused by a primary problem with their pancreas.

The goal of this study is to develop a test to distinguish these ...

The purpose of this study is to demonstrate the performance of the Guardian™ Sensor (3) with an advanced algorithm in subjects age 2 - 80 years, for the span of 170 hours (7 days).

The primary purpose of this study is to prospectively assess symptoms of bloating (severity, prevalence) in patients with diabetic gastroparesis.

The purpose of this study is to track the treatment burden experienced by patients living with Type 2 Diabetes Mellitus (T2DM) experience as they work to manage their illness in the context of social distancing measures. 

To promote social distancing during the COVID-19 pandemic, health care institutions around the world have rapidly expanded their use of telemedicine to replace in-office appointments where possible.1 For patients with diabetes, who spend considerable time and energy engaging with various components of the health care system,2,3 this unexpected and abrupt transition to virtual health care may signal significant changes to ...

The purpose of this study is to evaluate the safety and efficacy of oral Pyridorin 300 mg BID in reducing the rate of progression of nephropathy due to type 2 diabetes mellitus.

The purpose of this study is to evaluate the effect of Aramchol as compared to placebo on NASH resolution, fibrosis improvement and clinical outcomes related to progression of liver disease (fibrosis stages 2-3 who are overweight or obese and have prediabetes or type 2 diabetes).

The purpose of this study is to evaluate the ability of appropriately-trained family physicians to screen for and identify Diabetic Retinopathy using retinal camera and, secondarily, to describe patients’ perception of the convenience and cost-effectiveness of retinal imaging.

The primary purpose of this study is to evaluate the impact of dapagliflozin, as compared with placebo, on heart failure disease-specific biomarkers, symptoms, health status, and quality of life in patients who have type 2 diabetes and chronic heart failure with reduced systolic function.

Hypothesis: We hypothesize that patients from the Family Medicine Department at Mayo Clinic Florida who participate in RPM will have significantly reduced emergency room visits, hospitalizations, and hospital contacts.  

Aims, purpose, or objectives: In this study, we will compare the RPM group to a control group that does not receive RPM. The primary objective is to determine if there are significant group differences in emergency room visits, hospitalizations, outpatient primary care visits, outpatient specialty care visits, and hospital contacts (inbound patient portal messages and phone calls). The secondary objective is to determine if there are ...

The purpose of this research is to determine if CGM (continuous glucose monitors) used in the hospital in patients with COVID-19 and diabetes treated with insulin will be as accurate as POC (point of care) glucose monitors. Also if found to be accurate, CGM reading data will be used together with POC glucometers to dose insulin therapy.

The purpose of this study is to evaluate the effect of fenofibrate compared with placebo for prevention of diabetic retinopathy (DR) worsening or center-involved diabetic macular edema (CI-DME) with vision loss through 4 years of follow-up in participants with mild to moderately severe non-proliferative DR (NPDR) and no CI-DME at baseline.

The purpose of this study is to assess painful diabetic peripheral neuropathy after high-frequency spinal cord stimulation.

The purpose of this study is to examine the evolution of diabetic kindey injury over an extended period in a group of subjects who previously completed a clinical trial which assessed the ability of losartan to protect the kidney from injury in early diabetic kidney disease. We will also explore the relationship between diabetic kidney disease and other diabetes complications, including neuropathy and retinopathy.

The purpose of this study is to evaluate the effietiveness of remdesivir (RDV) in reducing the rate of of all-cause medically attended visits (MAVs; medical visits attended in person by the participant and a health care professional) or death in non-hospitalized participants with early stage coronavirus disease 2019 (COVID-19) and to evaluate the safety of RDV administered in an outpatient setting.

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• Type 2 diabetes

Type 2 diabetes is a condition that happens because of a problem in the way the body regulates and uses sugar as a fuel. That sugar also is called glucose. This long-term condition results in too much sugar circulating in the blood. Eventually, high blood sugar levels can lead to disorders of the circulatory, nervous and immune systems.

In type 2 diabetes, there are primarily two problems. The pancreas does not produce enough insulin — a hormone that regulates the movement of sugar into the cells. And cells respond poorly to insulin and take in less sugar.

Type 2 diabetes used to be known as adult-onset diabetes, but both type 1 and type 2 diabetes can begin during childhood and adulthood. Type 2 is more common in older adults. But the increase in the number of children with obesity has led to more cases of type 2 diabetes in younger people.

There's no cure for type 2 diabetes. Losing weight, eating well and exercising can help manage the disease. If diet and exercise aren't enough to control blood sugar, diabetes medications or insulin therapy may be recommended.

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Symptoms of type 2 diabetes often develop slowly. In fact, you can be living with type 2 diabetes for years and not know it. When symptoms are present, they may include:

• Increased thirst.
• Frequent urination.
• Increased hunger.
• Unintended weight loss.
• Blurred vision.
• Slow-healing sores.
• Frequent infections.
• Numbness or tingling in the hands or feet.
• Areas of darkened skin, usually in the armpits and neck.

When to see a doctor

See your health care provider if you notice any symptoms of type 2 diabetes.

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Type 2 diabetes is mainly the result of two problems:

• Cells in muscle, fat and the liver become resistant to insulin As a result, the cells don't take in enough sugar.
• The pancreas can't make enough insulin to keep blood sugar levels within a healthy range.

Exactly why this happens is not known. Being overweight and inactive are key contributing factors.

How insulin works

Insulin is a hormone that comes from the pancreas — a gland located behind and below the stomach. Insulin controls how the body uses sugar in the following ways:

• Sugar in the bloodstream triggers the pancreas to release insulin.
• Insulin circulates in the bloodstream, enabling sugar to enter the cells.
• The amount of sugar in the bloodstream drops.
• In response to this drop, the pancreas releases less insulin.

The role of glucose

Glucose — a sugar — is a main source of energy for the cells that make up muscles and other tissues. The use and regulation of glucose includes the following:

• Glucose comes from two major sources: food and the liver.
• Glucose is absorbed into the bloodstream, where it enters cells with the help of insulin.
• The liver stores and makes glucose.
• When glucose levels are low, the liver breaks down stored glycogen into glucose to keep the body's glucose level within a healthy range.

In type 2 diabetes, this process doesn't work well. Instead of moving into the cells, sugar builds up in the blood. As blood sugar levels rise, the pancreas releases more insulin. Eventually the cells in the pancreas that make insulin become damaged and can't make enough insulin to meet the body's needs.

Risk factors

Factors that may increase the risk of type 2 diabetes include:

• Weight. Being overweight or obese is a main risk.
• Fat distribution. Storing fat mainly in the abdomen — rather than the hips and thighs — indicates a greater risk. The risk of type 2 diabetes is higher in men with a waist circumference above 40 inches (101.6 centimeters) and in women with a waist measurement above 35 inches (88.9 centimeters).
• Inactivity. The less active a person is, the greater the risk. Physical activity helps control weight, uses up glucose as energy and makes cells more sensitive to insulin.
• Family history. An individual's risk of type 2 diabetes increases if a parent or sibling has type 2 diabetes.
• Race and ethnicity. Although it's unclear why, people of certain races and ethnicities — including Black, Hispanic, Native American and Asian people, and Pacific Islanders — are more likely to develop type 2 diabetes than white people are.
• Blood lipid levels. An increased risk is associated with low levels of high-density lipoprotein (HDL) cholesterol — the "good" cholesterol — and high levels of triglycerides.
• Age. The risk of type 2 diabetes increases with age, especially after age 35.
• Prediabetes. Prediabetes is a condition in which the blood sugar level is higher than normal, but not high enough to be classified as diabetes. Left untreated, prediabetes often progresses to type 2 diabetes.
• Pregnancy-related risks. The risk of developing type 2 diabetes is higher in people who had gestational diabetes when they were pregnant and in those who gave birth to a baby weighing more than 9 pounds (4 kilograms).
• Polycystic ovary syndrome. Having polycystic ovary syndrome — a condition characterized by irregular menstrual periods, excess hair growth and obesity — increases the risk of diabetes.

Complications

Type 2 diabetes affects many major organs, including the heart, blood vessels, nerves, eyes and kidneys. Also, factors that increase the risk of diabetes are risk factors for other serious diseases. Managing diabetes and controlling blood sugar can lower the risk for these complications and other medical conditions, including:

• Heart and blood vessel disease. Diabetes is associated with an increased risk of heart disease, stroke, high blood pressure and narrowing of blood vessels, a condition called atherosclerosis.
• Nerve damage in limbs. This condition is called neuropathy. High blood sugar over time can damage or destroy nerves. That may result in tingling, numbness, burning, pain or eventual loss of feeling that usually begins at the tips of the toes or fingers and gradually spreads upward.
• Other nerve damage. Damage to nerves of the heart can contribute to irregular heart rhythms. Nerve damage in the digestive system can cause problems with nausea, vomiting, diarrhea or constipation. Nerve damage also may cause erectile dysfunction.
• Kidney disease. Diabetes may lead to chronic kidney disease or end-stage kidney disease that can't be reversed. That may require dialysis or a kidney transplant.
• Eye damage. Diabetes increases the risk of serious eye diseases, such as cataracts and glaucoma, and may damage the blood vessels of the retina, potentially leading to blindness.
• Skin conditions. Diabetes may raise the risk of some skin problems, including bacterial and fungal infections.
• Slow healing. Left untreated, cuts and blisters can become serious infections, which may heal poorly. Severe damage might require toe, foot or leg amputation.
• Hearing impairment. Hearing problems are more common in people with diabetes.
• Sleep apnea. Obstructive sleep apnea is common in people living with type 2 diabetes. Obesity may be the main contributing factor to both conditions.
• Dementia. Type 2 diabetes seems to increase the risk of Alzheimer's disease and other disorders that cause dementia. Poor control of blood sugar is linked to a more rapid decline in memory and other thinking skills.

Healthy lifestyle choices can help prevent type 2 diabetes. If you've received a diagnosis of prediabetes, lifestyle changes may slow or stop the progression to diabetes.

A healthy lifestyle includes:

• Eating healthy foods. Choose foods lower in fat and calories and higher in fiber. Focus on fruits, vegetables and whole grains.
• Getting active. Aim for 150 or more minutes a week of moderate to vigorous aerobic activity, such as a brisk walk, bicycling, running or swimming.
• Losing weight. If you are overweight, losing a modest amount of weight and keeping it off may delay the progression from prediabetes to type 2 diabetes. If you have prediabetes, losing 7% to 10% of your body weight may reduce the risk of diabetes.
• Avoiding long stretches of inactivity. Sitting still for long periods of time can increase the risk of type 2 diabetes. Try to get up every 30 minutes and move around for at least a few minutes.

For people with prediabetes, metformin (Fortamet, Glumetza, others), a diabetes medication, may be prescribed to reduce the risk of type 2 diabetes. This is usually prescribed for older adults who are obese and unable to lower blood sugar levels with lifestyle changes.

More Information

• Diabetes prevention: 5 tips for taking control
• Professional Practice Committee: Standards of Medical Care in Diabetes — 2020. Diabetes Care. 2020; doi:10.2337/dc20-Sppc.
• Diabetes mellitus. Merck Manual Professional Version. https://www.merckmanuals.com/professional/endocrine-and-metabolic-disorders/diabetes-mellitus-and-disorders-of-carbohydrate-metabolism/diabetes-mellitus-dm. Accessed Dec. 7, 2020.
• Melmed S, et al. Williams Textbook of Endocrinology. 14th ed. Elsevier; 2020. https://www.clinicalkey.com. Accessed Dec. 3, 2020.
• Diabetes overview. National Institute of Diabetes and Digestive and Kidney Diseases. https://www.niddk.nih.gov/health-information/diabetes/overview/all-content. Accessed Dec. 4, 2020.
• AskMayoExpert. Type 2 diabetes. Mayo Clinic; 2018.
• Feldman M, et al., eds. Surgical and endoscopic treatment of obesity. In: Sleisenger and Fordtran's Gastrointestinal and Liver Disease: Pathophysiology, Diagnosis, Management. 11th ed. Elsevier; 2021. https://www.clinicalkey.com. Accessed Oct. 20, 2020.
• Hypersmolar hyperglycemic state (HHS). Merck Manual Professional Version. https://www.merckmanuals.com/professional/endocrine-and-metabolic-disorders/diabetes-mellitus-and-disorders-of-carbohydrate-metabolism/hyperosmolar-hyperglycemic-state-hhs. Accessed Dec. 11, 2020.
• Diabetic ketoacidosis (DKA). Merck Manual Professional Version. https://www.merckmanuals.com/professional/endocrine-and-metabolic-disorders/diabetes-mellitus-and-disorders-of-carbohydrate-metabolism/diabetic-ketoacidosis-dka. Accessed Dec. 11, 2020.
• Hypoglycemia. Merck Manual Professional Version. https://www.merckmanuals.com/professional/endocrine-and-metabolic-disorders/diabetes-mellitus-and-disorders-of-carbohydrate-metabolism/hypoglycemia. Accessed Dec. 11, 2020.
• 6 things to know about diabetes and dietary supplements. National Center for Complementary and Integrative Health. https://www.nccih.nih.gov/health/tips/things-to-know-about-type-diabetes-and-dietary-supplements. Accessed Dec. 11, 2020.
• Type 2 diabetes and dietary supplements: What the science says. National Center for Complementary and Integrative Health. https://www.nccih.nih.gov/health/providers/digest/type-2-diabetes-and-dietary-supplements-science. Accessed Dec. 11, 2020.
• Preventing diabetes problems. National Institute of Diabetes and Digestive and Kidney Diseases. https://www.niddk.nih.gov/health-information/diabetes/overview/preventing-problems/all-content. Accessed Dec. 3, 2020.
• Schillie S, et al. Prevention of hepatitis B virus infection in the United States: Recommendations of the Advisory Committee on Immunization Practices. MMWR Recommendations and Reports. 2018; doi:10.15585/mmwr.rr6701a1.
• Caffeine: Does it affect blood sugar?
• GLP-1 agonists: Diabetes drugs and weight loss
• Hyperinsulinemia: Is it diabetes?
• Medications for type 2 diabetes

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A promising new pathway to treating type 2 diabetes

This year marks the 100th anniversary of the discovery of insulin, a scientific breakthrough that transformed Type 1 diabetes, once known as juvenile diabetes or insulin-dependent diabetes, from a terminal disease into a manageable condition.

Today, Type 2 diabetes is 24 times more prevalent than Type 1. The rise in rates of obesity and incidence of Type 2 diabetes are related and require new approaches, according to University of Arizona researchers, who believe the liver may hold the key to innovative new treatments.

"All current therapeutics for Type 2 diabetes primarily aim to decrease blood glucose. So, they are treating a symptom, much like treating the flu by decreasing the fever," said Benjamin Renquist, an associate professor in the UArizona College of Agriculture and Life Sciences and BIO5 Institute member. "We need another breakthrough."

In two newly published papers in Cell Reports , Renquist, along with researchers from Washington University in St. Louis, the University of Pennsylvania and Northwestern University, outline a new target for Type 2 diabetes treatment.

Renquist, whose research lab aims to address obesity-related diseases, has spent the last nine years working to better understand the correlation between obesity, fatty liver disease and diabetes, particularly how the liver affects insulin sensitivity.

"Obesity is known to be a cause of Type 2 diabetes and, for a long time, we have known that the amount of fat in the liver increases with obesity," Renquist said. "As fat increases in the liver, the incidence of diabetes increases."

This suggested that fat in the liver might be causing Type 2 Diabetes, but how fat in the liver could cause the body to become resistant to insulin or cause the pancreas to over-secrete insulin remained a mystery, Renquist said.

