An accurate genetic diagnosis of maturity-onset diabetes of the young (MODY) is critical for personalized treatment. To avoid misdiagnosis, only genes with strong evidence of causality must be tested. Heterozygous variants in NEUROD1, PDX1, APPL1, and WFS1 have been implicated in MODY, but strong genetic evidence supporting causality is lacking. We therefore assessed their existing genetic evidence and performed gene-level burden tests in a large MODY cohort, alongside two established MODY genes as positive controls (HNF1A- high penetrance, RFX6 -low penetrance). The first reported MODY-associated variants in NEUROD1, PDX1, APPL1, and WFS1 were <1:20,000 frequency. Based on the small number of large published pedigrees per gene (n < 3), MODY-associated variants showed only modest cosegregation in these genes. Crucially, ultra-rare (minor allele frequency <1:10,000) protein-truncating and predicted-damaging missense variants in APPL1 and WFS1 were not enriched in a MODY cohort (n = 2,571) compared with population control individuals (n = 155,501; all P > 0.05). In contrast, variants in NEUROD1 and PDX1 were enriched, albeit at levels comparable to RFX6. Multiple sensitivity analyses corroborated these findings. In summary, rare heterozygous variants in NEUROD1 and PDX1 are low-penetrance causes of MODY, while those in APPL1 and WFS1 lack robust genetic evidence for causality and should not be included in MODY testing panels.

The underlying molecular pathogenesis of the Asian phenotype of insulin resistance remains to be understood. We carried out metabolic phenotyping of study participants without diabetes according to insulin sensitivity indices derived from hyperinsulinemic-euglycemic clamp procedures. We identified lipidomic signatures of insulin resistance and metabolic plasticity. These lipidomic signatures have the potential to help in risk stratification of insulin resistance and metabolic dysfunction for early intervention.

Vesicle-associated membrane protein 8 (VAMP8) localizes to endosomal vesicles and mediates their exocytosis in pancreatic β-cells. VAMP8-dependent vesicle fusion delivers glucagon-like peptide 1 receptor and GLUT2 to the plasma membrane. VAMP8 overexpression inhibits insulin granule exocytosis. "Newcomer" exocytosis likely involves endosomal compartments, not insulin granules.

Abnormal glucose tolerance (AGT) in youth has become an alarming global public health issue; however, approaches to identify high-risk population among young people have not been well-established. Can the long-term risk of AGT be stratified by the subclasses of glucose trajectories defined in childhood? Subclasses defined in childhood can efficiently stratify the risk of AGT in adolescence and young adulthood. The subclass membership was strongly associated with cardiometabolic disorders in childhood and maternal cardiometabolic disorders during pregnancy. This subclass method provides a potential strategy to identify those at risk of later cardiometabolic disorders from childhood for more intensive evaluation of intervention. The close relationship between maternal cardiometabolic disorders and subclass membership of children highlighted the potential influence of gestational cardiometabolic health on the development of cardiometabolic disorders in offspring.

In combatting the obesity crisis, leveraging mechanisms that lower body weight is critical. The finding that treatment with tirzepatide, a glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) receptor agonist, produces profound weight loss highlights the value of activating the incretin receptors. Supporting this, recent studies have revealed mechanisms by which GIP receptor (GIPR) activation is beneficial in pancreatic islets, the central nervous system (CNS), and adipose tissue. Paradoxically, a hypothesis has emerged that GIPR antagonism could be an additional option in treating obesity. This concept stems from concern that GIP facilitates lipid uptake and storage in adipose tissue, although the lipid-buffering capacity of adipocytes versus other cell types is metabolically favorable. In this article, we highlight the natural physiology of the incretins, noting GIP as the primary incretin. In the CNS, GIPR agonism attenuates nausea and suppresses appetite, features that also help GLP-1 receptor agonism promote a negative energy balance. Further, we provide rationale that, in protecting against ectopic fat distribution and augmenting substrate utilization to promote insulin sensitivity, GIPR activity in adipose tissue is advantageous. Collectively, these attributes support GIPR agonism in the treatment of obesity and metabolic disease.

