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The following represent additions to UpToDate from the past six months that were considered by the editors and authors to be of particular interest. The most recent What's New entries are at the top of each subsection.

ADRENAL DISORDERS

Crinecerfont for classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (August 2024)

Crinecerfont, an oral antagonist to the CRF type 1 receptor, is in development as adjunctive therapy for patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21-OHD CAH). In randomized trials in almost 300 children and adults with 21-OHD CAH managed with supraphysiologic glucocorticoid doses, participants assigned to crinecerfont had more effective suppression of androstenedione compared with placebo [ 1,2 ]. By trial end (24 to 28 weeks), participants taking crinecerfont achieved a greater reduction in glucocorticoid dose compared to placebo while maintaining androstenedione below mean baseline levels. Additional data are needed to determine optimal dosing and approach to adjustment of glucocorticoid doses for patients treated with crinecerfont. (See "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children" and "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in adults" .)

DIABETES MELLITUS

Investigational once-weekly basal insulin therapy (insulin efsitora) for diabetes management (October 2024)

Insulin efsitora alfa is an investigational, ultra-long-acting insulin. In a trial comparing once-weekly insulin efsitora with once-daily insulin degludec in 928 insulin-naïve adults with type 2 diabetes, mean change in A1C after 52 weeks was similar in both groups (-1.26 and -1.17 percentage points, respectively) [ 3 ]. Clinically significant (glucose <54 mg/dL [<3 mmol/L]) or severe hypoglycemia was infrequent and did not differ between treatments. In a parallel trial comparing insulin efsitora with insulin degludec in 692 adults with type 1 diabetes, the mean change in A1C after 26 weeks was comparable between groups (-0.51 and -0.56 percentage points, respectively) [ 4 ]. More participants in the efsitora group experienced severe hypoglycemia (10 versus 3 percent with degludec). Additional trials will help inform the potential clinical utility of insulin efsitora in the treatment of type 1 and type 2 diabetes. (See "General principles of insulin therapy in diabetes mellitus", section on 'Basal insulin analogs' .)

A1C values underestimate blood glucose in G6PD deficiency (September 2024)

Glycated hemoglobin (A1C) estimates average blood glucose over time. When red blood cell turnover increases, as in hemolytic anemias, there is less time for hemoglobin to be glycosylated, and the A1C underestimates glycemia. In a cohort study that evaluated nearly 4000 patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency and nearly 20,000 matched controls with similar fasting blood glucose values, individuals with G6PD deficiency had lower mean A1C levels, were less likely to have A1C ≥6.5, and, if they had diabetes, were less likely to be prescribed diabetes medications and more likely to have complications of diabetes [ 5 ]. These findings reinforce the importance of using other measures of glycemia in individuals with any type of hemolytic anemia. (See "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency", section on 'Underestimation of blood glucose by HbA1C' .)

Fenofibrate therapy and diabetic retinopathy progression (August 2024)

In a trial in 1151 adults with mild diabetic retinopathy (median triglyceride level 137 mg/dL, mean A1C 8.2 percent), participants who were randomly assigned to treatment with fenofibrate 145 mg daily had a lower rate of progression to referable retinopathy or maculopathy over a median follow-up of four years compared with those assigned to placebo (22.7 versus 29.2 percent, respectively) [ 6 ]. Fenofibrate therapy also reduced the incidence of macular edema. These protective effects were evident despite only an approximately 15 percent mean reduction in serum triglycerides. There was no effect on visual function or visual acuity. The main adverse effect of fenofibrate was a modest decline in estimate glomerular filtration rate. These findings add to the evidence reporting a reduction in retinopathy progression with fenofibrate and suggest benefit independent of triglyceride lowering. (See "Diabetic retinopathy: Prevention and treatment", section on 'Lipid-lowering therapy' .)

No reduction in diabetic retinopathy incidence with omega-3 fatty acid supplementation (June 2024)

Omega-3 fatty acids have shown protective effects in preclinical models of diabetic retinopathy. However, in a primary prevention cardiovascular outcome trial that randomly assigned 15,480 adults with diabetes to treatment with omega-3 fatty acids (1 mg daily) or placebo, no association was found between omega-3 fatty acid treatment and the incidence of referable retinopathy or maculopathy over 6.5 years of follow-up [ 7 ]. These findings argue against additive benefit of omega-3 fatty acid supplementation to glycemic and blood pressure management for retinopathy prevention. (See "Diabetic retinopathy: Prevention and treatment", section on 'Prevention' .)

Subcutaneous semaglutide and risk of kidney disease progression in type 2 diabetes (June 2024)

In a trial evaluating subcutaneous semaglutide (1 mg weekly) versus placebo in over 3500 adults with type 2 diabetes (mean age 67 years, mean A1C 7.8 percent) and chronic kidney disease (CKD; mean estimated glomerular filtration rate [eGFR] 47 mL/min/1.73 m 2 with median urinary albumin-to-creatinine ratio of 567 mg/g), semaglutide reduced the incidence of major kidney events (a composite of kidney failure onset, ≥50 percent reduction in eGFR from baseline, or kidney- or cardiovascular-related mortality) [ 8 ]. Benefits were observed specifically for reduction in eGFR from baseline and cardiovascular mortality. These findings further support the use of semaglutide in people with type 2 diabetes and CKD, particularly when substantial glucose and/or body weight lowering are major goals of care. (See "Management of persistent hyperglycemia in type 2 diabetes mellitus", section on 'Our approach' and "Glucagon-like peptide 1-based therapies for the treatment of type 2 diabetes mellitus", section on 'Microvascular outcomes' .)

Glucagon-like peptide 1 receptor agonist use and thyroid cancer risk (April 2024)

Preclinical studies suggest that glucagon-like peptide 1 (GLP-1) receptor agonists may increase risk of thyroid neoplasia, but whether clinical use of these agents increases thyroid cancer risk is uncertain. A recent cohort study evaluated thyroid cancer incidence in individuals initiating treatment with a GLP-1 receptor agonist (predominantly liraglutide and semaglutide ) compared with a dipeptidyl peptidase 4 (DDP-4) inhibitor. After a mean follow-up of 3.9 years, GLP-1 receptor agonist use was not associated with an increased risk of any thyroid cancer or medullary thyroid cancer [ 9 ]. DPP-4 inhibitors raise endogenous GLP-1 levels and therefore may not be an optimal comparator. Until more data are available, this study does not change our practice of avoiding GLP-1-based therapies in individuals with a personal or family history of medullary thyroid cancer or multiple endocrine neoplasia type 2A or 2B. (See "Glucagon-like peptide 1-based therapies for the treatment of type 2 diabetes mellitus", section on 'Other' .)

Extended-interval intravitreal aflibercept dosing for diabetic macular edema (April 2024)

For individuals with diabetic macular edema (DME) and impaired visual acuity, vascular endothelial growth factor (VEGF) inhibitors are often used as initial therapy. However, anti-VEGF therapy requires repeated intravitreal injections, contributing to nonadherence and undertreatment. In a 48-week trial of aflibercept in 660 adults (mean age 62 years) with type 1 or type 2 diabetes and center-involved DME, participants were randomly assigned to one of the following regimens after completing initial monthly dosing: 2 mg every 8 weeks (standard dosing), 8 mg every 12 weeks, or 8 mg every 16 weeks [ 10 ]. Improvement in visual acuity was similar among treatment groups (mean change +9.2, +8.8, and +7.9 letters, respectively). In individuals with center-involved DME,higher doses of aflibercept at extended intervals appear effective and may substantially reduce treatment burden. (See "Diabetic retinopathy: Prevention and treatment", section on 'Anti-VEGF agents' .)

FEMALE REPRODUCTION

Inositol appears ineffective for metabolic and endocrine outcomes in polycystic ovary syndrome (June 2024)

Inositol, in particular myo-inositol (MI), has been suggested as a potential therapy to improve insulin sensitivity and ovulation in patients with polycystic ovary syndrome. However, evidence to date does not support its use. In a systematic review and meta-analysis of five trials comparing MI to placebo, combined estrogen-progestin oral contraceptives, or MI with folic acid , no significant improvements in anthropometric (body mass index), metabolic (fasting insulin, fasting glucose, homeostasis model assessment of insulin resistance), or hormonal (luteinizing hormone, follicle-stimulating hormone, estradiol, serum androgens) measurements were observed [ 11 ]. (See "Treatment of polycystic ovary syndrome in adults", section on 'Ovulation induction medications' .)