Renquist and his collaborators focused on fatty liver, measuring neurotransmitters released from the liver in animal models of obesity, to better understand how the liver communicates with the brain to influence metabolic changes seen in obesity and diabetes.

"We found that fat in the liver increased the release of the inhibitory neurotransmitter Gamma-aminobutyric acid, or GABA," Renquist said. "We then identified the pathway by which GABA synthesis was occurring and the key enzyme that is responsible for liver GABA production -- GABA transaminase."

A naturally occurring amino acid, GABA is the primary inhibitory neurotransmitter in the central nervous system, meaning it decreases nerve activity.

Nerves provide a conduit by which the brain and the rest of the body communicate. That communication is not only from the brain to other tissues, but also from tissues back to the brain, Renquist explained.

"When the liver produces GABA, it decreases activity of those nerves that run from the liver to the brain. Thus, fatty liver, by producing GABA, is decreasing firing activity to the brain," Renquist said. "That decrease in firing is sensed by the central nervous system, which changes outgoing signals that affect glucose homeostasis."

To determine if increased liver GABA synthesis was causing insulin resistance, graduate students in Renquist's lab, Caroline Geisler and Susma Ghimire, pharmacologically inhibited liver GABA transaminase in animal models of Type 2 diabetes.

"Inhibition of excess liver GABA production restored insulin sensitivity within days," said Geisler, now a postdoctoral researcher at the University of Pennsylvania and lead author on the papers. "Longer term inhibition of GABA-transaminase resulted in decreased food intake and weight loss."

Researchers wanted to ensure the findings would translate to humans. Kendra Miller, a research technician in Renquist's lab, identified variations in the genome near GABA transaminase that were associated with Type 2 diabetes. Collaborating with investigators at Washington University, the researchers showed that in people with insulin resistance, the liver more highly expressed genes involved in GABA production and release.

The findings are the foundation of an Arizona Biomedical Research Commission-funded clinical trial currently underway at Washington University School of Medicine in St. Louis with collaborator Samuel Klein, co-author on the study and a Washington University professor of medicine and nutritional science. The trial will investigate the use of a commercially available Food and Drug Administration-approved inhibitor of GABA transaminase to improve insulin sensitivity in people who are obese.

"A novel pharmacological target is just the first step in application; we are years away from anything reaching the neighborhood pharmacy," Renquist said. "The magnitude of the obesity crisis makes these promising findings an important first step that we hope will eventually impact the health of our family, friends and community."

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Story Source:

Materials provided by University of Arizona . Original written by Rosemary Brandt. Note: Content may be edited for style and length.

Journal Reference :

• Caroline E. Geisler, Susma Ghimire, Stephanie M. Bruggink, Kendra E. Miller, Savanna N. Weninger, Jason M. Kronenfeld, Jun Yoshino, Samuel Klein, Frank A. Duca, Benjamin J. Renquist. A critical role of hepatic GABA in the metabolic dysfunction and hyperphagia of obesity . Cell Reports , 2021; 35 (13): 109301 DOI: 10.1016/j.celrep.2021.109301

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Large-scale study reveals new genetic details of diabetes

By wynne parry weill cornell medicine.

In experiments of unprecedented scale, investigators at Weill Cornell Medicine and the National Institutes of Health have revealed new aspects of the complex genetics behind Type 2 diabetes. Through these discoveries, and by providing a template for future studies, this research furthers efforts to better understand and ultimately treat this common metabolic disease.

Previous studies have generally examined the influence of individual genes. In research described Oct. 18 in Cell Metabolism, senior co-author Shuibing Chen , the Kilts Family Professor of Surgery at Weill Cornell Medicine, working alongside senior co-author Dr. Francis Collins , a senior investigator at the Center for Precision Health Research within the National Human Genome Research Institute of the U.S. National Institutes of Health, took a more comprehensive approach. Together, they looked at the contribution of 20 genes in a single effort.

“It’s very difficult to believe all these diabetes-related genes act independently of each other,” Chen said. By using a combination of technologies, the team examined the effects of shutting each down. By comparing the consequences for cell behavior and genetics, she said, “we found some common themes.”

As with other types of diabetes, Type 2 diabetes occurs when sugar levels in the blood are too high. In Type 2 diabetes, this happens in part because specialized cells in the pancreas, known as β-cells, don’t produce enough insulin, a hormone that tells cells to take sugar out of the blood for use as an energy source. Over time, high levels of blood sugar damage tissues and cause other problems, such as heart and kidney disease. According to the United States Centers for Disease Control and Prevention, nearly 9% of adults in the United States have been diagnosed with Type 2 diabetes. 

Both genetic and environmental factors, such as obesity and chronic stress, can increase risk for it. Yet evaluating the role of the genetic contributors alone is a massive project. So far, researchers have identified more than 290 locations within the genome where changes to DNA can raise the likelihood of developing the disease. Some of these locations fall within known genes, but most are found in regions that regulate the expression of nearby genes.

For the new research, the team focused on 20 genes clearly identified as contributors. They began their investigation by using the gene editing system CRISPR-Cas9 to shut down these genes, one at a time, within 20 sets of identical stem cells. 

These stem cells had the potential to generate any kind of mature cell, but the researchers coaxed them into becoming insulin-producing β-cells. They then examined the effects of losing each gene on five traits related to insulin production and the health of β-cells. They also documented the accompanying changes in gene expression and the accessibility of DNA for expression.

To make sense of the massive amount of data they collected, the team developed their own computational models to analyze it, leading to several discoveries: By comparing the effects of all 20 mutations on β-cells, they identified four additional genes, each representing a newly discovered pathway that contributes to insulin production. They also found that, of the original 20 genes, only one, called HNF4A, contributed to all five traits, apparently by acting as a master controller that regulates the activity of other genes. In one specific example, they explained how a small variation, located in a space between genes, contributes to the risk of diabetes by interfering with HNF4A’s ability to regulate nearby genes.

Ultimately, this study and others like it hold the promise of benefiting patients, Collins said. “We need to understand all the genetic and environmental factors involved so we can do a better job of preventing diabetes, and to develop new ideas about how to effectively treat it.”

Collins and Chen note that their approach may have relevance beyond diabetes, to other common diseases, such as Alzheimer’s, Parkinson’s and Crohn’s disease, that involve many genetic factors.

The work reported in this newsroom story was supported in part by the United States’ National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases and the American Diabetes Association.

Many Weill Cornell Medicine physicians and scientists maintain relationships and collaborate with external organizations to foster scientific innovation and provide expert guidance. The institution makes these disclosures public to ensure transparency. For this information, see the profile for Shuibing Chen .

Wynne Parry is a freelance writer for Weill Cornell Medicine.

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Changing our Future Through Research

The ADA is committed to innovation and breakthrough research that will improve the lives of all people living with diabetes.

ADA Research: Science. Progress. Hope.

ADA research provides critical funding for diabetes research. With 100% of donations directed to research, our goal is to ensure adequate financial resources to support innovative scientific discovery that will translate to life-changing treatments and eventual cures.

of our funded researchers remain dedicated to careers in diabetes science

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Every $1 the ADA invests in diabetes research leads to $12.47 in additional research funding

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Type 2 diabetes

Affiliations.

• 1 Diabetes Research Centre, University of Leicester and the Leicester NIHR Biomedical Research Centre, Leicester General Hospital, Leicester, UK.
• 2 Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, South Korea.
• 3 Family Medicine Department, Korle Bu Teaching Hospital, Accra Ghana and Community Health Department, University of Ghana Medical School, Accra, Ghana.
• 4 Diabetes Research Centre, University of Leicester and the Leicester NIHR Biomedical Research Centre, Leicester General Hospital, Leicester, UK. Electronic address: [email protected].
• PMID: 36332637
• DOI: 10.1016/S0140-6736(22)01655-5

Type 2 diabetes accounts for nearly 90% of the approximately 537 million cases of diabetes worldwide. The number affected is increasing rapidly with alarming trends in children and young adults (up to age 40 years). Early detection and proactive management are crucial for prevention and mitigation of microvascular and macrovascular complications and mortality burden. Access to novel therapies improves person-centred outcomes beyond glycaemic control. Precision medicine, including multiomics and pharmacogenomics, hold promise to enhance understanding of disease heterogeneity, leading to targeted therapies. Technology might improve outcomes, but its potential is yet to be realised. Despite advances, substantial barriers to changing the course of the epidemic remain. This Seminar offers a clinically focused review of the recent developments in type 2 diabetes care including controversies and future directions.

Copyright © 2022 Elsevier Ltd. All rights reserved.

Publication types

• Diabetes Mellitus, Type 2* / drug therapy
• Diabetes Mellitus, Type 2* / epidemiology
• Pharmacogenetics
• Precision Medicine
• Young Adult

Embracing complexity: making sense of diet, nutrition, obesity and type 2 diabetes

• Open access
• Published: 14 February 2023
• Volume 66 , pages 786–799, ( 2023 )

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• Nita G. Forouhi 1  

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Nutrition therapy has been emphasised for decades for people with type 2 diabetes, and the vital importance of diet and nutrition is now also recognised for type 2 diabetes prevention. However, the complexity of diet and mixed messages on what is unhealthy, healthy or optimal have led to confusion among people with diabetes and their physicians as well as the general public. What should people eat for the prevention, management and remission of type 2 diabetes? Recently, progress has been made in research evidence that has advanced our understanding in several areas of past uncertainty. This article examines some of these issues, focusing on the role of diet in weight management and in the prevention and management of type 2 diabetes. It considers nutritional strategies including low-energy, low-fat and low-carbohydrate diets, discusses inter-relationships between nutrients, foods and dietary patterns, and examines aspects of quantity and quality together with new developments, challenges and future directions.

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Diet, nutrition and type 2 diabetes: what is the evidence?

Diabetes is a metabolic disorder with the potential for multiple adverse health consequences. It is also a public health challenge, with a rising global burden. Estimates indicate that there were approximately 537 million people worldwide with diabetes in 2021, which is projected to rise to 783 million by 2045, with type 2 diabetes constituting the majority (>90%) of this burden [ 1 ]. Diet and nutrition are of indisputable significance in reducing this burden because the development of type 2 diabetes is characterised by obesity and insulin resistance, leading to hyperglycaemia, and both weight and glycaemic control are directly related to food consumption.

Diet and nutrition are thus central as modifiable factors in both the management and the prevention of type 2 diabetes. This is supported by three lines of evidence. First, when adhered to, medical nutrition therapy in those with type 2 diabetes can match or exceed the glycaemic control that can be achieved by glucose-lowering medication in the short term, and can be useful in maintaining control [ 2 ]. Second, the proof of principle was established in the early 2000s that, among people with non-diabetic hyperglycaemia, the onset of type 2 diabetes can be delayed or prevented, with as much as a 58% relative risk reduction, through a supported intensive lifestyle intervention including dietary changes and physical activity [ 3 ]. The real-world impact of lifestyle modification strategies has been demonstrated [ 4 ], outside the highly controlled conditions of clinical trials, and such a strategy has been found to be effective in the UK National Health Service (NHS) [ 5 ]. Third, it has been demonstrated that remission of type 2 diabetes can be achieved through dietary means [ 6 ], resulting in a major shift in scientific understanding of the pathophysiology of type 2 diabetes, from a condition previously thought to be progressive and irreversible to one that can be brought under control to normal functioning.

However, defining the optimal diet for type 2 diabetes is a challenge and dietary strategies used in research have varied between different studies. This is largely because diet is intensely complex, with multiple components and influences on food consumption (Fig. 1 ). Concomitantly, interest in diet, nutrition and health is intense, with a deluge of scientific publications, matched equally by popular media coverage that is saturated with nutrition over-claims and ‘miracle diets’. This is also a field where vested interests are rife [ 7 ]. A search on PubMed (25 November 2022) using the terms ‘diet OR nutrition OR food OR nutrient OR dietary pattern OR diet quality’ and ‘type 2 diabetes OR non-insulin dependent diabetes’ yielded 52,833 hits, with over 3000 articles published each year since 2014; repeating the search using the term ‘obesity’ yielded 165,617 hits. What evidence should we trust?

Complexity of diets and multiple influences affecting food intakes. HEI, Healthy Eating Index. Influencing factors (boxes) adapted with permission from Afshin et al [ 83 ] © 2014 John Wiley & Sons. This figure is available as a downloadable slide .

The hierarchy of evidence framework and quality assessment tools have been applied to sift through the vast amount of evidence. Several reviews of the research evidence have been carried out [ 8 , 9 , 10 , 11 , 12 , 13 , 14 ], enabling the incorporation of the best available evidence in dietary guidelines issued by authoritative agencies, including but not limited to the ADA [ 15 ] and Diabetes UK [ 16 ].

In a nutshell, this evidence highlights some key dietary principles. Healthy weight maintenance is critical to both prevent and manage type 2 diabetes; a pattern of food intake that mitigates type 2 diabetes risk includes the habitual consumption of vegetables, fruits, legumes, whole grains and cereal fibre, dairy products such as yoghurt, and nuts, and several overall dietary patterns are effective. In contrast, type 2 diabetes risk is elevated with a pattern of habitual dietary intake that includes processed and unprocessed red meat, refined grains and sugar-sweetened beverages. This evidence provides support that some foods should be emphasised and promoted while the consumption of others should be reduced or avoided, rather than the adage about everything in moderation.

This article does not cover the wide range of topics already discussed in existing reviews and guidelines. It focuses instead on selected hot topics that have been the subject of debate and on new developments in understanding in the field.

Weight management at the core, but how?

Body weight with increased adiposity is mechanistically linked to both the development and the progression of type 2 diabetes, typified by resistance to insulin action (insulin resistance) and an inadequate compensatory insulin secretory response by pancreatic beta cells. The relationship between adiposity, insulin resistance and beta cell function varies between individuals but the benefits of weight loss apply across the different pathophysiologies [ 17 ]. Weight loss is related to improved glycaemic control: the greater the weight loss, the greater the improvement in HbA 1c . A weight loss goal of 5–7% of initial body weight for people with overweight or obesity is recommended for clinical benefit, while weight loss of 15% can be disease modifying with the possibility of remission of type 2 diabetes [ 2 , 18 ].

Of the three options for weight management, bariatric surgery and pharmacotherapy are effective, but dietary strategies offer population-wide benefits without medicalisation. However, the weight loss and weight management diet market is vast and is projected to increase from US$192.2 billion in 2019 to US$295.3 billion by 2027. This promotion of a vast range of dietary products and strategies can be bewildering. An important question is therefore which dietary strategies are effective?

Remission of type 2 diabetes through diet-related weight loss

The proof of principle of the potential for reversibility or remission of type 2 diabetes with weight loss came first from the field of bariatric surgery [ 19 , 20 ]. However, surgery is not suitable for, or acceptable to, all people with type 2 diabetes. Surgery also has the potential for complications, side effects and challenges. One such challenge is the large prevalence of type 2 diabetes, which renders surgery an unrealistic option at the scale required, even if it were financially possible. There is high interest, therefore, in dietary means to achieve diabetes remission.

The nutritional basis for the remission of type 2 diabetes used in the UK-based Diabetes Remission Clinical Trial (DiRECT) was centred on major caloric restriction and weight loss with an associated reduction in hepatic fat and hepatic glucose output and improved beta cell function [ 6 ]. Among people with type 2 diabetes in primary care who were randomised to either a diet very low in energy (very low calorie diet) or usual care, mean body weight fell by 10 kg in the intervention group and 46% remained free of diabetes (i.e. in remission; HbA 1c <48 mmol/mol [<6.5%]) at 1 year and off all glucose-lowering and antihypertensive medications [ 21 ]. The intervention comprised total diet replacement (3452–3569 kJ/day [825–853 kcal/day] liquid formula diet for 12–20 weeks), stepped food reintroduction (2–8 weeks) and then structured support for weight loss maintenance. The greater the weight loss, the greater the likelihood of remission (86% at 1 year for weight loss ≥15kg; 57%, 34% and 7% for weight loss of 10–15 kg, 5–10 kg and <5 kg respectively). In addition, the effects were durable, with 36% of people in sustained remission at 2 years [ 22 ]. Further research is needed to understand the longer term effects of remission on the complications of type 2 diabetes, but current results support the remission of type 2 diabetes as a practical target in primary care.

In an endorsement of this approach, the UK NHS has rolled out a 12 week intervention consisting of a low-energy meal replacement diet for people with type 2 diabetes and a BMI >27 kg/m 2 (or >25 kg/m 2 if from a minority ethnic group in whom risk occurs at a lower BMI) ( https://www.england.nhs.uk/2022/01/nhs-soups-and-shakes-diet-helps-thousands-shed-the-pounds/ ). The goal is to recruit 5000 people from general practice; over 2000 people have already participated, showing the feasibility of this approach.

A focus on nutrients for weight and glycaemic control

Traditionally, dietary guidance has focused on macronutrient composition. Most dietary guidelines recommend intakes of <30–35% of energy from total fat, 45–55% of energy from carbohydrates and the remainder, ~15–20% of energy, from protein, both in the general population and in those with type 2 diabetes. For weight management, low-fat diets were favoured based on the higher energy density of fat, at 38kJ/g (9 kcal/g), compared with that of carbohydrate or protein, at 17kJ/g (4 kcal/g). More recently, low-carbohydrate diets have gained popularity. The optimal macronutrient composition is hotly debated.

Low-fat or low-carbohydrate diets for weight management?

The Look-AHEAD: Action for Health in Diabetes (Look-AHEAD) trial compared an intensive lifestyle intervention with a control condition of support and education in people with type 2 diabetes. The weight loss strategy, comprising energy reduction (5021–7531 kJ/day [1200–1800 kcal/day]) through a low-fat diet, was effective. Greater weight loss was achieved in the intervention group at 1 year, with a net difference in weight of –7.9% (95% CI –8.3% to –7.6%); at year 4, the net difference in weight was –3.9% (95% CI –4.4% to –3.5%) [ 23 ]. Similar low-fat diet approaches have been used in other trials of the primary prevention of type 2 diabetes [ 3 ]. In contrast, in the energy-deficit diet in the type 2 diabetes remission trial (DiRECT), the proportions of macronutrients were inconsequential, with >50% of energy coming from carbohydrates [ 22 ]. A recent umbrella review of the evidence concluded that weight management in type 2 diabetes using hypocaloric diets does not depend on any particular macronutrient profile [ 24 ].

More broadly, among adults with overweight or obesity in the population without consideration of type 2 diabetes, individual studies show differing results favouring one nutrient or another but, when the totality of the evidence is appraised, both low-fat and low-carbohydrate diets of varying protein content are effective for weight loss [ 25 ]. The challenge lies in adherence to the prescribed diets. A systematic review of the effects of low-fat and low-carbohydrate diets on weight loss in RCTs of at least 1 year’s duration and with a similar intervention intensity across groups found that low-fat diets were efficacious compared with usual intake [ 26 ]. But, when low-fat diets were compared with low-carbohydrate diets, there was greater weight loss in the low-carbohydrate diet group. However, the magnitude of the difference in weight loss between low-carbohydrate and low-fat diets was modest at only 1.15 kg, which is statistically significant but may have little clinical meaning. As a limitation, caloric restriction was a component of many of the weight loss interventions included, but not all; for example, some included studies gave dietary advice to eat a low-carbohydrate diet ad libitum [ 26 ]. Future research should seek to address design limitations; however, current research indicates that small effects on weight loss from one macronutrient type or another are unlikely to be of clinical significance. A key challenge is weight maintenance and prevention of weight regain, which is typical following weight loss.

Although overall dietary carbohydrate or fat content has been extensively studied in relation to weight loss and maintenance, protein intake has been less so. Higher protein intake after weight loss has been shown to result in significantly lower weight regain, related to increased satiety and energy efficiency [ 27 ]. For early weight loss maintenance over 6 months, an RCT tested different combinations of protein consumption and glycaemic index (GI) compared with a control diet among those who had lost at least 8% (equivalent to 11 kg) of their initial weight on a 3347 kJ/day (800 kcal/day) diet [ 28 ]. Consuming a low-protein/high GI diet led to subsequent weight regain (mean of 1.7 kg [95% CI 0.5 to 2.9]), while a modest increase in protein content and a modest reduction in GI led to improvements (reductions) in the degree of weight regain over 6 months. Evidence for long-term weight loss maintenance is generally sparse. Observational prospective data from the National Weight Loss Registry indicated that weight loss maintenance over 10 years was related to low-fat-based energy restraint combined with physical activity [ 29 ]. Further research is needed to better understand the dietary strategies and other factors important in weight loss maintenance.

Low-carbohydrate diets for glycaemic control in type 2 diabetes

For glycaemic control in type 2 diabetes, studies from clinical practice or from digital or commercial programmes have promoted low-carbohydrate diets based on significant benefits for HbA 1c , of a mean decrease of 11 mmol/mol (1% unit decrease), together with reductions in glucose-lowering medication use [ 30 , 31 ]. Interpretive challenges include the presence of bias owing to the lack of randomisation, self-selection into groups and unbalanced sample sizes or intensities of interventions in the study arms and lack of a comparator group. However, a number of systematic reviews and meta-analyses of RCTs are available that reduce such limitations [ 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 ].

Evidence from RCTs indicates that lower carbohydrate diets have benefits over higher carbohydrate diets in the short term up to 6 months, but these are not maintained over time [ 34 , 36 ]. In the UK, the Scientific Advisory Committee on Nutrition appraised the available evidence, including 48 individual RCTs from eight systematic reviews. It concluded that lower carbohydrate diets were effective for glycaemic control in type 2 diabetes compared with higher carbohydrate diets, with a greater reduction in HbA 1c (weighted mean difference –4.7 mmol/mol [–0.47%]) in the short term (3–6 months), but this benefit was not maintained at 12 months [ 39 ].

Despite extensive research on low-carbohydrate diets, there are several challenges that limit firm conclusions. First, definitions of what a ‘low-carbohydrate diet’ is range from moderate carbohydrate restriction to very-low-carbohydrate or ketogenic diets (see Text box ‘Definitions of carbohydrate-focused diets’). Across RCTs, prescribed carbohydrate intakes in the lower carbohydrate groups ranged widely, from 14% to 50% of energy intake, and reported carbohydrate intakes were moderate at 26–45% of energy intake in the majority of the primary RCTs [ 39 ]. Second, in the case of isoenergetic diets (maintaining the same overall energy intake), a low-carbohydrate diet is by default higher in fat and vice versa. As many individual studies did not specify isoenergetic study arms, it is difficult to tease out whether the glycaemic change was influenced by differential changes in weight as a result of differing energy intakes. Third, because of differences in or a lack of information in study protocols on adjustment of glucose-lowering medication, it is hard to infer whether criteria for remission of type 2 diabetes were met [ 40 ].

Low-carbohydrate diets seem to be generally safe and well tolerated in the short term; concerns in the longer term relate to the potential atherogenic lipid profile [ 38 , 41 ] or micronutrient deficiency [ 42 ] or their use in people with chronic kidney disease or pregnant women, in whom there is a need for further evaluation. Accumulating evidence from prospective studies with long-term follow-up data indicates that both high and low intakes of carbohydrates may have adverse health impacts on mortality risk, with a U-shaped relationship [ 43 ]. However, such research has been carried out in general populations and needs to be replicated, and further research is needed in those with type 2 diabetes. In the meantime, the ADA dietary guidelines for people with diabetes were updated in 2019, making it explicit that low-carbohydrate diets can be endorsed (see Text box ‘Definitions of carbohydrate-focused diets’).

Nutrition and pathways to obesity and type 2 diabetes

The above focus on energy and macronutrients is rooted in two contesting mechanistic explanations that link dietary intake to obesity and type 2 diabetes. In the energy balance model, energy matters because the law of thermodynamics dictates that when energy intake exceeds energy expenditure weight gain occurs. The link between obesity and the development of type 2 diabetes is strong and, with caloric deficit-induced weight loss, remission of type 2 diabetes is possible. In these scenarios, a calorie is a calorie and excess calories result in adipose tissue accumulation and weight gain.

In contrast, the ‘carbohydrate–insulin model’ proposes that obesity is a cause, not the consequence, of excess caloric intake [ 44 ]. Here, the dysregulation of fat storage and metabolism is the central defect, driven by high-carbohydrate diets that produce spikes of hyperinsulinaemia that promote glucose uptake into tissues, suppress release of fatty acids from adipose tissue and stimulate fat and glycogen storage. Thus, less energy remains available for use by the rest of the body, driving hunger and overeating. In this scenario, not all calories are equal. It has been proposed that energy from refined carbohydrates promote a disturbed hormonal milieu linked with increased hunger, a slower metabolic rate and reduced energy expenditure, leading to adiposity.

The debate between these mechanistic processes continues [ 45 , 46 , 47 ]. However, it is increasingly clear that a focus on energy intake does not account for the impact that diet quality has on long-term weight gain and type 2 diabetes through diverse physiological processes. These include diet-induced thermogenesis, brain reward, appetite, hunger, satiety, digestion, the release and action of hormones, for example insulin, hepatic de novo lipogenesis, interactions with the gut microbiome and energy expenditure [ 48 ]. Moreover, a focus on considering a single macronutrient type has limitations that can lead to unhelpful reductionist messages to avoid a macronutrient without reference to its quality and food sources.

Beyond a focus on nutrient quantity: the relevance of nutrient type, quality and food sources

RCTs of macronutrient manipulation have focused exclusively on quantity. This ignores the fact that health effects will vary substantially by nutrient type or quality. For dietary fats, a vast literature exists on the importance of distinguishing between saturated, polyunsaturated, monounsaturated and trans fats. Health effects also vary by carbohydrate type (starch, sugar or fibre), degree of processing (whole grain vs refined grain), glycaemic response after consumption (GI and load) and food structure (solid or liquid form).

There is substantial evidence from meta-analyses for inverse (beneficial) associations between the consumption of fibre [ 49 ], particularly cereal fibre [ 50 ] and wholegrains [ 11 ], and the incidence of type 2 diabetes. However, evidence is more mixed for the dietary GI, which reflects the differential blood glucose-raising potential of foods with similar carbohydrate content, and a related measure, the glycaemic load (GL), which accounts for the amount of available carbohydrate. For example, the meta-analysis by Reynolds et al found inverse associations between fibre intake and several disease endpoints, including type 2 diabetes and mortality, but associations with GI and GL were non-significant [ 49 ]. Mixed and inconclusive results were also reported in reviews of a link between GI, GL and HbA 1c or fasting glucose [ 15 ]. The OmniCarb RCT compared four diets with varying GI and carbohydrate content in overweight or obese individuals with hypertension or pre-hypertension. This was a crossover feeding study with each diet based on a Dietary Approaches to Stop Hypertension (DASH)-type diet pattern [ 51 ]. Compared with a high GI (65% on the glucose scale), high-carbohydrate (58% energy) diet, a low GI (40% on the glucose scale), low-carbohydrate (40% energy) diet did not significantly improve insulin sensitivity, lipid levels or blood pressure. This type of evidence indicates that GI values have a low utility, but further research contradicts this. Other reviews with a more nuanced approach have reported a positive association between GI or GL and type 2 diabetes [ 52 ]. Similarly, some reviews and individual large cohorts have also reported a positive (adverse) association of high GI or GL with CHD or CVD [ 53 ], as well as a likely benefit of low GI or GL dietary patterns for glycaemic control and cardiometabolic risk factors in people with type 1 diabetes or type 2 diabetes [ 54 ]. A take-home message is that multiple aspects of carbohydrate quality are relevant and should be considered where possible because intakes of fibre, wholegrain and the GI and GL values of foods are likely to be highly correlated and may have confounding effects if not accounted for in diet–disease associations.

A point to note is that, when consumption of one nutrient type is manipulated (to eat less or more of it), this impacts the consumption of other nutrient types—the so-called ‘nutrient substitution’, in which one nutrient substitutes for another within isoenergetic consumption. Moreover, there are both ‘healthy’ and ‘unhealthy’ low-fat or low-carbohydrate diets.

The Diet Intervention Examining The Factors Interacting with Treatment Success (DIETFITS) RCT tested diet quality, comparing ‘healthy’ low-carbohydrate and low-fat regimens [ 55 ]. Both diet groups were instructed to maximise their non-starchy vegetable intake, minimise added sugars, refined flours and trans fats and focus on whole foods. Both diet types were effective, with a mean weight loss of 5.3 kg and 6 kg for the healthy low-fat and healthy low-carbohydrate diets, respectively, at 12 months, but there was no significant between-group difference [ 55 ]. In both diet groups there were also improvements at 12 months in secondary outcomes, including fasting glucose and insulin levels, body fat percentage, waist circumference, blood pressure and lipid profiles, except for LDL-cholesterol level, which was reduced in the low-fat group but increased in the low-carbohydrate group.

A crossover trial compared different levels of carbohydrate restriction and food sources in people with prediabetes or type 2 diabetes over two 12 week periods. Carbohydrates comprised <20% of energy in the very-low-carbohydrate ketogenic diet and <40% in the low-carbohydrate Mediterranean-style diet [ 56 ]. Both diets incorporated non-starchy vegetables and avoided added sugars and refined grains; the ketogenic diet avoided legumes, most fruits (except a few berries in small amounts) and whole grains whereas the Mediterranean-style diet incorporated these foods. Both diets resulted in improvements that were not significantly different. Specifically, mean HbA 1c levels decreased by 9% and 7% in the ketogenic and Mediterranean-style diet groups, respectively, and weight decreased by 8% and 7%, respectively. The ketogenic diet group achieved greater improvements in triglyceride and HDL-cholesterol levels than the Mediterranean-style diet group but had higher LDL-cholesterol levels (percentage change +10% vs –5%, respectively). The diets were ad libitum but participants in both groups reported consuming on average 1046–1255 kJ/day (250–300 kcal/day) less compared with baseline. The ketogenic diet group had a lower fibre intake and consumed lower levels of micronutrients (folate, vitamin C and magnesium). This study was of short duration and longer term research is needed, but its findings do not justify achieving a low-carbohydrate status by avoiding fruits, legumes and whole grains, which are considered part of a healthy diet in other longstanding research.

In sum, the consideration of nutrients in isolation has led to unhelpful polarised debates on whether low-fat or low-carbohydrate diets are superior. Macronutrients are not homogeneous entities: individual nutrients are derived from foods and people eat food in overall dietary patterns.

Beyond nutrients: foods and dietary patterns

Foods are complex mixtures of thousands of components—the food matrix—that have different physicochemical properties and health effects. This is illustrated by the opposite directions of association with the incidence of CHD seen for different foods rich in saturated fats. Consumption of dairy products such as yoghurt and cheese is inversely related to CHD incidence whereas consumption of red and processed meat is positively associated with CHD incidence [ 57 ]. This was corroborated by research showing that people who ate more saturated fats from red meat and butter were more likely to develop CHD than those who ate more saturated fats from cheese, yoghurt and fish [ 58 ]. This highlights the need to consider food sources together with the macronutrients they contain rather than the nutrients in isolation.

A consensus on dietary factors for the prevention of type 2 diabetes has been established from the comprehensive evidence base and incorporated into dietary guidelines. Broadly this suggests the benefits of the consumption of fruit, vegetables, nuts, seeds, wholegrains and yoghurt and the potential harms associated with sugar-sweetened beverages and red and processed meat. For some foods, such as fruit juice, artificially sweetened beverages, lean and fatty fish, milk and eggs, uncertainty remains with regard to their benefits for type 2 diabetes prevention [ 14 ].