Risk of suicide attempts in polycystic ovary syndrome (June 2024)

Depression and anxiety are common comorbidities in females with polycystic ovary syndrome (PCOS). PCOS may also be associated with an increased risk for suicide attempts, as reported in a longitudinal national registry study of PCOS patients and controls matched for age, psychiatric diagnoses, and socioeconomic status [ 12 ]. After 1 to 15 years of follow-up, PCOS patients had a higher rate of suicide attempts (3.0 versus 0.3 percent in controls). Although concerning, the quality of the evidence is low and should therefore be interpreted with caution. (See "Clinical manifestations of polycystic ovary syndrome in adults", section on 'Mood disorders' .)

Premature ovarian insufficiency and impaired sexual function (June 2024)

Premature ovarian insufficiency (POI) has been associated with impaired sexual function. In a meta-analysis of five studies in 352 females with POI, sexual function, measured using the Female Sexual Function Index, was significantly lower than in females without POI [ 13 ]. Systemic estrogen therapy was not associated with an improvement in sexual function. Dyspareunia was a common symptom in the POI group, but the impact of vaginal estrogen, an effective therapy for dyspareunia and other aspects of sexual health, was not addressed. (See "Clinical manifestations and diagnosis of primary ovarian insufficiency (premature ovarian failure)", section on 'Sexual health' .)

Bariatric surgery, ovulation, and polycystic ovary syndrome (June 2024)

Anovulatory infertility and obesity are common in patients with polycystic ovary syndrome (PCOS). In a randomized trial comparing laparoscopic sleeve gastrectomy with medical therapy ( metformin and/or orlistat ) in 80 patients with PCOS and body mass index ≥35 kg/m 2 , those assigned to surgery had 2.5 times more biochemically confirmed spontaneous ovulatory events and a healthier cardiometabolic and anthropometric profile at 52 weeks; however, they remained oligo-ovulatory [ 14 ]. Although these findings support use of bariatric surgery as a possible option for treating anovulatory infertility in patients with PCOS who cannot lose weight through behavior or medical therapy alone, limitations include nonuse of glucagon-like peptide 1 (GLP1) agonists, which are currently the preferred medical therapy of PCOS, and lack of information about subsequent pregnancy rates. (See "Outcomes of bariatric surgery", section on 'Polycystic ovary syndrome' .)

THYROID DISORDERS

Motorized rotating needle for fine-needle aspiration of thyroid nodules (October 2024)

A motorized rotating needle device has regulatory approval in the United States for soft tissue biopsy. There are now retrospective data using this device for thyroid fine-needle aspiration (FNA) biopsy. Compared with conventional FNA, FNA with the motorized rotating needle was associated with fewer passes to obtain an adequate sample and a lower nondiagnostic rate (2 versus 10 percent) [ 15 ]. Additional data will help inform the potential clinical utility of this device. (See "Thyroid biopsy", section on 'Other techniques' .)

Potassium iodide for the treatment of thyroid storm (July 2024)

Iodine-containing solutions have traditionally been used to treat thyroid storm since iodine blocks the release of thyroid hormone from the thyroid gland within hours. In a retrospective analysis of a Japanese database, use of potassium iodide (KI) within two days of hospital admission for thyroid storm was associated with reduced length of stay and reduced costs compared with nonuse [ 16 ]. Although there was no difference in mortality overall, the subgroup with Graves' disease had reduced mortality (2.8 versus 5.8 percent). Since the etiology of the thyrotoxicosis is frequently uncertain at the time of treatment, we administer KI one hour after the initiation of thionamides; this approach prevents the iodine from being used as substrate for new hormone synthesis in patients subsequently diagnosed with toxic adenoma or toxic multinodular goiter. (See "Thyroid storm", section on 'Iodine' .)

Decision analyses for selecting thyroid nodules for fine needle aspiration biopsy (July 2024)

The analysis of thyroid nodules for likelihood of malignancy using the American College of Radiology Thyroid Imaging, Reporting, and Data System (ACR-TIRADS) and others seems quantitative, but these approaches suffer from extensive interobserver variability. In a retrospective study, the addition of an artificial intelligence (AI) decision support system for radiologists interpreting thyroid ultrasounds improved sensitivity, specificity, positive and negative predictive values, and interobserver variability compared with unassisted ultrasound review [ 17 ]. With the AI system, 80 percent of nodules initially classified as ACR-TIRADS 3 ( table 1 ) were reclassified into a lower risk category, thereby eliminating the need for fine needle aspiration biopsy (FNA). Pending further validation, this approach holds promise for improving existing methods to select patients for FNA. (See "Diagnostic approach to and treatment of thyroid nodules in adults", section on 'Sonographic criteria for FNA' .)

Selection of therapy for Graves' hyperthyroidism (June 2024)

There are three effective treatment options for Graves' disease: antithyroid drugs (thionamides), radioiodine, and surgery ( table 2 ). Selection of therapy is generally based upon individual patient factors (eg, severity of hyperthyroidism, older age) as well as patient values and preferences. In a 2023 global survey of endocrinologists, 91.5 percent of respondents preferred antithyroid drugs, 7 percent radioiodine, and 1.5 percent surgery [ 18 ]. In the United States, the preference for radioiodine declined from 60 to 11 percent of clinicians between 2012 and 2023. The decline in selection of radioiodine treatment may be related to patient preference to avoid hypothyroidism, patient fears regarding radiation exposure, and the association of radioiodine with worsening thyroid eye disease. (See "Graves' hyperthyroidism in nonpregnant adults: Overview of treatment", section on 'Treatment options' .)

Epidemiology of myxedema coma in the United States (May 2024)

Myxedema coma is a rare presentation of hypothyroidism. A 2024 analysis of a national inpatient database in the United States provides new information on the epidemiology and prognosis of myxedema coma [ 19 ]. The estimated incidence in the United States is 2.6 cases per million persons per year. The estimated in-hospital mortality was 6.8 percent, compared with 0.7 percent for patients hospitalized for hypothyroidism without myxedema coma. This mortality rate is substantially lower than prior mortality estimates, which ranged from 30 to 50 percent. The reason for the lower mortality rate in this analysis is uncertain but may be related to inclusion of patients with less severe myxedema coma or to recent improvements in intensive care unit management. (See "Myxedema coma", section on 'Prognosis' .)

Selenium deficiency and autoimmune thyroid disease (April 2024)

Selenium deficiency has been shown to exacerbate autoimmune thyroid disease. Reports of selenium supplementation for the treatment of Hashimoto thyroiditis are conflicting. In a recent meta-analysis evaluating selenium supplementation in individuals from selenium-deficient regions (eg, Europe and Asia) with Hashimoto thyroiditis, there was a reduction in thyroid-stimulating hormone in patients who were not receiving thyroid hormone replacement (seven trials; standard mean difference -0.21) [ 20 ]. This modest benefit is likely restricted to people from selenium-deficient regions of the world. In the United States, the soil in most states is rich in selenium, suggesting selenium deficiency is rare. (See "Treatment of primary hypothyroidism in adults", section on 'Selenium deficiency' .)

OTHER ENDOCRINOLOGY

Palopegteriparatide for the treatment of hypoparathyroidism (August 2024)

Palopegteriparatide , a long-acting prodrug of PTH (1-34), received regulatory approval in the United States for the treatment of hypoparathyroidism [ 21 ]. In double-blind, randomized trials of palopegteriparatide, the addition of the prodrug reduced supplemental calcium and calcitriol requirements compared with placebo [ 22-24 ]. In addition, there was a decrease in 24-hour urinary calcium and improvement in kidney function and quality-of-life scores. Palopegteriparatide is an option for adults with chronic hypoparathyroidism who cannot maintain stable serum and urinary calcium levels with conventional therapy (calcium and active vitamin D). It may be preferred to teriparatide due to its longer half-life and once daily administration. Depending on cost concerns, however, teriparatide would be a reasonable alternative. (See "Hypoparathyroidism", section on 'PTH-based therapies' .)