Highly processed or ultra-processed foods of both plant and animal origin are increasingly consumed globally and have been related to a number of adverse health impacts. They include foods that have undergone industrial processing and that contain added ingredients such as salt, sugar, fat and artificial preservatives, stabilisers or colours, prolonging shelf life and reducing cost. An RCT compared the ad libitum consumption of ultra-processed foods with consumption of unprocessed foods. A total of 20 participants received all meals, matched for energy and macronutrient content, in a controlled setting for 28 days [ 59 ]. Ultra-processed food consumption led to substantially greater energy intake (+2090 kJ/day [+500 kcal/day] on average over 14 days) and weight gain (+0.9 kg over 14 days vs weight loss of equal magnitude during the 14 days of the unprocessed diet phase). Longer term prospective studies have provided evidence for an association of ultra-processed food consumption with the development of type 2 diabetes [ 60 ].

A number of food-based dietary patterns have a place in the prevention of type 2 diabetes based on observational evidence, including the Mediterranean, DASH and plant-based diets, but only the Mediterranean diet has been investigated in an RCT, both for the prevention and for the management of type 2 diabetes [ 61 ]. For many named popular diets such as the paleo, Atkins, Ornish and Zone diets, there is RCT evidence for short-term weight management but without any meaningful differences between them [ 25 ], while no evidence for their role in the prevention of type 2 diabetes is available.

For dietary patterns, quality matters too. For instance, plant-based diets are generally considered healthy, but not all such diets are alike. In one study, plant-based diets that were high in refined carbohydrates or were ultra-processed were associated positively with the incidence of type 2 diabetes [ 62 ].

Embracing complexity: key messages

Diet is a complex risk exposure.

Diet is non-binary, unlike, for example, tobacco, for which zero is best. Diet is multidimensional and hierarchical in nature. Foods belong within food groups and may be consumed unprocessed (e.g. beef or pork) or processed (e.g. ham or bacon). Foods contain nutrients (e.g. meat fat or protein as macronutrients; haem iron as a micronutrient) or additives and preservatives if processed, and are part of overall dietary patterns (e.g. the Mediterranean diet with relatively low intakes of red meat or a low-carbohydrate diet regimen with relatively high intakes of meat).

The continuum of dietary exposures should be considered, as well as ‘food substitution effects’, because when more or less of one food type is consumed it impacts the consumption of other foods as part of the overall energy intake.

Diet is hard to measure

Tools such as food frequency questionnaires or 24 h dietary recall instruments are commonly used to assess habitual dietary intakes. Despite efforts towards validating these tools and their ability to produce credible estimates of diet–disease associations, critics have called for them to be abandoned, considering them flawed because of their reliance on memory and cognition and issues of bias and measurement error [ 63 , 64 ]. Suggestions for suitable alternatives are sparse, however. Emerging digital technologies—smartphone apps, cameras for food imaging and wearable devices—hold promise but are not yet of ‘research grade’, with demonstrable validity and reliability [ 65 ]. They are also not free from measurement error, nor gaming, consciously or subconsciously. A promising complementary approach is the use of objective biomarkers of dietary intakes, for instance plasma vitamin C and carotenoids as markers for fruit and vegetable intake, or plasma omega-3 fatty acids as a marker for seafood consumption [ 66 ]. However, these too have sources of random and systematic errors as well as interpretive challenges, that is, the extent to which circulating levels reflect intake compared with metabolism.

No method is perfect, but the use of validated dietary instruments with repeat measures can approximate habitual diet. Moreover, there are benefits in using a combination of methods to harness their complementary strengths and deal with relative weaknesses.

The study design of nutritional research is challenging

The RCT design is considered the gold standard in the hierarchy of evidence-based medicine framework, but for complex behavioural exposures such as diet, unlike for pharmaceuticals, RCTs are more challenging. The bulk of the evidence base for nutrition and health has come from long-term observational prospective cohort studies. Both observational and interventional studies have relative strengths and weaknesses. Observational studies are typically limited by confounding and bias but when rigorously conducted they can yield reliable and valid results, from which causal inference can be made [ 14 ]. Dietary RCTs have several challenges. They have a specific set of limitations including a lack of blinding, lack of an appropriate control group, issues with feasibility and cost and challenges of adherence and attrition. The inability to pinpoint the specific nutritional component(s) is another challenge, such as in some of the above-cited RCTs, which could not separate out the effects of macronutrient type and energy intake. Moreover, dietary trials can vary greatly in quality, and consistency of findings and comparability are limited by the populations and endpoints included, for example healthy or diseased participants, free-living or tightly controlled conditions, and a variety of intermediate endpoints or clinical outcomes. In practice, RCTs also suffer from poor methodology and unreliable findings, as evidenced by an appraisal of nearly 21,000 RCTs [ 67 ].

Causal inference is strengthened when there is consistent evidence from different study designs. Inferring causality from observational evidence is possible by applying the Bradford Hill criteria, and Mendelian randomisation is a tool that can be applied in some situations to evaluate causal relationships [ 68 ].

No design is perfect and the evolution of improvements in all study designs—RCTs and observational studies—must continue. New concepts are emerging, such as ‘ n -of-1’ trials and adaptive trial design, which need robust testing in the nutrition field. There is strong concordance in findings from prospective observational studies and RCTs and the two study designs should complement each other [ 7 ]. The best evidence base is that which evaluates all the relevant diverse types of evidence.

Uncertainty remains for some dietary factors

Consensus on the potential benefits and harms of many foods and dietary patterns has been established. However, for some dietary factors controversy remains, for example in the case of non-nutritive or artificial sweeteners such as aspartame, saccharin and sucralose. These sugar substitutes can help decrease daily energy and carbohydrate intakes but whether they are helpful for obesity and type 2 diabetes in the long term is debated [ 69 ]. The use of such sweeteners is predicted to rise in line with the public health policy on sugar reduction, which in the UK includes a soft drinks industry levy applied to soft drinks containing high amounts of added sugar; manufacturers have responded to this with reformulations using sugar substitutes. To resolve this uncertainty, future research will ideally use a combination of research designs including well-conducted short-term RCTs and long-term prospective studies and employ nutritional biomarkers of artificial sweeteners.

Noise and confusion are commonplace in the nutritional field

Everyone is interested in food. From news media to social media, books and blogs, information and misinformation on nutritional topics is everywhere. Conflicts of interest cannot always be avoided. Trusted resources are needed, including high-quality research evidence, improved dietary guidelines [ 70 ] and greater involvement of academic institutions and health agencies.

There are many influences on what we eat beyond individual lifestyle choice (Fig. 1 )

There is a gap between dietary advice and dietary intakes. Consider the public health message to eat five portions a day of fruit and vegetables. Despite strong health promotion efforts, ~12% of the population aged over 15 years in Europe meet this goal [ 71 ]. In a global context, compliance with eating five portions a day of fruit and vegetables is affected disproportionately by income, such that achieving this goal costs an estimated 52%, 18%, 16% and 2% of household income in low-, low- to middle-, middle- to upper- and high-income countries, respectively [ 72 ]. Further, sobering current examples of wider determinants of food choice include the effects of Brexit, the COVID-19 pandemic and the Russian invasion of Ukraine on availability, access and food security.

To improve and maintain dietary adherence, there is a need to operate both at the individual level and in the policy space across the entire food system (see Text box ‘Strategies to promote dietary adherence to healthy eating’). Education, dietary guidelines and strategies that enable people to make healthy food choices are necessary but not yet universally available.

Interest has recently risen in ‘food is medicine’ interventions in healthcare systems, such that a healthy diet can be prescribed in a manner equivalent to the prescription of medication, particularly for those with food insecurity. Such interventions include food prescriptions or the provision of medically tailored groceries or meals, which in those with diabetes can achieve improvements in diet quality and in HbA 1c of a comparable magnitude to those seen with glucose-lowering medication [ 73 ]. Pilot data in people with uncontrolled type 2 diabetes and food insecurity are impressive, with substantial reductions in HbA 1c in those enrolled to receive fresh food on prescription [ 74 ]. Similarly, a meta-analysis of healthy food prescription programmes reported that an increase in consumption of fruit and vegetables by a mean of 0.8 daily servings was associated with significant reductions in BMI and HbA 1c [ 75 ]. Although there were methodological limitations, these studies highlight the potential effectiveness of such dietary interventions and the case for investment in further research.

There are exciting new developments on the horizon

This is illustrated by two examples. First, greater understanding of the relationships between eating and circadian biology is emerging to shed light on so-called chrononutrition [ 76 ]. In addition to considerations of quantity and quality appraised above, chrononutrition considers the impact of the timing of food intake on metabolic health. As an example, the benefits of intermittent fasting and time-restricted feeding are becoming apparent for weight loss [ 77 ] and health more broadly [ 78 ], but research specifically targeted at type 2 diabetes is needed. Second, to improve on current dietary guidance, which is based on population averages, promising research on ‘precision nutrition’ aims to combine information from personal, biological, social and environmental factors to target individuals or population subgroups sharing similar characteristics [ 79 ]. Although still in its infancy, the use of technologies that enable information from genetics, metabolomics, proteomics and the gut microbiome to be integrated with clinical and biochemical data together with machine learning has the potential to enable the development of personalised nutrition interventions [ 80 ].

Conclusions

Diet and nutrition play a central role in both the prevention and the management of type 2 diabetes but the complexity of diet and some key controversies have posed challenges in the field. The latest research evidence has advanced our understanding of the importance of shifting away from the decades-long focus on the quantity of isolated nutrients to nutrient quality, nutrient food sources and overall dietary patterns. New advances in research hold promise for helping to resolve current ongoing uncertainties, and exciting future directions are anticipated (see Text box ‘Future directions: food for thought’).

Abbreviations

Dietary Approaches to Stop Hypertension

Glycaemic index

Glycaemic load

National Health Service

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Acknowledgements

I acknowledge D. Bhagtani’s help with Fig. 1 (MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine).

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NGF was a member of the Joint Scientific Advisory Committee on Nutrition/NHS England/Diabetes UK Working Group, which was initiated to review the evidence on lower carbohydrate diets compared with current government advice for adults with type 2 diabetes. The views expressed are her own and not those of the Group.

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The author was the sole contributor to this article.

NGF is supported by the Medical Research Council Epidemiology Unit (MC_UU_00006/3) and the NIHR Biomedical Research Centre Cambridge: Nutrition, Diet, and Lifestyle Research Theme (IS-BRC-1215-20014). She is an NIHR Senior Investigator. The views expressed are those of the author and not necessarily those of the NIHR or the Department of Health and Social Care.

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Forouhi, N.G. Embracing complexity: making sense of diet, nutrition, obesity and type 2 diabetes. Diabetologia 66 , 786–799 (2023). https://doi.org/10.1007/s00125-023-05873-z

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Living With Diabetes

Warning signs of diabetes, types of diabetes, type 1 vs type 2 diabetes, type 1 diabetes, type 1 diabetes causes, type 1 diabetes symptoms, is there a cure for type 1 diabetes, type 2 diabetes, type 2 diabetes treatment.

Educate teachers, school personnel and other child care providers about taking care of your child with type 1 diabetes. Download this helpful guide now.

Type 2 Diabetes is a serious condition which causes higher than normal blood sugar levels. It affects people from all social, economic, and ethnic backgrounds.

It is estimated that more than 34 million Americans have diabetes, including approximately 7 million who have the disease but have not yet been diagnosed. Worldwide, it is estimated that over 463 million people are living with some form of the disease.

Diabetes mellitus (type 2 diabetes), the medical term for the condition, occurs when the body cannot make or effectively use its own insulin, a hormone produced by special cells in the pancreas called islet (eye-let) cells. Insulin is like a key that opens the door of a cell so that food, or glucose, can enter. Without insulin, this glucose builds up in the blood and leads to starvation of the body’s cells, as well as dehydration and break down of body tissue.

There are multiple forms of diabetes. Type 2 diabetes is the most common form. Approximately 90 percent of those with diabetes have type 2. Unlike type 1 diabetes, in which all the insulin-producing cells are destroyed, people with type 2 diabetes are able to produce some of their own insulin, but their bodies are unable to use this insulin to completely control blood sugar levels. This is known as insulin resistance.

Who gets type 2 diabetes?

Type 2 diabetes usually develops after the age of 35, although it can occur in younger people as well, especially if they are overweight and have a sedentary lifestyle.

Commonly referred to as “adult onset” diabetes, 80% of those with this form of diabetes are overweight and have a family history of type 2 diabetes.

Certain ethnic groups have a higher risk of developing this form of the disease, including African Americans, Hispanics and American Indians. In addition, women who had diabetes during pregnancy (gestational diabetes) are also at greater risk of developing type 2 diabetes later in life.

What are the symptoms of type 2 diabetes?

Knowing the warning signs of type 2 diabetes is helpful for early diagnosis. Symptoms can include:

• Increased thirst
• Increased urination
• Unexplained weight loss
• Extreme hunger
• Extreme weakness or fatigue
• Blurred vision
• Infections which are slow or difficult to heal

The symptoms of type 2 diabetes usually happen over time, unlike the symptoms of type 1 diabetes which are sudden and often too severe to overlook. That’s why many people mistakenly overlook the warning signs of type 2, and often think the symptoms are signs of other conditions, such as aging, overworking, or hot weather. Because these symptoms are often ignored, it is estimated that more than seven million people in the United States have diabetes and are not aware of it.

Individuals who have undiagnosed or untreated diabetes for several years may develop some complications, such as nerve damage, pain or numbness in their hands and feet, or changes in their eyes or kidneys. People who are over 35, overweight, have a family history of diabetes, or who belong to a high-risk group should be checked at least once a year to detect diabetes at its earliest stages.

What is the treatment for type 2 diabetes?

The treatment for type 2 diabetes focuses on improving the person’s ability to more effectively use the insulin his/her own body produces to normalize blood sugar levels. A treatment program including diet, exercise, and weight loss will help decrease insulin resistance and, in turn, lower blood sugar levels. If blood sugar levels are still high, there are many medications which can help to either stimulate more insulin production in the pancreas or help the body better use the insulin it makes. Insulin injections may be needed if these oral medications, along with diet and exercise, do not lower blood sugar levels enough.

What are the problems associated with type 2 diabetes?

New advances in research and treatment methods are helping people with type 2 diabetes live full, active and healthy lives. However, it is important to remember that diabetes is a serious, chronic condition with potential short-term and long-term complications. Frequent self-monitoring of blood sugar levels and carefully following an individualized meal and exercise program is a good course of action.

People with undiagnosed, untreated or long-term diabetes are at risk of developing complications, including nerve and blood vessel damage. These potential complications, which can affect the eyes, kidneys, limbs, heart, brain, and stomach, may occur after many years of living with diabetes. Early detection, improved medications, and new technologies may help prevent or minimize diabetes-related complications.

Can type 2 diabetes be prevented?

The key to success is in preventing pre-diabetes and type 2 diabetes. Identifying risk means asking yourself the following key questions:

• Am I aged 35 years or older?
• Am I overweight?
• Do I have high blood pressure or cholesterol?
• Do I have a family history of diabetes?
• Am I African American, Hispanic, American Indian or Asian?
• Do I have a history of diabetes occurring during pregnancy?
• Did I deliver a baby weighing more than 9 pounds?

If you answered “yes” to any of these questions, then you should make an appointment with your physician to be screened. To lower your risk of pre-diabetes and type 2 diabetes try the following:

• Look for opportunities to move more during the day
• Exercise 30 minutes at least five times per week
• Eat a healthy meal plan including grains, cereals, fresh fruit and vegetables, low fat dairy and lean meat
• Reduce fat intake
• Reduce food portions
• Maintain an ideal body weight

Get more answers to your questions about type 1 diabetes, type 2 diabetes and gestational diabetes symptoms and treatments. (In Spanish: ¿Que es La Diabetes?).

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Get news about research toward a cure, diabetes management tips, information for parents of children with type 1 diabetes and more. Sign up and become a DRI Insider today!

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Elements and Minerals in Type 2 Diabetes Mellitus

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Trace elements are essential for the biological, chemical and molecular activities of cell. These agents play a key role in biochemical reactions by acting as cofactors for enzymes. The use of trace elements including copper, zinc, selenium, and magnesium is an important procedure in the management of type 2 ...

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• SUMMARY AND COMMENT | 

April 6, 2024

Semaglutide Improves Outcomes in Patients with Obesity, HFpEF, and Type 2 Diabetes

Karol E. Watson, MD, PhD, FACC , reviewing Kosiborod MN et al. N Engl J Med 2024 Apr 6

In a randomized, controlled trial, semaglutide resulted in greater weight loss, improved symptoms, and fewer serious adverse events compared with placebo.

Obesity and type 2 diabetes are common comorbidities in patients with heart failure with preserved ejection fraction (HFpEF). Currently, there are no FDA-approved therapies that specifically treat all three conditions at the same time; however, semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, has the potential to do so.

In an industry-funded trial ( NCT04916470 ), investigators randomized 616 adults with HFpEF (left ventricular ejection fraction ≥45%), body-mass index >30, and type 2 diabetes to receive semaglutide (2.4 mg) or matching placebo once weekly for 52 weeks. They assessed dual primary endpoints of change in heart failure symptoms via Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS; range, 0–100, with higher score indicating fewer symptoms) and change in body weight.

The mean change in the KCCQ-CSS was +13.7 points with semaglutide and +6.4 points with placebo, indicating improved symptoms with semaglutide. The mean change in body weight was −9.8% with semaglutide and −3.4% with placebo. Confirmatory secondary end points also favored semaglutide, including 6-minute walk distance, a composite end point (including death, heart failure events, and differences in KCCQ-CSS and 6-minute walk distance), and C-reactive protein level. Serious adverse events occurred in 18% of patients in the semaglutide group and 29% in the placebo group.

Semaglutide once again shows clinical benefit. Prior research has shown improved outcomes in patients with diabetes and high cardiovascular risk, in patients with overweight or obesity and high cardiovascular risk, and in patients with HFpEF and obesity but no diabetes. Now, this research shows efficacy in patients with HFpEF, obesity, and type 2 diabetes. The many benefits of semaglutide make me very likely to recommend this therapy in appropriate patients for improving symptoms and reducing cardiovascular risk.

Kosiborod MN et al. Semaglutide in patients with obesity-related heart failure with preserved ejection fraction and type 2 diabetes. N Engl J Med 2024 Apr 6; [e-pub]. ( https://doi.org/10.1056/NEJMoa2313917 )

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• Disclosures

Disclosures for Karol E. Watson, MD, PhD, FACC, at time of publication

Topics nutrition/obesity, latest in general medicine.

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BRD7 research points to alternative insulin signaling pathway

Bromodomain-containing protein 7 (BRD7) was initially identified as a tumor suppressor, but further research has shown it has a broader role in other cellular processes, including the remodeling of chromosomes and cell cycle progression.

Now, Boston Children’s  Division of Endocrinology  researchers have discovered another purpose for BRD7: It seems to be involved in an alternative insulin signaling pathway, the existence of which had been speculated about for decades. Their finding could lead to new insights on previously unknown aspects of insulin signaling in obesity . “The ultimate goal will be to find a way to reverse the  type 2 diabetic  features associated with obesity,” says  Sang Won Park, PhD , who was the corresponding author of this latest study on BRD7.

Looking at BRD7’s function in glucose regulation

BRD7 has a key role in the regulation of glucose homeostasis — the balancing of glucose uptake in response to insulin and glucose production in the liver. In 2014, Park and others found that the  restoration of reduced BRD7 in the liver is sufficient to reestablish glucose homeostasis in obesity . Four years later, they looked at  BRD7’s participation in the insulin signaling pathway and its mechanistic function in the regulation of glucose homeostasis. 

Building on that research, Park and others recently studied the interactive actions of BRD7 with insulin receptor substrates IRS-1 and IRS-2 (informally known as IRS1/2) in the livers of obese mice. IRS proteins were previously considered critical proteins required by the insulin receptor to transmit signals to downstream pathways.

Park’s team — which included study co-first authors Junsik Lee and Yoo Kim, PhD, both of whom worked in her lab — had two goals: investigate the involvement of BRD7 as a downstream component of the insulin receptor (InsR) protein and examine the requirement of IRS1/2 for the action of BRD7.

They found that BRD7 interacts with the insulin receptor. This establishes BRD7 as an integral component of insulin signaling, Park says. Notably, they also discovered that IRS1/2 is not necessary for BRD7’s regulation of glucose metabolism, particularly in the context of obesity. This finding indicates that BRD7 plays a role in an insulin signaling pathway independent of the pathway of the insulin receptor substrate-AKT axis.

Their findings were published in  Journal of Endocrinology .

Research continues to determine BRD7’s role in potential treatment

Park and colleagues are now back to work. They hope to definitively prove that an alternative insulin signaling pathway exists. Further research will also hopefully illustrate how BRD7 is activated, either in the recognized signaling pathway or the alternative one posited by her team.

“We think it is related to the amount of energy and nutrients present in the body,” Park says. “BRD7 somehow senses the availability of nutrition and blood glucose levels, but we’re not exactly sure how that works.” Further research will include focusing on how BRD7 works within the insulin signaling mechanisms of obesity and non-obesity. Fully knowing BRD7’s role could shape how a type 2 diabetes treatment is formed, Park says.

Learn more about the  Diabetes Program .

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• Spring 2024

Research Updates

Bariatric surgery provides long-term blood glucose control, type 2 diabetes remission.

People with type 2 diabetes who underwent bariatric surgery achieved better long-term blood glucose control compared to people who received medical management plus lifestyle interventions, according to a new study supported by NIDDK . In this large, pooled follow-up study, participants who underwent bariatric surgery, also called metabolic or weight-loss surgery, were also more likely to stop needing diabetes medications and had higher rates of diabetes remission up to 12 years post-surgery compared to participants who received medical management and lifestyle intervention for their diabetes. Additional exploratory analyses showed that bariatric surgery had important, beneficial effects on HbA1c and weight loss among participants with a body mass index (BMI) between 27 and 34 (within overweight and lower obesity ranges), which lend important information about the benefit of surgery in people with type 2 diabetes who fall short of the traditional, higher BMI threshold of 35 for bariatric surgery. These results were published in JAMA in February.

Discovery of gene in mice could open new therapeutic avenues for a rare neurodegenerative disorder

A recent study led by NIDDK researchers sheds light on a rare neurological disease, GM1 gangliosidosis, which occurs when people lack an enzyme responsible for breaking down the lipid known as GM1 ganglioside. As a result, the lipid accumulates in the brain and causes severe neurological symptoms. The researchers discovered that in mice, a gene called Neu3 creates an alternative pathway to help degrade the lipid, which may explain why mice exhibit a much milder form of GM1 gangliosidosis compared to what people with the disease experience. When the researchers turned off the Neu3 gene in mice, the severity of the disease increased. Specifically, the mice experienced a faster onset of neurological symptoms, greater neurodegeneration, and shorter lifespan. The findings, which published in the Journal of Lipid Research in December, advance understanding of the potential mechanisms underlying the severity of GM1 gangliosidosis and could lead to new therapies to alter the course of the disease. In future studies, the research team will explore whether the Neu3 gene modifies other neurodegenerative diseases resulting from a build-up of gangliosides in the brain.

Switching to a vegan or ketogenic diet rapidly affects immune system

Researchers at the National Institutes of Health, including NIDDK, observed rapid and distinct immune system changes in a small study of people who switched to a vegan or a ketogenic (also called keto) diet. Scientists closely monitored various biological responses of people who ate either a vegan or keto diet for two weeks, then switched to the opposite diet for another two weeks. They found that the vegan diet prompted responses linked to innate immunity—the body’s non-specific first line of defense against pathogens—while the keto diet prompted responses associated with adaptive immunity—pathogen-specific immunity built through exposures in daily life and vaccination. Metabolic changes and shifts in the participants’ microbiomes—communities of bacteria living in the gut—were also observed. More research is needed to determine if these changes are beneficial or detrimental and what effect they could have on nutritional interventions for diseases such as cancer or inflammatory conditions. The paper was published in Nature Medicine in January.

NIDDK scientists develop standard models of human fat cells to help advance research

Human fat is a complex organ that plays a critical role in sustaining health, and the lack of standardized models of brown and white adipose tissue, or fat cells, have made it challenging to understand its structural, functional, and genetic characteristics. In a new study, NIDDK researchers tackled this challenge by characterizing human brown and white adipose tissue cells donated by a male patient during an abdominal surgery. In analyzing these cells, the researchers identified the physiological mechanisms that allow brown fat cells to generate heat in response to cold temperatures, thus demonstrating how standardized models of fat tissue can be used to better advance knowledge on a cellular level. Standardized models of human fat cells will also help researchers generate reproducible study results. Published in December in Endocrinology , and selected as the journal’s “featured article of the week” in January, the study lays the groundwork for future physiologic, pharmacologic, and genetic studies on human fat and its role in metabolic disease and health.

NIDDK researchers develop analytical method to identify genes associated with risk of Alzheimer’s disease

A new NIDDK study has identified nine genes potentially linked to higher risk of Alzheimer’s disease (AD) in people of African descent. The researchers developed a “gene-constrained” analysis, in which they counted and compared only moderate- and high-risk gene variants affecting gene function. This approach differs from the more common “genome-wide association study” (GWAS) method, which looks at all regions across the genome and is typically used when searching for genetic variants associated with complex diseases involving many genes, such as AD.

One of the genes the researchers identified was GNB5, which regulates G-protein signaling. The discovery of GNB5 as a risk gene for AD suggests that regulation of G-protein signaling may be critically involved in the development of the disease. In addition, the nine genes the researchers identified were not among previously identified genes linked to AD by the GWAS method. The results, which were published in The American Journal of Human Genetics in March, indicate that the gene-constrained approach might complement the GWAS method by enhancing the detection of genes associated with AD and other polygenic diseases.

Research Has Shown That Childhood Obesity Not Only Increases The Risk Of Type 2 Diabetes And Hypertension But Is Also Linked To Weaker Cognitive Functioning

O ngoing research has shown that childhood obesity not only increases the risk of diseases such as hypertension and Type 2 diabetes but also leads to a problem that’s not often discussed – declining brain health.

In a study conducted by researchers working with the Radiological Society of North America, it was found that kids with a higher body mass index (BMI) before hitting adolescence tend to exhibit weaker cognitive abilities.

“We know being obese as an adult is associated with poor brain health,” said Simone Kaltenhauser, a radiology and biomedical imagine post-graduate research fellow at the Yale School of Medicine.

“However, previous studies on children have often focused on small, specific study populations or single aspects of brain health.”

So, the team analyzed MRI data from the Adolescent Brain Cognitive Development (ABCD) study. This research involved 11,878 children aged 9 to 10 from 21 locations nationwide, ensuring a varied sample that reflects the broader population.

They omitted children with eating disorders, neurodevelopmental and psychiatric conditions, and those who had suffered traumatic brain injuries – narrowing their focus to slightly over 5,100 participants.

By utilizing BMI z-scores, which adjust for age, gender, and height to assess relative weight, they found that 21% of these children were overweight, while 17.6% were classified as obese.

Next, the researchers assessed brain health through the analysis of data from structural MRI and resting-state functional MRI (fMRI) scans, which are techniques that monitor blood flow changes. They also employed diffusion tensor imaging to investigate the structure of the brain’s white matter.

Upon adjusting for variables such as age, gender, race-ethnicity, right or left-handedness, and socioeconomic status, the team observed changes in brain structure related to higher weight and BMI z-scores in children.

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Children classified as obese showed signs of compromised white matter integrity. In particular, damage was seen in the white matter of the corpus callosum, the crucial bridge facilitating communication between the brain’s two hemispheres.

Additionally, the researchers recorded a reduction in the thickness of the brain’s cortex, which plays a vital role in cognitive functions.

“It is striking that these changes were visible early on during childhood,” explained Kaltenhauser.

“We expected the decrease in cortical thickness among the higher weight and BMI z-score children, as this was found previously in smaller subsamples of the ABCD study. However, we were surprised by the extent of white matter impairment.”

Sam Payabvash, the study’s senior author, also noted that the results of this study provide a mechanistic understanding of previous research connecting high BMI in children with reduced cognitive abilities and academic achievements.

So, Payabvash recommends ongoing observation of these children for six to 10 years to track changes in their brain development over time.

To read the study’s complete findings, visit the link here .

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New Aspects of Diabetes Research and Therapeutic Development

Both type 1 and type 2 diabetes mellitus are advancing at exponential rates, placing significant burdens on health care networks worldwide. Although traditional pharmacologic therapies such as insulin and oral antidiabetic stalwarts like metformin and the sulfonylureas continue to be used, newer drugs are now on the market targeting novel blood glucose–lowering pathways. Furthermore, exciting new developments in the understanding of beta cell and islet biology are driving the potential for treatments targeting incretin action, islet transplantation with new methods for immunologic protection, and the generation of functional beta cells from stem cells. Here we discuss the mechanistic details underlying past, present, and future diabetes therapies and evaluate their potential to treat and possibly reverse type 1 and 2 diabetes in humans.

Significance Statement

Diabetes mellitus has reached epidemic proportions in the developed and developing world alike. As the last several years have seen many new developments in the field, a new and up to date review of these advances and their careful evaluation will help both clinical and research diabetologists to better understand where the field is currently heading.

I. Introduction

Diabetes mellitus, a metabolic disease defined by elevated fasting blood glucose levels due to insufficient insulin production, has reached epidemic proportions worldwide (World Health Organization, 2020 ). Type 1 and type 2 diabetes (T1D and T2D, respectively) make up the majority of diabetes cases with T1D characterized by autoimmune destruction of the insulin-producing pancreatic beta cells. The much more prevalent T2D arises in conjunction with peripheral tissue insulin resistance and beta cell failure and is estimated to increase to 21%–33% of the US population by the year 2050 (Boyle et al., 2010 ). To combat this growing health threat and its cardiac, renal, and neurologic comorbidities, new and more effective diabetes drugs and treatments are essential. As the last several years have seen many new developments in the field of diabetes pharmacology and therapy, we determined that a new and up to date review of these advances was in order. Our aim is to provide a careful evaluation of both old and new therapies ( Fig. 1 ) in a manner that we hope will be of interest to both clinical and bench diabetologists. Instead of the usual encyclopedic approach to this topic, we provide here a targeted and selective consideration of the underlying issues, promising new treatments, and a re-examination of more traditional approaches. Thus, we do not discuss less frequently used diabetes agents, such as alpha-glucosidase inhibitors; these were discussed in other recent reviews (Hedrington and Davis, 2019 ; Lebovitz, 2019 ).

Pharmacologic targeting of numerous organ systems for the treatment of diabetes. Treatment of diabetes involves targeting of various organ systems, including the kidney by SGLT2 inhibitors; the liver, gut, and adipose tissue by metformin; and direct actions upon the pancreatic beta cell. Beta cell compounds aim to increase secretion or mass and/or to protect from autoimmunity destruction. Ultimately, insulin therapy remains the final line of diabetes treatment with new technologies under development to more tightly regulate blood glucose levels similar to healthy beta cells. hESC, human embryonic stem cell.