• Sarafoglou K, Kim MS, Lodish M, et al. Phase 3 Trial of Crinecerfont in Pediatric Congenital Adrenal Hyperplasia. N Engl J Med 2024; 391:493.
• Auchus RJ, Hamidi O, Pivonello R, et al. Phase 3 Trial of Crinecerfont in Adult Congenital Adrenal Hyperplasia. N Engl J Med 2024; 391:504.
• Wysham C, Bajaj HS, Del Prato S, et al. Insulin Efsitora versus Degludec in Type 2 Diabetes without Previous Insulin Treatment. N Engl J Med 2024.
• Bergenstal RM, Philis-Tsimikas A, Wysham C, et al. Once-weekly insulin efsitora alfa: Design and rationale for the QWINT phase 3 clinical development programme. Diabetes Obes Metab 2024; 26:3020.
• Israel A, Raz I, Vinker S, et al. Type 2 Diabetes in Patients with G6PD Deficiency. N Engl J Med 2024; 391:568.
• Preiss D, Logue J, Sammons E, et al. Effect of Fenofibrate on Progression of Diabetic Retinopathy. NEJM Evid 2024; 3:EVIDoa2400179.
• Sammons EL, Buck G, Bowman LJ, et al. ASCEND-Eye: Effects of Omega-3 Fatty Acids on Diabetic Retinopathy. Ophthalmology 2024; 131:526.
• Perkovic V, Tuttle KR, Rossing P, et al. Effects of Semaglutide on Chronic Kidney Disease in Patients with Type 2 Diabetes. N Engl J Med 2024; 391:109.
• Pasternak B, Wintzell V, Hviid A, et al. Glucagon-like peptide 1 receptor agonist use and risk of thyroid cancer: Scandanavian cohort study. BMJ 2024; 385:e078225.
• Brown DM, Boyer DS, Do DV, et al. Intravitreal aflibercept 8 mg in diabetic macular oedema (PHOTON): 48-week results from a randomised, double-masked, non-inferiority, phase 2/3 trial. Lancet 2024; 403:1153.
• Fitz V, Graca S, Mahalingaiah S, et al. Inositol for Polycystic Ovary Syndrome: A Systematic Review and Meta-analysis to Inform the 2023 Update of the International Evidence-based PCOS Guidelines. J Clin Endocrinol Metab 2024; 109:1630.
• Hsu TW, Kao YC, Tsai SJ, et al. Suicide Attempts After a Diagnosis of Polycystic Ovary Syndrome : A Cohort Study. Ann Intern Med 2024; 177:335.
• van Zwol-Janssens C, Pastoor H, Laven JSE, et al. Sexual function in women with premature ovarian insufficiency (POI): Systematic review and meta-analysis. Maturitas 2024; 184:107994.
• Samarasinghe SNS, Leca B, Alabdulkader S, et al. Bariatric surgery for spontaneous ovulation in women living with polycystic ovary syndrome: the BAMBINI multicentre, open-label, randomised controlled trial. Lancet 2024; 403:2489.
• Verma A, McDowell R, Porreca A. Fine Needle Aspiration Versus the CytoCore® Motorized Rotating Needle Device for Thyroid Nodule Biopsies: A Retrospective Cohort Study. Acta Cytol 2024; :1.
• Matsuo Y, Miyawaki A, Watanabe H, et al. Potassium Iodide Use and Patient Outcomes for Thyroid Storm: An Observational Study. J Clin Endocrinol Metab 2024.
• Fernández Velasco P, Pérez López P, Torres Torres B, et al. Clinical Evaluation of an Artificial Intelligence-Based Decision Support System for the Diagnosis and American College of Radiology Thyroid Imaging Reporting and Data System Classification of Thyroid Nodules. Thyroid 2024; 34:510.
• Villagelin D, Cooper DS, Burch HB. A 2023 International Survey of Clinical Practice Patterns in the Management of Graves' Disease: A Decade of Change. J Clin Endocrinol Metab 2024.
• Chen DH, Hurtado CR, Chang P, et al. Clinical Features and Outcomes of Myxedema Coma in Patients Hospitalized for Hypothyroidism: Analysis of the United States National Inpatient Sample. Thyroid 2024; 34:419.
• Huwiler VV, Maissen-Abgottspon S, Stanga Z, et al. Selenium Supplementation in Patients with Hashimoto Thyroiditis: A Systematic Review and Meta-Analysis of Randomized Clinical Trials. Thyroid 2024; 34:295.
• https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-new-drug-hypoparathyroidism-rare-disorder (Accessed on August 28, 2024).
• Khan AA, Rejnmark L, Rubin M, et al. PaTH Forward: A Randomized, Double-Blind, Placebo-Controlled Phase 2 Trial of TransCon PTH in Adult Hypoparathyroidism. J Clin Endocrinol Metab 2022; 107:e372.
• Khan AA, Rubin MR, Schwarz P, et al. Efficacy and Safety of Parathyroid Hormone Replacement With TransCon PTH in Hypoparathyroidism: 26-Week Results From the Phase 3 PaTHway Trial. J Bone Miner Res 2023; 38:14.
• Rejnmark L, Gosmanova EO, Khan AA, et al. Palopegteriparatide Treatment Improves Renal Function in Adults with Chronic Hypoparathyroidism: 1-Year Results from the Phase 3 PaTHway Trial. Adv Ther 2024; 41:2500.

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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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Major Advances and Discoveries in Diabetes - 2019 in Review

Juleen r zierath.

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Issue date 2019.

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/ ), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

This review is based on a recent invited lecture at the American Diabetes Association’s 79th annual Scientific Sessions entitled “Major Advances and Discoveries in Diabetes - The Year in Review.”

Recent Findings

Here I provide a written account of my presentation entitled “Major Discoveries in Diabetes over the Past Year.” I highlight several recent advances in basic science that are relevant for the diabetes field, with insight into how the key takeaways impact basic science. I also speculate on how these breakthroughs challenge the field to move the basic science “discovery” into the clinic, as well as offering a perspective on unanswered questions in relation to these advances.

The review should in no way be taken as an endorsement of the highlighted work or a denunciation of any work not selected. Rather, it is a personal reflection that provides a glimpse into what is on the horizon in this rapidly evolving and exciting field!

Keywords: Diabetes, Metabolism, Obesity, Insulin resistance, Clinical physiology, Molecular biology

Introduction

Last February, I received an email from the American Diabetes Association’s (ADA) Scientific Sessions Planning Committee inviting me to participate as a speaker at the 79th annual meeting. I have always enjoyed attending the ADA Scientific Sessions, having done so each year since enrolling in my doctoral studies at Karolinska Institutet. In fact, my first scientific presentation in the diabetes field was communicated as a poster at the 50th annual meeting in 1990. Throughout my career, my interests have been focused on the pathophysiology of type 2 diabetes. In particular, on the role of epigenetic modifications in the development insulin resistance, as well the interaction between circadian rhythms and the metabolic response to exercise. The overarching goal of this research is to identify and validate molecules, pathways and ultimately new treatments that confer the benefits of exercise to improve insulin sensitivity, and attenuate the loss of skeletal muscle function with aging and type 2 diabetes. Needless to say, I was taken aback when I read the title of the proposed session - “Major Advances and Discoveries in Diabetes - The Year in Review.” This was a new concept that the program committee was exploring and they invited me and Dr. Daniel J. Drucker to be their test drivers. The session was divided into two parts to highlight “ Major Breakthroughs ” in the Clinic and at the Bench. Dr. Drucker was asked to speak about clinical developments, and I was tasked with covering advances in basic science. The session was designed to facilitate discussions between clinicians and basic scientists, with the hope of enlightening basic scientists on the latest clinical advancements and clinicians on where the field is headed in terms of bench research.

With this review, I will provide a written account of my presentation entitled “ Major Discoveries in Diabetes over the Past Year. ” I will highlight a few recent advances in basic science and give my perspective on unanswered questions and unmet needs in relationship to these advances from published literature over the last 12–18 months. Before commencing, I wish to share a few words about the process I took to select the different “ Major Breakthroughs. ” Each year, thousands of articles are written on different aspects of diabetes research and care. My initial reaction when I accepted this task was that I would never be able to go through all of this literature in the few months I had to prepare. Even if I had unlimited time to review all of the papers published over this period, any short-list would simply be my own view. Certainly another person facing the same challenge may come up with a completely different list. Diabetes is a huge field and I did not want the session to be limited to my views on this broad topic. I felt for this topic to be of interest to a wider audience, diverse views from people at different career stages and scientific interests needed to be taken into account. Consequently, I sought input from my research group and other colleagues in the field by asking “ What do you think is the major breakthrough in the field this year ”?