II. Diabetes Therapies

A. metformin.

Metformin is a biguanide originally based on the natural product galegine, which was extracted from the French lilac (Bailey, 1992 ; Rojas and Gomes, 2013 ; Witters, 2001 ). A closely related biguanide, phenformin, was also used initially for its hypoglycemic actions. Based on its successful track record as a safe, effective, and inexpensive oral medication, metformin has become the most widely prescribed oral agent in the world in treating T2D (Rojas and Gomes, 2013 ; He and Wondisford, 2015 ; Witters, 2001 ), whereas phenformin has been largely bypassed due to its unacceptably high association with lactic acidosis (Misbin, 2004 ). Unlike sulfonylureas, metformin lowers blood glucose without provoking hypoglycemia and improves insulin sensitivity (Bailey, 1992 ). Despite these well known beneficial metabolic actions, metformin’s mechanism of action and even its main target organ remain controversial. In fact, metformin has multiple mechanisms of action at the organ as well as the cellular level, which has hindered our understanding of its most important molecular effects on glucose metabolism (Witters, 2001 ). Adding to this, a specific receptor for metformin has never been identified. Metformin has actions on several tissues, although the primary foci of most studies have been the liver, skeletal muscle, and the intestine (Foretz et al., 2014 ; Rena et al., 2017 ). Metformin and phenformin clearly suppress hepatic glucose production and gluconeogenesis, and they improve insulin sensitivity in the liver and elsewhere (Bailey, 1992 ). The hepatic actions of metformin have been the most exhaustively studied to date, and there is little doubt that these actions are of some importance. However, several of the studies remain highly controversial, and there are still open questions.

One of the first reported specific molecular targets of metformin was mitochondrial complex I of the electron transport chain. Inhibition of this complex results in reduced oxidative phosphorylation and consequently decreased hepatic ATP production (El-Mir et al., 2008 ; Evans et al., 2005 ; Owen et al., 2000 ). As is the case in many other studies of metformin, however, high concentrations of the drug were found to be necessary to depress metabolism at this site (El-Mir et al., 2000 ; He and Wondisford, 2015 ; Owen et al., 2000 ). Also controversial is whether metformin works by activating 5′ AMP-activated protein kinase (AMPK), a molecular energy sensor that is known to be a major metabolic sensor in cells, or if not AMPK directly, then one of its upstream regulators such as liver kinase B2 (Zhou et al., 2001 ). Although metformin was shown to activate AMPK in several excellent studies, other studies directly contradicted the AMPK hypothesis. Most dramatic were studies showing that metformin’s actions to suppress hepatic gluconeogenesis persisted despite genetic deletion of the AMPK’s catalytic domain (Foretz et al., 2010 ). More recent studies identified additional or alternative targets, such as cAMP signaling in the liver (Miller et al., 2013 ) or glycogen synthase kinase-3 (Link, 2003 ). Other work showed that the phosphorylation of acetyl-CoA carboxylase and acetyl-CoA carboxylase 2 are involved in regulating lipid homeostasis and improving insulin sensitivity after exposure to metformin (Fullerton et al., 2013 ).

Although there are strong data to support each of these pathways, it is not entirely clear which signaling pathway(s) is most essential to the actions of metformin in hepatocytes. Metformin clearly inhibits complex I and concomitantly decreases ATP and increases AMP. The latter results in AMPK activation, reduced fatty acid synthesis, and improved insulin receptor activation, and increased AMP has been shown to inhibit adenylate cyclase to reduce cAMP and thus protein kinase A activation. Downstream, this reduces the expression of phosphoenolpyruvate carboxykinase and glucose 6-phosphatase via decreased cAMP response element-binding protein, the cAMP-sensitive transcription factor. Decreased PKA also promotes ATP-dependent 6-phosphofructokinase, liver type activity via fructose 2,6-bisphosphate and reduces gluconeogenesis, as fructose-bisphosphatase 1 is inhibited by fructose 2,6-bisphosphate, along with other mechanisms (Rena et al., 2017 ; Pernicova and Korbonits, 2014 ).

More recent work has shown that metformin at pharmacological rather than suprapharmacological doses increases mitochondrial respiration and complex 1 activity and also increases mitochondrial fission, now thought to be critical for maintaining proper mitochondrial density in hepatocytes and other cells. This improvement in respiratory activity occurs via AMPK activation (Wang et al., 2019 ).

Although the liver has historically been the major suspected site of metformin action, recent studies have suggested that the gut instead of the liver is a major target, a concept supported by the increased efficacy of extended-release formulations of metformin that reside for a longer duration in the gut after their administration (Buse et al., 2016 ). An older, but in our view an important observation, is that the intravenous administration of metformin has little or no effect on blood glucose, whereas, in contrast, orally administered metformin is much more effective (Bonora et al., 1984 ). Recent imaging studies using labeled glucose have shown directly that metformin stimulates glucose uptake by the gut in patients with T2D to reduce plasma glucose concentrations (Koffert et al., 2017 ; Massollo et al., 2013 ). Additionally, it is possible that metformin may exert its effect in the gut by inducing intestinal glucagon-like peptide-1 (GLP-1) release (Mulherin et al., 2011 ; Preiss et al., 2017) to potentiate beta cell insulin secretion and by stimulating the central nervous system (CNS) to exert control over both blood glucose and liver function. Indeed, CNS effects produced by metformin have been proposed to occur via the local release of GLP-1 to activate intestinal nerve endings of ascending nerve pathways that are involved in CNS glucose regulation (Duca et al., 2015 ). Lastly, several papers have now implicated that metformin may act by altering the gut microbiome, suggesting that changes in gut flora may be critical for metformin’s actions (McCreight et al., 2016 ; Wu et al., 2017 ; Devaraj et al., 2016 ). A new study proposed that activation of the intestinal farnesoid X receptor may be the means by which microbiota alter hyperglycemia (Sun et al., 2018 ). However, these studies will require more mechanistic detail and confirmation before they can be fully accepted by the field. In addition to the action of metformin on gut flora, the production of imidazole propionate by gut microbes in turn has been shown to interfere with metformin action through a p38-dependent mechanism and AMPK inhibition. Levels of imidazole propionate are especially higher in patients with T2D who are treated with metformin (Koh et al., 2020 ).

In summary, the combined contribution of these various effects of metformin on multiple cellular targets residing in many tissues may be key to the benefits of metformin treatment on lowering blood glucose in patients with type 2 diabetes (Foretz et al., 2019 ). In contrast, exciting new work showing metformin leads to weight loss by increasing circulating levels of the peptide hormone growth differentiation factor 15 and activation of brainstem glial cell-derived neurotropic factor family receptor alpha like receptors to reduce food intake and energy expenditure works independently of metformin’s glucose-lowering effect (Coll et al., 2020 ).

B. Sulfonylureas and Beta Cell Burnout

The class of compounds known as sulfonylureas includes one of the oldest oral antidiabetic drugs in the pharmacopoeia: tolbutamide. Tolbutamide is a “first generation” oral sulfonylurea secretagogue whose clinical usefulness is due to its prompt stimulation of insulin release from pancreatic beta cells. “Second generation” sulfonylureas include drugs such as glyburide, gliclazide, and glipizide. Sulfonylureas act by binding to a high affinity sulfonylurea binding site, the sulfonylurea receptor 1 subunit of the K(ATP) channel, which closes the channel. These drugs mimic the physiologic effects of glucose, which closes the K(ATP) channel by raising cytosolic ATP/ADP. This in turn provokes beta cell depolarization, resulting in increased Ca 2+ influx into the beta cell (Ozanne et al., 1995 ; Ashcroft and Rorsman, 1989 ; Nichols, 2006 ). Importantly, sulfonylureas, and all drugs that directly increase insulin secretion, are associated with hypoglycemia, which can be severe, and which limits their widespread use in the clinic (Yu et al., 2018 ). Meglitinides are another class of oral insulin secretagogues that, like the sulfonylureas, bind to sulfonylurea receptor 1 and inhibit K(ATP) channel activity (although at a different site of action). The rapid kinetics of the meglitinides enable them to effectively blunt the postprandial glycemic excursions that are a hallmark (along with elevated fasting glucose) of T2D (Rosenstock et al., 2004). However, the need for their frequent dosing (e.g., administration before each meal) has limited their appeal to patients.

The efficacy of sulfonylureas is known to decrease over time, leading to failure of the class for effective long-term treatment of T2D (Harrower, 1991 ). More broadly, it is now widely accepted that the number of functional beta cells in humans declines during the progression of T2D. Thus, one would expect that due to this decline, all manner of oral agents intended to target the beta cell and increase its cell function (and especially insulin secretion) will fail over time (RISE Consortium, 2019 ), a process referred to as “beta cell failure” (Prentki and Nolan, 2006 ). Currently, treatments that can expand beta cell mass or improve beta cell function or survival over time are not yet available for use in the clinic. As a result, treatments that may be able to help patients cope with beta cell burnout such as islet cell transplantation, insulin pumps, or stem cell therapy are alternatives that will be discussed below.

C. Ca 2+ Channel Blockers and Type 1 Diabetes

Strategies to treat and prevent T1D have historically focused on ameliorating the toxic consequences of immune dysregulation resulting in autoimmune destruction of pancreatic beta cells. More recently, a concerted focus on alleviating the intrinsic beta cell defects (Sims et al., 2020 ; Soleimanpour and Stoffers, 2013 ) that also contribute to T1D pathogenesis have been gaining traction at both the bench and the bedside. Several recent preclinical studies suggest that Ca 2+ -induced metabolic overload induces beta cell failure (Osipovich et al., 2020 ; Stancill et al., 2017 ; Xu et al., 2012 ), with the potential that excitotoxicity contributes to beta cell demise in both T1D and T2D, similar to the well known connection between excitotoxicity and, concomitantly, increased Ca 2+ loading of the cells and neuronal dysfunction. Indeed, the use of the phenylalkylamine Ca 2+ channel blocker verapamil has been successful in ameliorating beta cell dysfunction in preclinical models of both T1D and T2D (Stancill et al., 2017 ; Xu et al., 2012 ). Verapamil is a well known blocker of L-type Ca 2+ channels, and, in normally activated beta cells, it limits Ca 2+ entry into the beta cell (Ohnishi and Endo, 1981 ; Vasseur et al., 1987 ). This would be expected to, in turn, alter the expression of many Ca 2+ influx–dependent beta cell genes (Stancill et al., 2017 ), and the evidence to date suggests it is likely that verapamil preserves beta cell function in diabetes models by repressing thioredoxin-interacting protein (TXNIP) expression and thus protecting the beta cell. This is somewhat surprising given the physiologic role of Ca 2+ is to acutely trigger insulin secretion; this process would be expected to be inhibited by L-type Ca 2+ channel blockers (Ashcroft and Rorsman, 1989 ; Satin et al., 1995 ).

Hyperglycemia is a well known inducer of TXNIP expression, and a lack of TXNIP has been shown to protect against beta cell apoptosis after inflammatory stress (Chen et al., 2008a ; Shalev et al., 2002 ; Chen et al., 2008b ). Excitingly, the use of verapamil in patients with recent-onset T1D improved beta cell function and improved glycemic control for up to 12 months after the initiation of therapy, suggesting there is indeed promise for targeting calcium and TXNIP activation in T1D. Use of verapamil for a repurposed indication in the preservation of beta cell function in T1D is attractive due its well known safety profile as well as its cardiac benefits (Chen et al., 2009 ). Although the long-term efficacy of verapamil to maintain beta cell function in vivo is unclear, a recently described TXNIP inhibitor may also show promise in suppressing the hyperglucagonemia that also contributes to glucose intolerance in T2D (Thielen et al., 2020 ). As there is a clear need for increased Ca 2+ influx into the beta cell to trigger and maintain glucose-dependent insulin secretion (Ashcroft and Rorsman, 1990 ; Satin et al., 1995 ), it remains to be seen how well regulated insulin secretion is preserved in the presence of L-type Ca 2+ channel blockers like verapamil in the system. One might speculate that reducing but not fully eliminating beta cell Ca 2+ influx might reduce TXNIP levels while preserving enough influx to maintain glucose-stimulated insulin release. Alternatively, these two phenomena may operate on entirely different time scales. At present, these issues clearly will require further investigation.

D. GLP-1 and the Incretins

Studies dating back to the 1960s revealed that administering glucose in equal amounts via the peripheral circulation versus the gastrointestinal tract led to dramatically different amounts of glucose-induced insulin secretion (Elrick et al., 1964 ; McIntyre et al., 1964 ; Perley and Kipnis, 1967 ). Gastrointestinal glucose administration greatly increased insulin secretion versus intravenous glucose, and this came to be known as the “incretin effect” (Nauck et al., 1986a ; Nauck et al., 1986b ). Subsequent work showed that release of the gut hormone GLP-1 mediated this effect such that food ingestion induced intestinal cell hormone secretion. GLP-1 so released would then circulate to the pancreas via the blood to prime beta cells to secrete more insulin when glucose became elevated because these hormones stimulated beta cell cAMP formation (Drucker et al., 1987 ). The discovery that a natural peptide corresponding to GLP-1 could be found in the saliva of the Gila monster, a desert lizard, hastened progress in the field, and ample in vitro studies subsequently confirmed that GLP-1 potentiated insulin secretion in a glucose-dependent manner. GLP-1 has little or no significant action on insulin secretion in the absence of elevated glucose (such as might typically correspond to the postprandial case or during fasting), thus minimizing the likelihood of hypoglycemia provoked by GLP-1 in treated patients (Kreymann et al., 1987 ). Although not completely understood, the glucose dependence of GLP-1 likely reflects the requirement for adenine nucleotides to close glucose-inhibited K(ATP) channels and thus subsequently activate Ca 2+ influx–dependent insulin exocytosis. Besides potentiating GSIS at the level of the beta cell, glucagon-like peptide-1 receptor (GLP-1R) agonists also decrease glucagon secretion from pancreatic islet alpha cells, reduce gastric emptying, and may also increase beta cell proliferation, among other cellular actions (reviewed in Drucker, 2018 ; Muller et al., 2019).

Intense interest in the incretins by basic scientists, clinicians, and the pharma community led to the rapid development of new drugs for treating primarily T2D. These drugs include a range of GLP-1R agonists and inhibitors of the incretin hormone degrading enzyme dipeptidyl peptidase 4 (DPP4), whose targeting increases the half-lives of GLP-1 and gastric inhibitory polypeptide (GIP) and thereby increases protein hormone levels in plasma. GLP-1R agonists have been associated with not only a lowering of plasma glucose but also weight loss, decreased appetite, reduced risk of cardiovascular events, and other favorable outcomes (Gerstein et al., 2019; Hernandez et al., 2018; Husain et al., 2019; Marso et al., 2016a; Marso et al., 2016b ; Buse et al., 2004). Regarding their untoward actions, although hypoglycemia is not a major concern, there have been reports of pancreatitis and pancreatic cancer from use of GLP-1R agonists. However, a recent meta-analysis covering four large-scale clinical trials and over 33,000 participants noted no significantly increased risk for pancreatitis/pancreatic cancer in patients using GLP-1R agonists (Bethel et al., 2018).