In the early spring, I met with my team to discuss several dozen papers highlighting potential “ Major Breakthroughs ” in diabetes research. We interrogated this literature by asking: 1) What was the question raised? 2) What did they find? 3) How does this impact basic science? 4) What was the key takeaway from the study? 5) What were the limitations? 6) What are the challenges to move the “discovery” into the clinic? In the end, we pruned the list to 19 papers. I will briefly review these papers by taking these questions into account. A caveat with shortlisting a few select papers is that I likely have missed one of your favorite discoveries or advances. Thus, I apologize in advance for any omissions. Importantly, the fact that I have selected one paper over another is by no means an endorsement of the highlighted work or a denunciation of any work not selected.

Many Subgroups of Type 2 Diabetes

For decades, diabetes has been classified into two forms, based on the presence (type 1 diabetes) or the absence (type 2 diabetes) of autoantibodies against pancreatic islet β-cell antigens and age at diagnosis. Nevertheless, diabetes is a highly heterogeneous disorder and consequently current classifications are not sufficient for disease stratification and outcome prediction. Indeed, this is exemplified by the identification of a third subgroup of diabetes termed “latent autoimmune diabetes in adults” that is diagnosed by the presence of glutamic acid decarboxylase antibodies. Refining diabetes classification based on biomarkers and deep phenotyping may bring clinicians closer to personalized medicine and better assessment of the risk of complications at diagnosis.

To assess whether type 2 diabetes is a uniform disease and if the response to intervention can be predicted based biomarkers, Leif Groop and colleagues [ 1 ] performed a “data-driven” cluster analysis in patients with newly diagnosed diabetes from the Swedish All New Diabetics in Scania cohort. Clusters were based on six variables including glutamate decarboxylase antibodies, age at diagnosis, body mass index (BMI), glycated hemoglobin (HbA1c), and homeostatic model assessment 2 estimates of β-cell function and insulin resistance, and were related to prospective data from patient records on the development of complications and prescription of medication. The study was replicated in three independent cohorts. The authors identified five novel subgroups of adult-onset diabetes and their association with clinical outcomes including severe autoimmune diabetes (SAID); severe insulin-deficient diabetes (SIDD); severe insulin-resistant diabetes (SIRD); mild obesity-related diabetes (MOD); and mild age-related diabetes (MARD). The authors propose that the combined information from the six variables, which are central to the development of diabetes, offers a superior metric for sub-classification of type 2 diabetes versus the conventional assessment of glucose levels. They conclude that implementation of this new substratification may eventually help to tailor and target early treatment to patients, thereby representing a first step towards precision medicine in diabetes. In addition to the obvious clinical advances from this study directed towards improving the care of people living with diabetes, these findings also impact basic science. Each subgroup might differ from a genetic or epigenetic perspective, and thus understanding the biology associated with each subtype may uncover novel molecular mechanisms controlling glucose homeostasis and complications arising from diabetes. Nevertheless, this study has some limitations in that only a few markers were identified and this approach may not necessarily reveal all of the subgroups of type 2 diabetes. Other limitations include that these phenotypic variables may change throughout the disease course, such that they can only be applied at the time the clusters were derived here, i.e. soon after disease onset; and that one thing is to derive clusters from a large body of data and quite another to be able to place an individual categorically within a cluster, given the quantitative distribution of these variables in people. However, the clustering approach has direct clinical relevance and can be readily applied to existing cohorts, moving the field one step closer to personalized medicine. In addition, the stratification offers insight into the progression of disease over time and insight into risk for complications including chronic kidney disease and retinopathy. Clinicians may also use these markers to stratify patients to assess outcomes to different therapeutic interventions.

Studying Obesity to Learn More about Thinness

Obesity is a chronic lifelong condition that results from the interaction between heritable factors with environmental influences. Excess fat accumulation due to an imbalance between energy intake and expenditure causes obesity. The increasing prevalence of obesity is recognized as a major risk for a variety of diseases including type 2 diabetes, cardiovascular disease, cancer, and musculoskeletal disorders. Given that obesity is a driving force behind the diabetes epidemic, better adherence to exercise and diet regimes, as well as safe, effective and durable weight loss therapies are needed. To this end, I. Sadaf Farooqi and colleagues [ 2 ] studied the melanocortin 4 receptor (MC4R), a brain-expressed G protein coupled receptor (GPCR) involved in weight regulation. The authors were interested in gaining a more refined understanding of MC4R signaling and its impact on clinical phenotypes. Such knowledge could inform the design of drugs targeting this pathway to treat common obesity and its complications. Earlier studies report a frameshift mutation in MC4R that reduces Gαs-mediated cyclic adenosine monophosphate accumulation is associated with dominantly inherited obesity in humans [ 3 , 4 ]. Here, the authors characterized 61 MC4R variants identified in 0.5 million people from the UK Biobank and examined the associations of these variants with BMI and obesity-related cardiometabolic diseases. They found that gain-of-function variants in the MC4R gene were associated with lower BMI and lower odds of obesity, type 2 diabetes, and coronary artery disease. These variants exhibited a signaling bias for the recruitment of β-arrestin, rather than canonical Gαs-mediated cAMP production. One limitation of the study is that the functional characterization of this obesity protective variant was performed in cell culture models. Thus, the authors provide indirect evidence for a genetic association between the variant and the clinical features of the carriers. To move this discovery into the clinic, additional functional validation using in vivo models would be required to confirm the protective effects of this variant on energy homeostasis and the development of cardiometabolic impairments. Pharmacological studies are also warranted, with exploratory efforts directed towards the development of preferential agonists rather than broad spectrum agonists with a bias towards β-arrestin signaling for weight loss and for the treatment of obesity-associated metabolic disease. Overall, the authors provide insight into molecular mechanisms underpinning genetic associations with the development and protection against obesity and cardiometabolic diseases.

New Insight into Insulin Signaling

The canonical signal transduction pathways controlling glucose metabolism involve insulin binding to the insulin receptor α-subunit, followed by autophosphorylation of the β-subunit, leading to activation of down-stream signaling events. Insulin-receptor substrates are regulatory docking proteins that associate with the insulin receptor and play a central role in the selection and differentiation of the insulin signal towards further metabolic or mitogenic events. Two papers that gained particular attention this year dealt with novel aspects of the insulin signaling cascade [ 5 , 6 ]. The insulin receptor is a cell-surface receptor, however, John G. Flanagan and colleagues [ 5 ] asked whether there is a non-canonical pathway, whereby the insulin receptor play a role within the nucleus and exerts long-term effects of insulin including transcriptional regulation. They provide evidence that the insulin receptor translocates to the nuclei and interacts with transcriptional machinery at promoters, thereby identifying a novel non-canonical pathway regulating target genes highly enriched for insulin-related functions including lipid metabolism and protein synthesis and diseases including diabetes, neurodegeneration, and cancer. This finding may have relevance for type 2 diabetes, given that insulin receptor binding was impaired in an insulin-resistant disease model. However, the mechanism was mainly elucidated in HepG2 cells and ob / ob mice. Thus, further evidence from clinical material from people with diabetes studied under physiological conditions is required before fully understanding the impact of this pathway in the pathophysiology of insulin resistance in humans. Moreover, the importance of this pathway for gene regulation versus the canonical signaling pathway for metabolic regulation needs to be elucidated. Insulin receptor translocation to the nuclei is however a new pathway to enhance our understanding of insulin signaling and insulin resistance.

Mutations in the insulin receptor cause severe forms of insulin resistance [ 7 ]. Keeping with the theme of insulin receptor signaling, Nicolas Rohner and colleagues [ 6 ] used a rather unconventional model to study diabetes-associated pathologies, namely the cave-dwelling fish species A. mexicanus (cavefish). They found that these particular cavefish had higher fasting blood glucose levels and insulin resistant features that were attributed to a mutation in the insulin receptor that decreased insulin binding. The hyperglycemic insulin receptor mutant cavefish, paradoxically were otherwise healthy and had a normal life span. The cavefish may have acquired compensatory mechanisms to circumvent the typical deleterious effects associated with insulin resistance and hyperglycemia. In this case, reduced insulin signaling may be beneficial in a nutrient-limited environment. Despite the fact that this study was conducted in cavefish, there may be some translation to humans. The mutation identified in the insulin receptor of these cavefish is implicated in at least two known cases of the Rabson-Mendenhall syndrome, a form of severe insulin resistance in humans. A deeper analysis of these mutant cavefish might uncover an underlying evolutionary force responsible for the striking metabolic adaptations. Identification of the putative mechanisms allowing the mutant cavefish to thrive despite severe insulin resistance and hyperglycemia could be relevant for the treatment of hyperglycemia-related complications in people with diabetes.

Breakthroughs in Islet Cell Biology

Autoimmune destruction of insulin-producing pancreatic β cells, resulting in persistent hyperglycemia, underlies the pathogenesis of type 1 diabetes. Preserving and restoring functional β-cell mass is therefore a fundamental objective of diabetes therapy. However, adult human β cells have limited regeneration potential, therefore the possibility of reprogramming other cell types into glucose-responsive, insulin-secreting β-like cells is being actively pursued. Pancreatic α cells represent a potential source of β-like cells due to their developmental similarities and their location in the pancreatic islet. Moreover, a marked decrease in α cells in mice does not affect normal glucose metabolism. Pedro L. Herrera and colleagues interrogated mechanisms regulating islet cell plasticity [ 8 , 9 ]. They determined the cellular mechanisms regulating the expression of insulin in glucagon + α cells with a focus on the “brake” signals [ 8 ]. They found that paracrine repressive signals originating from β and δ cells maintain the α-cell identity, with a constant repressive influence of somatostatin and insulin. Local signals drive the conversion of α-cells, such that inhibition of proximal β and δ cells leads to a substantial increase in insulin + α-cell numbers. Finally, they report that α-cell conversion is only partially improved by dual inhibition of insulin and somatostatin signals, which suggests that α-cell conversion is synergistically influenced by multiple signals. These findings provide mechanistic insights into how the cell identity–differentiation equilibrium is established and advice the notion that differentiated cells maintain some “plasticity potential”. One key takeaway from this study is the finding that spontaneous insulin production in α cells is not simply due to uncontrolled stress-induced insulin gene dysregulation, but is dynamically regulated, representing a physiological compensatory response to cope with insulin insufficiency. A limitation of the work is the lack of long-term, detailed metabolic studies, and a focus primarily on rodent cells. To move this discovery into the clinic, additional studies using human cells, as well a thorough characterization of the signals that promote insulin production in α cells are warranted.

In a complementary study using islets from donors with and without diabetes they addressed the notion of “cell-identity switches”, a process in which terminally differentiated cells are converted into different cell types when stressed [ 9 ]. They found that α cells and polypeptide-producing γ cells, obtained from pancreatic islet cells from deceased human donors with and without diabetes, can be lineage traced and reprogrammed by the transcription factors PDX1 and MAFA to produce and secrete insulin in a glucose-responsive manner. The modified α cells triggered a weaker immune response when co-cultured with T cells from people with type 1 diabetes, and thus might be less likely to be destroyed than native β cells as they retain the α-cell identity. When transplanted into diabetic mice, the converted human α cells ameliorated diabetes and produced insulin for several months. These findings advance basic science in that they may lead to the identification of a gene signature to confer glucose-stimulated insulin secretion to non-β cells, possibly through small-molecule screening. This study provides conceptual evidence for islet plasticity of human cells and confirms that cell identity and maturity are flexible states. To move this “discovery” into the clinic, further work is required to elucidate pharmacological or gene therapy approaches to stimulate cell interconversion within the patient’s own pancreas, but without causing adverse effects on other cell types.

In addition to the cell reprogramming strategies highlighted above, other groups are working to restore insulin-producing β cells by immunomodulation approaches to suppress the autoimmune attack characteristic of type 1 diabetes. This is a clinically relevant approach since type 1 diabetes is characterized by pancreatic islet infiltration by autoreactive immune cells and a nearly complete loss of β cells. Using several genetically modified mouse models of severe diabetes, Rohit N. Kulkarni and colleagues [ 10 ] report that enhancing β-cell proliferation before an immune attack provides protection against the development of type 1 diabetes by preserving the immunological self-tolerance of islets through the induction of regulatory T cells. This study advances the notion that increased β-cell proliferation early in life, before immune cell invasion, prevents the progression of type 1 diabetes. While the translational significance of the findings in mouse models to human type 1 diabetes needs to be determined, the findings suggest that parental history of diabetes, or alterations secondary to obesity, type 2 diabetes, or the sex of the parent, may affect β-cell proliferation in offspring and the identity of β cells to influence the onset of type 1 diabetes in the offspring. Moving forward, future studies to determine the factors that impact the identity of β cells and trigger type 1 diabetes in the offspring are required.

The Gut Microbiome and Metabolism

The gut microbiome has co-evolved with its host and influences health and disease throughout the lifespan. Interactions between the gut microbiota, diet, and the host have been associated with metabolic diseases including obesity, diabetes, and cardiovascular disease. Nevertheless this link is often correlative, with only a few studies investigating whether specific microbiota or microbiota-dependent metabolites can directly affect metabolic homeostasis. Microbiota-dependent metabolites in systemic circulation may influence peripheral organs and modify insulin sensitivity. Fredrik Bäckhed and colleagues [ 11 ] performed a metabolomics screen of plasma from patients with type 2 diabetes and severe obesity, and BMI-matched subjects without diabetes to identify circulating amino acid-derived metabolites. They found the concentration of imidazole propionate, a microbially produced amino acid-derived metabolite, was higher in portal and peripheral blood from the obese people with type 2 diabetes. They also reported that daily injection of imidazole propionate into germ-free mice impairs glucose tolerance and insulin signaling, suggesting imidazole propionate directly affects glucose metabolism. Using a variety of cell models, they also report that imidazole propionate inhibits insulin receptor substrate signaling through mTORC1. The key finding is the identification of imidazole propionate, a microbiota-dependent metabolite, which is coupled to the development of insulin resistance. Nevertheless, there are some caveats as this metabolite is unlikely to cause all forms of type 2 diabetes. The authors measured imidazole propionate levels in obese people with or without type 2 diabetes and a different profile may emerge for moderately overweight or normal weight people with insulin resistance or type 2 diabetes. Given that dietary factors influence the gut microbiome, clarification of the interplay between diets, bacteria and the gut environment would also be important to understand, as different macro or micro nutrients may influence the metabolomics profile in people with type 2 diabetes or obesity. Finally, to move this “discovery” into the clinic, further insight into the identity of the molecular mechanism and signaling pathways induced by imidazole propionate or other microbiota-dependent metabolites may reveal pharmacological targets to treat metabolic diseases.

Endothelial-to-Adipocyte Extracellular Vesicle Cross-Talk

An area of fertile research is the identification of systemic factors that integrate the individual organ response with the entire body. Many researchers have been focused on identifying secreted proteins (“ tissue-kines” ) that are produced and released by various organs that exert autocrine, paracrine and/or endocrine effects on tissue-specific or whole body glucose or energy homeostasis. Philipp E. Scherer and colleagues [ 12 ] have discovered the existence of extracellular vesicle-mediated signal transduction between cell types within adipose tissue. This unexpected finding was made when the team generated an adipocyte-specific caveolin 1 knockout mouse. Caveolin 1 is a membrane-bound structural and signaling protein that is highly abundant in adipocytes and endothelial cells. Although they were successful in ablating the caveolin 1 gene from adipocytes, unexpectedly, the protein remained abundant in the cells. They found that endothelial cells in close proximity to the adipocytes delivered caveolin 1 protein in extracellular vesicle to the cells. They uncovered a network of extracellular vesicle-mediated exchange of cellular material exists in adipose tissue, whereby this exchange can replace protein levels of caveolin 1 in adipocytes despite gene disruption. This extracellular vesicle trafficking process is regulated by the systemic metabolic state and requires communication between endothelial cells in order to package the extracellular cargo into vesicles for release into the adipose tissue. The study uncovers new insight into the complex signaling mechanisms that exist among various cell types including adipocytes and vascular cells, which may also affect distal organs. The transfer of cargo packaged in these extracellular vesicles is not a passive process, but rather a physiologically regulated event, participating in the tissue response to changes in the systemic nutrient state induced by fasting/refeeding paradigms or obesity. The study has implications for the interpretation of tissue-specific knockout models and importance of single cell sequencing. While the clinical relevance may not be immediately obvious, the findings may advance the development of tissue-specific drug delivery systems by targeting endogenous extracellular vesicles or engineering biosynthetic vesicles to treat diabetes.