Ongoing and future developments in the use of proglucagon-derived peptides such as GLP-1 and glucagon include the use of combined GLP-1/GIP, glucagon/GLP-1, and agents targeting all three peptides in combination (reviewed in Alexiadou and Tan, 2020 ). Although short-term infusions of GLP-1 with GIP failed to yield metabolic benefits beyond those seen with GLP-1 alone (Bergmann et al., 2019 ), several GLP-1/GIP dual agonists are currently in development and have shown promising metabolic results in clinical trials (Frias et al., 2017 ; Frias et al., 2020 ; Frias et al., 2018 ). At the level of the pancreatic islet, beneficial effects of dual GLP-1/GIP agonists may be related to imbalanced and biased preferences of these agonists for the gastric inhibitory polypeptide receptor over the GLP-1R (Willard et al., 2020 ) and possibly were not simply to dual hormone agonism in parallel. Dual glucagon/GLP-1 agonist therapy has also been shown to have promising metabolic effects in humans (Ambery et al., 2018 ; Tillner et al., 2019 ). Oxyntomodulin is a natural dual glucagon/GLP-1 receptor agonist and proglucagon cleavage product that is also secreted from intestinal enteroendocrine cells, which has beneficial effects on insulin secretion, appetite regulation, and body weight in both humans and rodents (Cohen et al., 2003 ; Dakin et al., 2001 ; Dakin et al., 2002 ; Shankar et al., 2018 ; Wynne et al., 2005 ). Interestingly, alpha cell crosstalk to beta cells through the combined effects of glucagon and GLP-1 is necessary to obtain optimal glycemic control, suggesting a potential pathway for therapeutic dual glucagon/GLP-1 agonism within the islets of patients with T2D (Capozzi et al., 2019a ; Capozzi et al., 2019b ). Although the early results appear promising, more studies will be necessary to better understand the mechanistic and clinical impacts of these multiagonist agents.

E. DPP4 Inhibitors

Inhibition of DPP4, the incretin hormone degrading enzyme, is one of the most common T2D treatments to increase GLP-1 and GIP plasma hormone levels. These DPP4 inhibitors or “gliptins” are generally used in conjunction with other T2D drugs such as metformin or sulfonylureas to obtain the positive benefits discussed above (Lambeir et al., 2008 ). DPP4 is a primarily membrane-bound peptidase belonging to the serine peptidase/prolyl oligopeptidase gene family, which cleaves a large number of substrates in addition to the incretin hormones (Makrilakis, 2019 ). DPP4 inhibitors provide glucose-lowering benefits while being generally well tolerated, and the variety of available drugs (including sitagliptin, saxagliptin, vildagliptin, alogliptin, and linagliptin) with slightly different dosing frequency, half-life, and mode of excretion/metabolism allows for use in multiple patient populations (Makrilakis, 2019 ). This includes the elderly and individuals with renal or hepatic insufficiency (Makrilakis, 2019 ).

Although hypoglycemia is not a concern for DPP4 inhibitor use, other considerations should be made. DPP4 inhibitors tend to be more expensive than metformin or other second-line oral drugs in addition to having more modest glycemic effects than GLP-1R agonists (Munir and Lamos, 2017 ). Finally, meta-analysis of randomized and observational studies concluded that heart failure in patients with T2D was not associated with use of DPP4 inhibitors; however, this study was limited by the short follow-up and lack of high-quality data (Li et al., 2016 ). Thus, the US Food and Drug Administration (FDA) did recommend assessing risk of heart failure hospitalization in patients with pre-existing cardiovascular disease, prior heart failure, and chronic kidney disease when using saxagliptin and alogliptin (Munir and Lamos, 2017 ).

F. Sodium Glucose Cotransporter 2 Inhibitors

A recent development in the field of T2D drugs are sodium glucose cotransporter 2 (SGLT2) inhibitors, which have an interesting and very different mechanism of action. Within the proximal tubule of the nephron, SGLT2 transports ingested glucose into the lumen of the proximal tubule between the epithelial layers, thereby reclaiming glucose by this reabsorption process (reviewed in Vallon, 2015 ). SGLT2 inhibitors target this transporter and increase glucose in the tubular fluid and ultimately increase it in the urine. In patients with diabetes, SGLT2 inhibition results in a lowering of plasma glucose with urine glucose content rising substantially (Adachi et al., 2000 ; Vallon, 2015 ). These drugs, although they are relatively new, have become an area of great interest for not only patients with T2D (Grempler et al., 2012 ; Imamura et al., 2012 ; Meng et al., 2008 ; Nomura et al., 2010 ) but also for patients with T1D (Luippold et al., 2012 ; Mudaliar et al., 2012 ). Part of their appeal also rests on reports that their use can lead to a statistically significant decline in cardiac events that are known to occur secondarily to diabetes, possibly independently of plasma glucose regulation (reviewed in Kurosaki and Ogasawara, 2013 ). Although the long-term consequences of their clinical use cannot yet be determined, raising the glucose content of the urogenital tract leads to an increased risk of urinary tract infections and other related infections in some patients (Kurosaki and Ogasawara, 2013 ).

Another recent concern about the use of SGLT2 inhibitors has been the development of normoglycemic diabetic ketoacidosis (DKA). Despite the efficacy of SGLT2 inhibitors, observations of hyperglucagonemia in patients with euglycemic DKA has led to a number of recent studies focused on SGLT2 actions on pancreatic islets. Initial studies of isolated human islets treated with small interfering RNA directed against SGLT2 and/or SGLT2 inhibitors demonstrated increased glucagon release. These studies were complemented by the finding of elevations in glucagon release in mice that were administered SGLT2 inhibitors in vivo (Bonner et al., 2015 ). Insights into the possible mechanistic links between SGLT2 inhibition, DKA frequency, and glucagon secretion in humans may relate to the observation of heterogeneity in SGLT2 expression, as SGLT2 expression appears to have a high frequency of interdonor and intradonor variability (Saponaro et al., 2020 ). More recently, both insulin and GLP-1 have been demonstrated to modulate SGLT2-dependent glucagon release through effects on somatostatin release from delta cells (Vergari et al., 2019 ; Saponaro et al., 2019 ), suggesting potentially complex paracrine effects that may affect the efficacy of these compounds.

On the other hand, several recent studies question that the development of euglycemic DKA after SGLT2 inhibitor therapy may be through alpha cell–dependent mechanisms. Three recent studies found no effect of SGLT2 inhibitors to promote glucagon secretion in mouse and/or rat models and could not detect SGLT2 expression in human alpha cells (Chae et al., 2020 ; Kuhre et al., 2019 ; Suga et al., 2019 ). A fourth study demonstrated only a brief transient effect of SGLT2 inhibition to raise circulating glucagon concentrations in immunodeficient mice transplanted with human islets, which returned to baseline levels after longer exposures to SGLT2 inhibitors (Dai et al., 2020 ). Furthermore, SGLT2 protein levels were again undetectable in human islets (Dai et al., 2020 ). These results could suggest alternative islet-independent mechanisms by which patients develop DKA, including alterations in ketone generation and/or clearance, which underscore the additional need for further studies both in molecular models and at the bedside. Nevertheless, SGLT2 inhibitors continue to hold promise as a valuable therapy for T2D, especially in the large segment of patients who also have superimposed cardiovascular risk (McMurray et al., 2019; Wiviott et al., 2019; Zinman et al., 2015).

G. Thiazolidinediones

Once among the most commonly used oral agents in the armamentarium to treat T2D, thiazolidinediones (TZDs) were clinically popular in their utilization to act specifically as insulin sensitizers. TZDs improve peripheral insulin sensitivity through their action as peroxisome proliferator-activated receptor (PPAR) γ agonists, but their clinical use fell sharply after studies suggested a connection between cardiovascular toxicity with rosiglitazone and bladder cancer risk with pioglitazone (Lebovitz, 2019 ). Importantly, an FDA panel eventually removed restrictions related to cardiovascular risk with rosiglitazone in 2013 (Hiatt et al., 2013 ). Similarly, concerns regarding use of bladder cancer risk with pioglitazone were later abated after a series of large clinical studies found that pioglitazone did not increase bladder cancer (Lewis et al., 2015 ; Schwartz et al., 2015 ). However, usage of TZDs had already substantially decreased and has not since recovered.

Although concerns regarding edema, congestive heart failure, and fractures persist with TZD use, there have been several studies suggesting that TZDs protect beta cell function. In the ADOPT study, use of rosiglitazone monotherapy in patients newly diagnosed with T2D led to improved glycemic control compared with metformin or sulfonylureas (Kahn et al., 2006). Later analyses revealed that TZD-treated subjects had a slower deterioration of beta cell function than metformin- or sulfonylurea-treated subjects (Kahn et al., 2011). Furthermore, pioglitazone use improved beta cell function in the prevention of T2D in the ACT NOW study (Defronzo et al., 2013; Kahn et al., 2011). Mechanistically, it is unclear if TZDs lead to beneficial beta cell function through direct effects or through indirect effects of reduced beta cell demand due to enhanced peripheral insulin sensitivity. Indeed, a beta cell–specific knockout of PPAR γ did not impair glucose homeostasis, nor did it impair the antidiabetic effects of TZD use in mice (Rosen et al., 2003 ). However, other reports demonstrated PPAR-responsive elements within the promoters of both glucose transporter 2 and glucokinase that enhance beta cell glucose sensing and function, which could explain beta cell–specific benefits for TZDs (Kim et al., 2002 ; Kim et al., 2000 ). Furthermore, TZDs have been shown to improve beta cell function by upregulating cholesterol transport (Brunham et al., 2007 ; Sturek et al., 2010 ). Additionally, use of TZDs in the nonobese diabetic (NOD) mouse model of T1D augmented the beta cell unfolded protein response and prevented beta cell death, suggesting potential benefits for TZDs in both T1D and T2D (Evans-Molina et al., 2009 ; Maganti et al., 2016 ). With a now refined knowledge of demographics in which to avoid TZD treatment due to adverse effects, together with genetic approaches to identify candidates more likely to respond effectively to TZD therapy (Hu et al., 2019 ; Soccio et al., 2015 ), it remains to be seen if TZD therapy will return to more prominent use in the treatment of diabetes.

H. Insulin and Beyond: The Use of “Smart” Insulin and Closed Loop Systems in Diabetes Treatment

Due to recombinant DNA technology, numerous insulin analogs are now available in various forms ranging from fast acting crystalline insulin to insulin glargine; all of these analogs exhibit equally effective insulin receptor binding. Most are generated by altering amino acids in the B26–B30 region of the molecule (Kurtzhals et al., 2000 ). The American Diabetes Association delineates these insulins by their 1) onset or time before insulin reaches the blood stream, 2) peak time or duration of maximum blood glucose–lowering efficacy, and 3) the duration of blood glucose–lowering time. Insulin administration is independent of the residuum of surviving and/or functioning beta cells in the patient and remains the principal pharmacological treatment of both T1D and T2D. The availability of multiple types of delivery methods, i.e., insulin pens, syringes, pumps, and inhalants, provides clinicians with a solid and varied tool kit with which to treat diabetes. The downsides, however, are that 1) hypoglycemia is a constant threat, 2) proper insulin doses are not trivial to calculate, 3) compliance can vary especially in children and young adults, and 4) there can be side effects of a variety of types. Nonetheless, insulin therapy remains a mainstay treatment of diabetes.

To eliminate the downsides of insulin therapy, research in the past several decades has worked toward generating glucose-sensitive or “smart” insulin molecules. These molecules change insulin bioavailability and become active only upon high blood glucose using glucose-binding proteins such as concanavalin A, glucose oxidase to alter pH sensitivity, and phenylboronic acid (PBA), which forms reversible ester linkages with diol-containing molecules including glucose itself (reviewed in Rege et al., 2017 ). Indeed, promising recent studies included various PBA moieties covalently bonded to an acylated insulin analog (insulin detemir, which contains myristic acid coupled to Lys B29 ). The detemir allows for binding to serum albumin to prolong insulin’s half-life in the circulation, and PBA provided reversible glucose binding (Chou et al., 2015 ). The most promising of the PBA-modified conjugates showed higher potency and responsiveness in lowering blood glucose levels compared with native insulin in diabetic mouse models and decreased hypoglycemia in healthy mice, although the molecular mechanisms have not yet been determined (Chou et al., 2015 ).

An additional active area of research includes structurally defining the interaction between insulin and the insulin receptor ectodomain. Importantly, a major conformational change was discovered that may be exploited to impair insulin receptor binding under hypoglycemic conditions (Menting et al., 2013 ; Rege et al., 2017 ). Challenges in the design, testing, and execution of glucose-responsive insulins may be overcome by the adaptation of novel modeling approaches (Yang et al., 2020 ), which may allow for more rapid screening of candidate compounds.

Technologies have also progressed in the field of artificial pancreas design and development. Currently two “closed loop” systems are now available: Minimed 670G from Medtronic and Control-IQ from Tandem Diabetes Care. Both systems use a continuous glucose monitor, insulin pump, and computer algorithm to predict correct insulin doses and administer them in real time. Such algorithm systems also take into account insulin potency, the rate of blood glucose increase, and the patient’s heart rate and temperature to adjust insulin delivery levels during exercise and after a meal. In addition, so-called “artificial pancreas” systems have also been clinically tested, which use both insulin and glucagon and as such result in fewer reports of hypoglycemic episodes (El-Khatib et al., 2017 ). These types of systems will continue to become more popular as the development of room temperature–stable glucagon analogs continue, such as GVOKE by Xeris Pharmaceuticals (currently available in an injectable syringe) and Baqsimi, a nasally administered glucagon from Eli Lilly.

I. Present and Future Therapies: Beta Cell Transplantation, Replication, and Immune Protection

1. islet transplantation.

The idea to use pancreatic allo/xenografts to treat diabetes remarkably dates back to the late 1800s (Minkowski, 1892 ; Pybus, 1924 ; Williams, 1894 ). Before proceeding to the discovery of insulin (together with Best, MacLeod, and Collip), Frederick Banting also postulated the potential for transplantation of pancreatic tissue emulsions to treat diabetes in dog models in a notebook entry in 1921 (Bliss, 1982 ). Decades later, Paul Lacy, David Scharp, and colleagues successfully isolated intact functional pancreatic islets and transplanted them into rodent models (Kemp et al., 1973 ). These studies led to the initial proof of concept studies for humans, with the first successful islet transplant in a patient with T1D occurring in 1977 (Sutherland et al., 1978 ). A rapid expansion of islet transplantation, inspired by these original studies led to key observations of successfully prolonged islet engraftment by the “Edmonton protocol” whereby corticosteroid-sparing immunosuppression was applied, and islets from at least two allogeneic donors were used to achieve insulin independence (Shapiro et al., 2000 ). More recent work has focused on improving upon the efficiency and long-term engraftment of allogeneic transplants leading to more prolonged graft function (to the 5-year mark) and successful transplantation from a single islet donor (Hering et al., 2016; Hering et al., 2005 ; Rickels et al., 2013 ). Critical to these efforts to improve the success rate was the recognition that the earlier generation of immunosuppressive agents to counter tissue rejection was toxic to islets (Delaunay et al., 1997 ; Paty et al., 2002 ; Soleimanpour et al., 2010 ) and that more appropriate and less toxic agents were needed (Hirshberg et al., 2003 ; Soleimanpour et al., 2012 ).

Certainly, islet transplantation as a therapeutic approach for patients with T1D has been scrutinized due to several challenges, including (but not limited to) the lack of available donor supply to contend with demand, limited long-term functional efficacy of islet allografts, the potential for re-emergence of autoimmune islet destruction and/or metabolic overload-induced islet failure, and significant adverse effects of prolonged immunosuppression (Harlan, 2016 ). Furthermore, although islet transplantation is not currently available for individuals with T2D, simultaneous pancreas-kidney transplantation in T2D had similar favorable outcomes to simultaneous pancreas-kidney transplantation in T1D; therefore, islet-kidney transplantation may eventually be a feasible option to treat T2D, as patients will already be on immunosuppressors (Sampaio et al., 2011 ; Westerman et al., 1983 ). An additional significant obstacle is the tremendous expense associated with islet transplantation therapy. Indeed, the maintenance, operation, and utilization of an FDA-approved and Good Manufacturing Practice–compliant islet laboratory can lead to operating costs at nearly $150,000 per islet transplant, which is not cost effective for the vast majority of patients with T1D (Naftanel and Harlan, 2004 ; Wallner et al., 2016 ). At present, the focus has been to obtain FDA approval for islet allo-transplantation as a therapy for T1D to allow for insurance compensation (Hering et al., 2016; Rickels and Robertson, 2019 ). In the interim, the islet biology, stem cell, immunology, and bioengineering communities have continued the development of cell-based therapies for T1D by other approaches to overcome the challenges identified during the islet transplantation boom of the 1990s and 2000s.