New Insight into an Old Drug - Metformin

Metformin is one of the most widely prescribed drugs to treat type 2 diabetes [ 13 ]. The drug was first used to treat diabetes over 60 years ago and is currently recommended in many clinical guidelines on the management of type 2 diabetes as the first-line oral glucose-lowering agent. Metformin mainly works by inhibiting hepatic glucose production, and enhancing insulin sensitivity. Nevertheless, the precise mode of action for the glucose lowering effects of metformin remain somewhat elusive and several mechanisms have been evoked including inhibition of mitochondrial respiration, elevation of 5′-adenosine monophosphate (AMP) levels, and activation of AMP-kinase. Kei Sakamoto and colleagues [ 14 ] revisit this question and ask whether metformin targets the AMP-inhibited enzyme fructose-1,6-bisphosphatase-1 (FBP1) to lower hepatic glucose production. They found that metformin induces a mild energy stress in liver, thereby increasing the AMP concentration, which allosterically inhibits the AMP-inhibited enzyme FBP1, to lower hepatic glucose production. Using molecular approaches, they identified a point mutation in FBP1 that rendered it insensitive to AMP. Thereafter, they studied “knock-in” mice harboring the mutant form of FBP1 and found they are insensitive to metformin. The authors discovered that FBP1, a rate-controlling enzyme in gluconeogenesis, functions as a major contributor to the therapeutic action of metformin. These results are clinically relevant and suggest that FBP1 could be a key target for the treatment of type 2 diabetes, either directly using targeted inhibition, or indirectly as a consequence of inducing energy stress.

Timing Matters - Aligning the Circadian Clock with Environmental Cues, with Implications for Chronomedicine to Treat Metabolic Diseases

The next set of “Major Discoveries” are focused on recent advances in circadian biology, including mechanism of action, impact on cellular and whole-body metabolism, and alignment of the circadian clock with diet and exercise paradigms. Circadian rhythms are controlled by central and peripheral molecular clocks that anticipate day/night cycles to optimize numerous physiological and behavioral responses over a ~24 h cycle. Perturbed circadian rhythms are associated with metabolic dysfunction, obesity, and type 2 diabetes [ 15 ]. Over the past years, there has been a surge in interest in understanding how an alignment between the molecular circadian clocks and hormone action or environmental cues (diet, exercise, and sleep) can affect metabolism.

Insight from Structural Biology or Melatonin Receptors

Melatonin is a hormone that is involved in synchronizing circadian rhythms and regulating the sleep–wake cycle. One new advance in receptor biology, by Vadim Cherezov and colleagues [ 16 ] deals specifically with the structural biology of the melatonin receptors MT1 and MT2, two GPCRs involved in the regulation of circadian rhythm and sleep patterns. These receptors are candidates for drug development efforts to treat insomnia, circadian rhythm and mood disorders, cancer, and type 2 diabetes. The authors used mutated and stabilized MT2 to determine structural differences to MT1, as well as altered melatonin dissociation kinetics. The authors reveal insight into the molecular understanding of melatonin receptor subtype selectivity and ligand access modes, which may be important for the design of selective melatonin tool compounds and therapeutic agents that will help to dissect the melatonin system. Single-nucleotide polymorphisms associated with type 2 diabetes mapped onto MT2 structure clustered at residues near the ligand binding pocket, and receptor surface. This implies that single-nucleotide polymorphisms associated with altered melatonin sensing may be involved in the pathogenesis of type 2 diabetes, but this finding requires additional confirmation and physiological validation. The potential long-term outcome from this work may be the development of therapies targeted towards melatonin receptors for the treatment of type 2 diabetes and metabolic disease. Nevertheless, the realization of this goal may be decades away.

Insulin Resets the Clock

Circadian rhythms are generated by an auto-regulatory transcriptional-translational feedback loop composed of positive regulators (CLOCK/BMAL1) and repressors (CRY1/2 and PER1/2) that control a large fraction of protein coding genes in mammalian cells. The central clock located in the suprachiasmatic nuclei of the hypothalamus is mainly entrained by light, while peripheral clocks respond to external cues including temperature, feeding/fasting cycles, exercise and hormones. Recent work by John S. O’Neill and colleagues [ 17 ] tested whether insulin and insulin-like growth factor 1 (IGF1), two hormones important for the control of growth and metabolism, provide signals to the molecular clock machinery in conjunction with meals. In a series of elegant work, they report that insulin and IGF1 reset circadian clocks by inducing the PER protein. The effect of insulin and IGF1 on PER protein synthesis is not restricted to any particular tissue, and facilitates circadian entrainment of gene expression, thereby providing a mechanism by which feeding cues synchronize biological clocks throughout the body. The insulin/IGF-1 induction of PER protein requires mTOR activation, increased phosphoinositide signaling and microRNA downregulation. Whether these findings have physiological relevance is still an unresolved question since the level of insulin (600 nM) that was used for many of the experiments is lethal in humans. Moreover, there is an interplay between insulin and a variety of hormones and peptides that contribute to food entrainment, and thus the effect of other nutritional cues has yet to be unraveled. Nevertheless, this work has clinical relevance since disturbing the temporal relationship between light cures and hormonal cues may be a key physiological driver underlying the association between disturbances in circadian rhythms (shift-work, jet lag) and ill health. Management of light exposure and meal timing may prevent the adverse physiological consequences of circadian disturbances on metabolic health.

Timing of Dietary Cues

Over-nutrition/obesity has been associated with disturbed circadian rhythms and altered expression of genes controlling metabolism. Obesity may drive a vicious cycle to further impact global transcriptional and epigenomic circadian rhythms. Nevertheless, the underlying mechanism by which nutritional/dietary cues impact circadian rhythms are not well understood. Mitchell A. Lazar and co-workers, [ 18 ] studied high-fat diet-induced obese mice and reported that obesity remodeled circadian enhancers in liver, triggering synchronous high-amplitude circadian rhythms of opposing lipid pathways namely fatty acid synthesis and oxidation. The obesity-enhanced circadian transcription of lipid genes in liver required genes involved in lipogenesis (SREBP) and fatty acid oxidation (PPARα). Of interest, pharmacological lipid lowering drug therapy was more effective in the obese mice when treatment was timed at the peak expression of the nuclear receptor and fatty acid oxidation gene PPARα. The key takeaway from this study is that at least in mice, over-nutrition intensifies circadian rhythms of the non-core clock factors SREBP and PPARα in liver, such that pharmacological lipid lowering drugs are more effective when PPARα is highest. If similar results are observed in obese humans, this work may have clinical relevance. For example, it may be possible to take circadian rhythms into consideration when prescribing PPARα agonists as lipid lowering therapy to achieve optimal effects on fat oxidation and energy homeostasis. The application of “ chronomedicine ” by aligning circadian rhythms with medicine/drugs or diet/exercise/sleep regimes to manage diabetes may be a clinical reality in the future.

In keeping with the theme chronomedicine , Satchidananda Panda and his team have been studying the interaction between eating and timing [ 19 ]. Remarkably, they have reported that obese mice maintained on a feeding schedule in which food availability is restricted to a defined period of 8–12 h (so called time-restricted feeding ), have sustained rhythmic expression of circadian clock components and many key metabolic regulators. Strikingly, time-restricted feeding ameliorates obesity-associated metabolic disorders compared to mice fed an isocaloric diet ad libitum [ 20 ]. In this latest work, they studied high-fat fed obese whole-body Cry1;Cry2 and liver-specific Bmal1 and Rev-erbα/β knockout mice subjected to time-restricted feeding or ad libitum diets and reported that feeding-fasting rhythms are sufficient to alleviate key metabolic diseases, including obesity and metabolic syndrome, independently of the circadian clock. Time-restricted feeding restored rhythms in feeding-fasting, metabolic and nutrient-sensing pathways and prevented fatty liver, dyslipidemia and glucose intolerance and activated cellular homeostasis maintenance pathways in clock mutant mice. This finding was unexpected given the importance of the core clock machinery in controlling gene expression. A key takeaway as from this study is that the circadian clock maintains metabolic homeostasis by sustaining daily rhythms in feeding-fasting and by maintaining balance between nutrient and cellular stress responses. The benefits of time-restricted feeding regimes in the long-term have not been assess, nor have studies been confirmed in older mice. Consequently, the durability of this dietary regime to sustain the improvements in metabolic homeostasis is unknown. In translating these findings into the clinic, it may be important to determine whether humans with circadian rhythm defects, (jet lag, shift-workers), who may be predisposed to aberrant eating patterns, as well as people with metabolic disease, can voluntarily impose a strict time-restricted eating regime to prevent or reverse metabolic diseases. The type of diet and calorie content are also other important considerations for maintaining metabolic health. For example, Bente Kiens and coworkers [ 21 ] reported saturated or polyunsaturated fat-rich diets induce extensive metabolic adaptations that maintain peripheral insulin sensitivity, lower circulating lipids, and decrease hepatic de novo lipogenesis and gluconeogenesis, enabling disposition of dietary fat without metabolic complications in humans and mice, irrespective of fatty acid type, provided caloric intake is balanced. This was an unexpected finding, but reinforces the importance of calorie balance rather than degree of fat in the diet. Thus, at least in healthy slightly overweight men, as long as calorie balance is maintained, fat-rich diets appear to be well-tolerated.

Timing of Exercise

Time of day may be important to achieve the most robust effects of exercise training on metabolic homeostasis. Acute exercise increases glucose uptake, promotes mitochondrial biogenesis, and enhances insulin sensitivity [ 22 ], consequently regular physical exercise is recommended for the treatment and prevention of chronic conditions/diseases including obesity and diabetes [ 23 ]. Nevertheless, the most effective time of day to achieve beneficial effects on blood glucose control in people with type 2 diabetes remains unknown. In a recent study men with type 2 diabetes underwent a randomized crossover trial of two weeks morning versus afternoon high intensity interval exercise training [ 24 ]. Afternoon high intensity interval training (4 PM) was more efficacious than morning interval training (8 AM) at improving blood glucose control as assessed in the men with type 2 diabetes by continuous glucose monitors. Strikingly, morning exercise training had an acute, deleterious effect, increasing blood glucose levels, which may be related to an exaggerated counter-regulatory hormonal responses in men with type 2 diabetes after maximal dynamic exercise [ 25 ]. While the study supports the long-standing view that exercise is a critical adjunct in the management of type 2 diabetes, it highlights the importance of optimizing the timing of exercise sessions to improve glycemic control in people with type 2 diabetes. The effect of exercise training on blood glucose control at various times of day may also differ in response to exercise intensity or modality, as well as age, sex, and metabolic status (metabolically healthy, type 1 diabetes, type 2 diabetes, obesity, gestational diabetes) of the participant. Integrating regular exercise training into a daily routine, with workouts at a consistent time of day, may help to ensure that daily activity goals are met. Thus, for most people, the best time to exercise is when you can do it.

Exercise-Responsive Systemic Factors that Control Metabolism

Exercise perturbs whole body homeostasis and ultimately every cell and organ in the body needs to adapt to the increased mechanical, metabolic, and thermoregulatory demands associated with the increased work load [ 26 ]. Exercise-responsive factors can be released from a variety of peripheral organs during work and recovery to communicate information about the status of the different tissues to maintain whole body glucose and energy homeostasis [ 27 ]. In searching for novel adipose tissue derived exercise-responsive secreted factors Laurie J. Goodyear and colleagues [ 28 ] asked whether transforming growth factor-β2 (TGF-β2) contributes to the exercise-induced improvements in metabolic homeostasis. TGF-β2 regulates embryonic development and is an immune suppressor. They found that endurance exercise training increased TGF-β2 mRNA in subcutaneous white adipose tissue from healthy young men and mice. They report TGF-β2 is an exercise-induced “adipokine” that increases with training and promotes glucose and fatty acid metabolism, presumably by normalizing inflammation. Treatment of mice for 12 days with recombinant TGF-β2 reversed the deleterious effects of high-fat diet on glucose and lipid metabolism. While the mechanism remains elusive, exercise-induced elevations in lactate appear to act as a trigger to modulate TGF-β2 expression. To move this discovery into the clinic, additional mechanistic studies are warranted, particularly in regard to the mode of action and whether any side-effects develop from TGF-β2 treatment on inflammation. Dosing will also be a factor to titer out- given that levels during exercise are transient, and levels during a protein-based therapy may be sustained. Nevertheless, the findings uncover novel molecular connections between adipose tissue and skeletal muscle in the context of exercise physiology.

Interleukin-6 (IL-6) is another exercise-responsive “ tissue-kine ” implicated in metabolic regulation [ 29 , 30 ]. IL-6 is released from skeletal muscle during exercise and stimulates lipolysis. Two recent studies further biologically validate IL-6 at the level of adipose tissue as treatment for obesity [ 30 ] and at the level of the gut for the control of gastric emptying [ 29 ]. To determine the role of IL-6 on exercise-induced reductions in visceral adiposity in Krogh-Madsen and colleagues [ 30 ] performed a randomized placebo-controlled trial whereby abdominally obese adults were treated with tocilizumab (IL-6 receptor antibody) or placebo during a 12-week intervention with either bicycle exercise or no exercise. Strikingly, they found treatment with an IL-6 receptor agonist prevented the exercise-induced loss of visceral fat, indicating IL-6 is required for the training-induced reductions in adiposity. Conversely, the cardiorespiratory improvements following exercise training were IL-6-independent. In addition to the effects of IL-6 on weight loss, Helga Ellingsgaard and colleagues [ 29 ] report an acute increase in IL-6 improves glycemic in healthy and type 2 diabetic men by inhibiting gastric motility in a GLP-1-dependent manner. Treatment with the IL-6 receptor agonist also enhance gastric emptying after acute exercise in healthy men. Collectively, these two studies provide clues regarding possible therapeutic targets for treatment of obesity and insulin resistance, implicating exercise-induced IL-6 may be required to achieve weight loss and improve glucose homeostasis. The results also raise a potential concern for increased adiposity or gastric emptying in patients prescribed IL-6 receptor agonists for the treatment of some forms of arthritis. Patients receiving this type of therapy may have difficulty in preventing weight gain or promoting weight loss with exercise, or may have issues related to the mechanisms controlling neurohumoral signals that regulate gastric emptying.

Concluding Remarks

This is an exciting time of great discovery and advances in the field of diabetology and endocrinology as many researchers are striving to move basic discoveries towards the clinic. The need for continued support of basic research is stronger than ever given the complexity associated with diabetes and obesity, the increasing number of individuals suffering with these diseases, and the long journey from discovery to treatment. If there are no discoveries emanating from basic biology, there will be no advances to translate into the clinic. Hopefully, some of the discoveries highlighted in this review will move into the clinic. Several of the “breakthroughs” discussed, particularly those related to diet and exercise, are already being practiced in the clinic and are important for the prevention of metabolic diseases and the promotion of healthy living. In closing, I have provided just a glimpse of what is on the horizon in this rapidly evolving and exciting field! The task has been daunting, but for every breakthrough highlighted, there are surely hundreds more to come! I hope you have enjoyed the year in review.

J.R.Z is supported by grants from the Novo Nordisk Foundation (NNF14OC0011493, NNF14OC0009941), Swedish Diabetes Foundation (DIA2018-357), Swedish Research Council (2015–00165), and the Strategic Research Program in Diabetes at Karolinska Institutet (2009–1068).

Funding Information

Open access funding provided by Karolinska Institute.

Compliance with Ethical Standards

Conflict of interest.