2. Pharmacologic Induction of Beta Cell Replication

Besides transplantation, progress in islet cell biology and especially in developmental biology of beta cells over several decades raised the additional possibility that beta cell mass reduction in diabetes might be countered by increasing beta cell number through mitogenic means. A key method to expand pancreatic beta cell mass is through the enhancement of beta cell replication. Although the study of pancreatic beta cell replication has been an area of intense focus in the beta cell biology field for several decades, only recently has this seemed truly feasible. Seminal studies identified that human beta cells are essentially postmitotic, with a rapid phase of growth occurring in the prenatal period that dramatically tapers off shortly thereafter (Gregg et al., 2012 ; Meier et al., 2008 ). The plasticity of rodent beta cells is considerably higher than that of human beta cells (Dai et al., 2016 ), which has led to a renewed focus on validation of pharmacologic agents to enhance rodent beta cell replication using isolated and/or engrafted human islets (Bernal-Mizrachi et al., 2014 ; Kulkarni et al., 2012 ; Stewart et al., 2015 ). Indeed, a large percentage of agents that were successful when applied to rodent systems were largely unsuccessful at inducing replication in human beta cells (Bernal-Mizrachi et al., 2014 ; Kulkarni et al., 2012 ; Stewart et al., 2015 ). However, several recent studies have begun to make significant progress on successfully pushing human beta cells to replicate.

Several groups have reported successful human beta cell proliferation, both in vitro and in vivo, in response to inhibitors of the dual specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A). These inhibitors include harmine, INDY, GNF4877, 5-iodotubericidin, leucettine-42, TG003, AZ191, CC-401, and more specific, recently developed DYRK1A inhibitors (Ackeifi et al., 2020 ). Although DYRK1A is conclusively established as the important mediator of human beta cell proliferation, comprehensively determining other cellular targets and if additional gene inhibition amplifies the proliferative response is still in process. New evidence from Wang and Stewart shows dual specificity tyrosine phosphorylation-regulated kinase 1B to be an additional mitogenic target and also describes variability in the range of activated kinases within cells and/or levels of inhibition for the many DYRK1A inhibitors listed above (Ackeifi et al., 2020 ). Interestingly, opposite to these human studies, earlier mouse studies from the Scharfmann group demonstrated that Dyrk1a haploinsufficiency leads to decreased proliferation and loss of beta cell mass (Rachdi et al., 2014b ). In addition, overexpression of Dyrk1a in mice led to beta cell mass expansion with increased glucose tolerance (Rachdi et al., 2014a ).

Although important differences in beta cell proliferative capacity have been shown between human and rodent species, there are also significant differences in the mitogenic capacity of beta cells from juvenile, adult, and pregnant individuals. This demonstrates that proliferative stimuli appear to act within the complex islet, pancreas, and whole-body environments unique to each time point. For example, the administration of the hormones platelet-derived growth factor alpha or GLP-1 result in enhanced proliferation in juvenile human beta cells yet are ineffective in adult human beta cells (Chen et al., 2011 ; Dai et al., 2017 ). This has been shown to be due to a loss of platelet-derived growth factor alpha receptor expression as beta cells age but appears to be unrelated to GLP-1 receptor expression levels (Chen et al., 2011 ). Indeed, the GLP-1 receptor is highly expressed in adult beta cells, and GLP-1 secretion increases insulin secretion, as detailed previously; however, the induction of proliferative factors such as nuclear factor of activated T cells, cytoplasmic 1; forkhead box protein 1; and cyclin A1 is only seen in juvenile islets (Dai et al., 2017 ). Human studies using cadaveric pancreata from pregnant donors also showed increased beta cell mass, yet lactogenic hormones from the pituitary or placenta (prolactin, placental lactogen, or growth hormone) are unable to stimulate proliferation in human beta cells despite their ability to produce robust proliferation in mouse beta cells (reviewed in Baeyens et al., 2016 ). Experiments overexpressing mouse versus human signal transducer and activator of transcription 5, the final signaling factor inducing beta cell adaptation, in human beta cells allows for prolactin-mediated proliferation revealing fundamental differences in prolactin pathway competency in human (Chen et al., 2015 ). Overcoming the barrier of recapitulating human pregnancy’s effect on beta cells through isolating placental cells or blood serum during pregnancy may result in the discovery of a factor(s) that facilitates the increase in beta cell mass observed during human pregnancy.

Mechanisms that stimulate beta cell proliferation have also been discovered from studying genetic mutations that result in insulinomas, spontaneous insulin-producing beta cell adenomas. The most common hereditary mutation occurs in the multiple endocrine neoplasia type 1 (MEN1) gene. Indeed, administration of a MEN1 inhibitor in addition to a GLP-1 agonist (which cannot induce proliferation alone) is able to increase beta cell proliferation in isolated human islets through synergistic activation of KRAS proto-oncogene, GTPase downstream signals (Chamberlain et al., 2014 ). Interestingly, MEN1 mutations are uncommon in sporadic insulinomas, yet assaying genomic and epigenetic changes in a large cohort of non-MEN1 insulinomas found alterations in trithorax and polycomb chromatin modifying genes that were functionally related to MEN1 (Wang et al., 2017 ). Stewart and colleagues hypothesized that changes in histone 3 lysine 27 and histone 3 lysine 4 methylation status led to increased enhancer of zeste homolog 2 and lysine demethylase 6A, decreased cyclin-dependent kinase inhibitor 1C, and thereby increased beta cell proliferation, among other phenotypes. They also proposed that these findings help to explain why increased proliferation always occurs despite broad heterogeneity of mutations found between individual insulinomas (Wang et al., 2017 ).

Although factors that induce proliferation are continuing to be discovered, there are drawbacks that still limit their clinical application. Harmine and other DYRK1A inhibitors are not beta cell specific, nor have all their cellular targets been determined (Ackeifi et al., 2020 ). Targeting other pathways to induce human beta cell proliferation such as modulation of prostaglandin E2 receptors (i.e., inhibition of prostaglandin E receptor 3 alone or in combination with prostaglandin E receptor 4 activation) showed promising increases in proliferative rate yet suffers from the same lack of specificity (Carboneau et al., 2017 ). Induction of proliferation may also come at the expense of glucose sensing as in insulinomas, which have an increased expression of “disallowed genes” and alterations in glucose transporter and hexokinase expression (Wang et al., 2017 ). A further untoward consequence that must be avoided is the production of cancerous cells through unchecked proliferation. Finally, increasing beta cell mass through low rates of proliferation may increase the pool of functional insulin-secreting cells in T2D, but without additional measures, these beta cells will still ultimately be targeted for immune cell destruction in T1D.

3. Beta Cell Stress Relieving Therapies

Metabolic, inflammatory, and endoplasmic reticulum (ER) stress contribute to beta cell dysfunction and failure in both T1D and T2D. Although reduction of metabolic overload of beta cells by early exogenous insulin therapy or insulin sensitizers can temporarily reduce loss of beta cell mass/function early in diabetes, a focus on relieving ER and inflammatory stress is also of interest to preserve beta cell health.

ER stress is a well known contributor to beta cell demise both in T1D and T2D (Laybutt et al., 2007 ; Marchetti et al., 2007 ; Marhfour et al., 2012 ; Tersey et al., 2012 ) and a target of interest in the prevention of beta cell loss in both diseases. Preclinical studies suggest that the use of chemical chaperones, including 4-phenylbutyric acid and tauroursodeoxycholic acid (TUDCA), to alleviate ER stress improves beta cell function and insulin sensitivity in mouse models of T2D (Cnop et al., 2017 ; Ozcan et al., 2006 ). Furthermore, TUDCA has been shown to preserve beta cell mass and reduce ER stress in mouse models of T1D (Engin et al., 2013 ). Interestingly, TUDCA has shown promise at improving insulin action in obese nondiabetic human subjects, yet beta cell function and insulin secretion were not assessed (Kars et al., 2010 ). A clinical trial regarding the use of TUDCA for humans with new-onset T1D is also ongoing ( {"type":"clinical-trial","attrs":{"text":"NCT02218619","term_id":"NCT02218619"}} NCT02218619 ). However, a note of caution regarding use of ER chaperones is that they may prevent low level ER stress necessary to potentiate beta cell replication during states of increased insulin demand (Sharma et al., 2015 ), suggesting that the broad use of ER chaperone therapies should be carefully considered.

The blockade of inflammatory stress has long been an area of interest for treatments of both T1D and T2D (Donath et al., 2019 ; Eguchi and Nagai, 2017 ). Indeed, use of nonsteroidal anti-inflammatory drugs (NSAIDs), which block cyclooxygenase, have been observed to improve metabolic control in patients with diabetes since the turn of the 20th century (Williamson, 1901 ). Salicylates have been shown to improve insulin secretion and beta cell function in both obese human subjects and those with T2D (Fernandez-Real et al., 2008; Giugliano et al., 1985 ). However, another NSAID, salsalate, has not been shown to improve beta cell function while improving other metabolic outcomes (Kim et al., 2014 ; Penesova et al., 2015 ), possibly suggesting distinct mechanisms of action for anti-inflammatory compounds. The regular use of NSAIDs to enhance metabolic outcomes is also often limited to the tolerability of long-term use of these agents due to adverse effects. Recently, golilumab, a monoclonal antibody against the proinflammatory cytokine tumor necrosis factor alpha, was demonstrated to improve beta cell function in new-onset T1D, suggesting that targeting the underlying inflammatory milieu may have benefits to preserve beta cell mass and function in T1D (Quattrin et al., 2020). Taken together, both new and old approaches to target beta cell stressors still remain of long-term interest to improve beta cell viability and function in both T1D and T2D.

3. New Players to Induce Islet Immune Protection

Countless researchers have expended intense industry to determine T1D disease etiology and treatments focused on immunotherapy and tolerogenic methods. Multiple, highly comprehensive reviews are available describing these efforts (Goudy and Tisch, 2005 ; Rewers and Gottlieb, 2009 ; Stojanovic et al., 2017 ). Here we will focus on the protection of beta cells through programmed cell death protein-1 ligand (PD-L1) overexpression, major histocompatibility complex class I, A, B, C (HLA-A,B,C) mutated human embryonic stem cell–derived beta cells, and islet encapsulation methods.

Cancer immunotherapies that block immune checkpoints are beneficial for treating advanced stage cancers, yet induction of autoimmune diseases, including T1D, remains a potential side effect (Stamatouli et al., 2018 ; Perdigoto et al., 2019 ). A subset of these drugs target either the programmed cell death-1 protein on the surface of activated T lymphocytes or its receptor PD-L1 (Stamatouli et al., 2018 ; Perdigoto et al., 2019 ). PD-L1 expression was found in insulin-positive beta cells from T1D but not insulin-negative islets or nondiabetic islets, leading to the hypothesis that PD-L1 is upregulated in an attempt to drive immune cell attenuation (Osum et al., 2018 ; Colli et al., 2018 ). Adenoviral overexpression of PD-L1 specifically in beta cells rescued hyperglycemia in the NOD mouse model of T1D, but these animals eventually succumbed to diabetes by the study’s termination (El Khatib et al., 2015 ). A more promising report from Ben Nasr et al. ( 2017 ) demonstrated that pharmacologically or genetically induced overexpression of PD-L1 in hematopoietic stem and progenitor cells inhibited beta cell autoimmunity in the NOD mouse as well as in vitro using human hematopoietic stem and progenitor cells from patients with T1D.

As mentioned above, islet transplantation to treat T1D is limited by islet availability, cost, and the requirement for continuous immunosuppression. Islet cells generated by differentiating embryonic or induced pluripotent stem (iPS) cells could circumvent these limitations. Ideally, iPS-derived beta cells could be manipulated to eliminate the expression of polymorphic HLA-A,B,C molecules, which were found to be upregulated in T1D beta cells (Bottazzo et al., 1985 ; Richardson et al., 2016 ). These molecules allow peptide presentation to CD8+ T cells or cytotoxic T lymphocytes and may lead to beta cell removal. Interestingly, remaining insulin-positive cells in T1D donor pancreas are not HLA-A,B,C positive (Nejentsev et al., 2007; Rodriguez-Calvo et al., 2015 ). However, current differentiation protocols are still limited in their ability to produce fully glucose-responsive beta cells without transplantation into animal models to induce mature characteristics. Additionally, use of iPS-derived beta cells will still lead to concerns regarding DNA mutagenesis resulting from the methods used to obtain pluripotency or teratoma formation from cells that have escaped differentiation.

Encapsulation devices would protect islets or stem cells from immune cell infiltration while allowing for the proper exchange of nutrients and hormones. Macroencapsulation uses removable devices that would help assuage fears surrounding mutation or tumor formation; indeed, the first human trial using encapsulated hESC-derived beta cells will be completed in January 2021 ( {"type":"clinical-trial","attrs":{"text":"NCT02239354","term_id":"NCT02239354"}} NCT02239354 ). Macroencapsulation of islets prior to transplantation using various alginate-based hydrogels has historically been impeded by a strong in vivo foreign body immune response (Desai and Shea, 2017 ; Doloff et al., 2017 ; Pueyo et al., 1993 ). More recently, chemically modified forms of alginate that avoid macrophage recognition and fibrous deposition have been successfully used in rodents and for up to 6 months in nonhuman primates (Vegas et al., 2016 ). Indeed, Bochenek et al. ( 2018 ) successfully transplanted alginate protected islets for 4 months without immunosuppression in the bursa omentalis of nonhuman primates demonstrating the feasibility for this approach to be extended to humans. It remains to be seen if these devices will be successful for long-term use, perhaps decades, in patients with diabetes.

III. Summary

Although existing drug therapies using classic oral antidiabetic drugs like sulfonylureas and metformin or injected insulin remain mainstays of diabetes treatment, newer drugs based on incretin hormone actions or SGLT2 inhibitors have increased the pharmacological armamentarium available to diabetologists ( Fig. 1 ). However, the explosion of progress in beta cell biology has identified potential avenues that can increase beta cell mass in sophisticated ways by employing stem cell differentiation or enhancement of beta cell proliferation. Taken together, there should be optimism that the increased incidence of both T1D and T2D is being matched by the creativity and hard work of the diabetes research community.

Abbreviations

Authorship contributions.

Wrote and contributed to the writing of the manuscript: Satin, Soleimanpour, Walker

This work was supported by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [Grant R01-DK46409] (to L.S.S.), [Grant R01-DK108921] (to S.A.S.), and [Grant P30-DK020572 pilot and feasibility grant] (to S.A.S.), the Juvenile Diabetes Research Foundation (JDRF) [Grant CDA-2016-189] (to L.S.S. and S.A.S.), [Grant SRA-2018-539] (to S.A.S.), and [Grant COE-2019-861] (to S.A.S.), and the US Department of Veterans Affairs [Grant I01 BX004444] (to S.A.S.). The JDRF Career Development Award to S.A.S. is partly supported by the Danish Diabetes Academy and the Novo Nordisk Foundation.

https://doi.org/10.1124/pharmrev.120.000160

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