Juleen R. Zierath declares that she has no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by the author.

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Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

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Type 1 diabetes articles from across Nature Portfolio

Type 1 diabetes (also known as diabetes mellitus) is an autoimmune disease in which immune cells attack and destroy the insulin-producing cells of the pancreas. The loss of insulin leads to the inability to regulate blood sugar levels. Patients are usually treated by insulin-replacement therapy.

Latest Research and Reviews

The epidemiology of type 1 diabetes mellitus in older adults

This Review discusses the incidence, prevalence and disease burden of type 1 diabetes mellitus in older adults in diverse geographical regions. The challenges involved in defining and diagnosing type 1 diabetes mellitus in this population and the implications of these challenges for epidemiological studies of this disease are also addressed.

• Dunya Tomic
• Jessica L. Harding
• Dianna J. Magliano

Epigenetic programming of obesity in early life through modulation of the kynurenine pathway

• Mojgan Gharipour
• Jeffrey M. Craig
• Garth Stephenson

Clinical importance of cytokine (IL-6, IL-8, and IL-10) and vitamin D levels among patients with Type-1 diabetes

• Azharuddin Sajid Syed Khaja
• Naif K. Binsaleh
• Ibrahim Abdelmageed Mohamed Ginawi

TGF-β-mediated crosstalk between TIGIT + Tregs and CD226 + CD8 + T cells in the progression and remission of type 1 diabetes

Type 1 diabetes (T1D) manifests as hyperglycemia, with spontaneous remission occasionally observed, but the underneath mechanisms are unclear. Here the authors analyses patients at different stages to find two populations of immune cells correlating with disease progression or remission, while results from mouse diabetes models validate these observations.

Tankyrase inhibition promotes endocrine commitment of hPSC-derived pancreatic progenitors

“Here the authors demonstrate that ß cell differentiation from human pluripotent stem cells can be improved by replacing nicotinamide with tankyrase inhibitors. This results in pancreatic progenitors that form islet-like cells with increased ß cell frequencies and glucose responsiveness.”

• Frankie Poon
• Rangarajan Sambathkumar
• M. Cristina Nostro

Crinophagic granules in pancreatic β cells contribute to mouse autoimmune diabetes by diversifying pathogenic epitope repertoire

Dense-core granules (DCG) store insulin in pancreatic β cells. Here the authors show that crinosome, formed by fusing lysosome and DCGs, are pathogenic in mouse models of type 1 diabetes by diversifying local insulin epitopes beyond those tolerizing ones expressed in the thymus, thereby inducing autoreactive CD4 T cells for β cell death and insulin deficiency.

• Anthony N. Vomund
• Xiaoxiao Wan

News and Comment

Combination therapy increases human β-cell mass in vivo

• Olivia Tysoe

How medical schools can prepare students for new technologies

Patient educators and nurses can demonstrate the real-life use of health technologies.

• Chantal Mathieu

Reply to ‘Slowly progressive insulin dependent diabetes mellitus in type 1 diabetes endotype 2’

• Maria J. Redondo
• Noel G. Morgan

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

• Tetsuro Kobayashi
• Takashi Kadowaki

METTL3 restrains autoimmunity in β-cells

Activation of innate immunity has been linked to the progression of type 1 diabetes. A study now shows that overexpression of METTL3, a writer protein of the m 6 A machinery that modifies mRNA, restrains interferon-stimulated genes when expressed in pancreatic β-cells, identifying it as a promising therapeutic target.

• Balasubramanian Krishnamurthy
• Helen E. Thomas

Type 1 diabetes mellitus: a brave new world

One hundred years after the Nobel prize was bestowed on Banting and McLeod for the ‘discovery’ of insulin, we are again seeing major evolutions in the management of type 1 diabetes mellitus, with the prospect of achieving disease control beyond mere management now becoming real. Here, we discuss the latest, most notable developments.

• Pieter-Jan Martens

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Metformin intolerance in type 2 diabetes mellitus – the possibility of using a multi-strain probiotic, estimated glomerular filtration rate in elderly patients with type 2 diabetes, xxv scientific congress of diabetes poland, 23–25 may 2024, warsaw - abstracts.

Type 2 Diabetes Research At-a-Glance

The ADA is committed to continuing progress in the fight against type 2 diabetes by funding research, including support for potential new treatments, a better understating of genetic factors, addressing disparities, and more. For specific examples of projects currently funded by the ADA, see below.

Greg J. Morton, PhD

University of Washington

Project: Neurocircuits regulating glucose homeostasis

“The health consequences of diabetes can be devastating, and new treatments and therapies are needed. My research career has focused on understanding how blood sugar levels are regulated and what contributes to the development of diabetes. This research will provide insights into the role of the brain in the control of blood sugar levels and has potential to facilitate the development of novel approaches to diabetes treatment.”

The problem: Type 2 diabetes (T2D) is among the most pressing and costly medical challenges confronting modern society. Even with currently available therapies, the control and management of blood sugar levels remains a challenge in T2D patients and can thereby increase the risk of diabetes-related complications. Continued progress with newer, better therapies is needed to help people with T2D.

The project: Humans have special cells, called brown fat cells, which generate heat to maintain optimal body temperature. Dr. Morton has found that these cells use large amounts of glucose to drive this heat production, thus serving as a potential way to lower blood sugar, a key goal for any diabetes treatment. Dr. Morton is working to understand what role the brain plays in turning these brown fat cells on and off.

The potential outcome: This work has the potential to fundamentally advance our understanding of how the brain regulates blood sugar levels and to identify novel targets for the treatment of T2D.

Tracey Lynn McLaughlin, MD

Stanford University

Project: Role of altered nutrient transit and incretin hormones in glucose lowering after Roux-en-Y gastric bypass surgery

“This award is very important to me personally not only because the enteroinsular axis (gut-insulin-glucose metabolism) is a new kid on the block that requires rigorous physiologic studies in humans to better understand how it contributes to glucose metabolism, but also because the subjects who develop severe hypoglycemia after gastric bypass are largely ignored in society and there is no treatment for this devastating and very dangerous condition.”

The problem: Roux-en-Y gastric bypass (RYGB) surgery is the single-most effective treatment for type 2 diabetes, with persistent remission in 85% of cases. However, the underlying ways by which the surgery improves glucose control is not yet understood, limiting the ability to potentially mimic the surgery in a non-invasive way. Furthermore, a minority of RYGB patients develop severe, disabling, and life-threatening low-blood sugar, for which there is no current treatment.

The project: Utilizing a unique and rigorous human experimental model, the proposed research will attempt to gain a better understanding on how RYGB surgery improves glucose control. Dr. McLaughlin will also test a hypothesis which she believes could play an important role in the persistent low-blood sugar that is observed in some patients post-surgery.

The potential outcome: This research has the potential to identify novel molecules that could represent targets for new antidiabetic therapies. It is also an important step to identifying people at risk for low-blood sugar following RYGB and to develop postsurgical treatment strategies.

Rebekah J. Walker, PhD

Medical College of Wisconsin

Project: Lowering the impact of food insecurity in African Americans with type 2 diabetes

“I became interested in diabetes research during my doctoral training, and since that time have become passionate about addressing social determinants of health and health disparities, specifically in individuals with diabetes. Living in one of the most racially segregated cities in the nation, the burden to address the needs of individuals at particularly high risk of poor outcomes has become important to me both personally and professionally.”

The problem: Food insecurity is defined as the inability to or limitation in accessing nutritionally adequate food and may be one way to address increased diabetes risk in high-risk populations. Food insecure individuals with diabetes have worse diabetes outcomes and have more difficulty following a healthy diet compared to those who are not food insecure.

The project: Dr. Walker’s study will gather information to improve and then will test an intervention to improve blood sugar control, dietary intake, self-care management, and quality of life in food insecure African Americans with diabetes. The intervention will include weekly culturally appropriate food boxes mailed to the participants and telephone-delivered diabetes education and skills training. It will be one of the first studies focused on the unique needs of food insecure African American populations with diabetes using culturally tailored strategies.

The potential outcome: This study has the potential to guide and improve policies impacting low-income minorities with diabetes. In addition, Dr. Walker’s study will help determine if food supplementation is important in improving diabetes outcomes beyond diabetes education alone.

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