Current and emerging strategies to therapeutically target weight management include pairing agonism of the glucagon-like peptide 1 receptor (GLP-1R) with either agonism or antagonism of the glucose-dependent insulinotropic polypeptide receptor (GIPR). On the surface, these two approaches seem contradictory, yet they have produced similar effects for weight loss in clinical studies. Arguments that support the rationale for both approaches are made in these point-counterpoint articles, founded on preclinical studies, human genetics, and clinical outcomes. Here, we attempt to reconcile how two opposing approaches can produce similar effects on body weight by evaluating the leading hypotheses derived from the available evidence.

Obesity is a prevalent disease that also contributes to the incidence and severity of many other chronic diseases and health conditions. Treatment approaches include lifestyle intervention, bariatric surgery, and pharmacological approaches, with glucagon-like peptide 1 (GLP-1) receptor agonists approved specifically for weight loss having changed the treatment landscape significantly in the last 5 years. Targeting the glucose-dependent insulinotropic polypeptide (GIP) receptor may enhance the metabolic benefits of GLP-1 receptor agonism. These beneficial effects are seen with both GIP receptor antagonism and GIP receptor agonism, although the mechanisms underlying this apparent paradox remain unknown. Here, we summarize the physiologic, genetic, and clinical evidence for pursuing GIP receptor antagonism to achieve metabolic and weight benefits. Both global and central nervous system knockout of GIP receptors protects mice fed a high-fat diet from obesity and insulin resistance. Genome-wide association studies in humans support this notion, correlating lower BMI with GIP receptor genetic variants with reduced function. Pharmacologic approaches in mice and monkeys confirm that GIP receptor antagonism enhances GLP-1-induced weight reduction and other metabolic benefits, and a phase 1 study provides proof of principle that beneficial effects extend to humans. GIP receptor antagonism may represent an important new mechanism to expand the treatment options available to individuals living with obesity.

Senescence is a β-cell stress response in type 1 diabetes (T1D), the origins of which are not understood. We wanted to determine the role of the T cell-mediated autoimmune process in β-cell senescence during T1D. In the nonobese diabetic mouse model, β-cell senescence largely depended on damage inflicted by autoreactive CD4+ and CD8+ T cells during the development of T1D. Chronic exposure to sublethal doses of proinflammatory cytokines associated with the diabetogenic process was sufficient to elicit stable senescence phenotypes in human islets in culture. Our findings suggest that autoreactive T cells trigger not only β-cell death but also β-cell senescence, potentially via cytokine-dependent mechanisms in T1D. This finding has implications for understanding the mechanisms of action and beneficial impacts of immunotherapy using CD3 antibodies in T1D.

Circulating glucagon concentrations differ between individuals with no diabetes (ND) and those with type 1 diabetes (T1D). We combined an isotope dilution technique using stable tracers [6,22-13C9,15N1]glucagon and [6,14,19,22-13C9,15N1]glucagon with splanchnic and leg catheterization in participants with ND (n = 8; age 23.1 ± 2.9 years, BMI 26.6 ± 3.5 kg/m2, HbA1c 5.0 ± 0.2% [31 ± 2 mmol/mol]) and T1D (n = 6; 29.0 ± 8.8 years, BMI 26.3 ± 5.0 kg/m2, HbA1c 7.9 ± 0.8% [63 ± 8 mmol/mol]) in the overnight fasted state. After baseline period, exogenous glucagon was infused at rates designed to achieve plasma glucagon concentrations spanning the physiological ranges, to determine the effects of rising glucagon concentrations on splanchnic and leg glucagon balance. At baseline, splanchnic glucagon extraction (SGE) was similar (30.7 ± 2.7 vs. 29.1 ± 2.9%) but leg glucagon extraction (LGE) was lower (27.0 ± 4.2 vs. 40.6 ± 3.1%) in participants with T1D versus those with ND. However, with increasing plasma glucagon concentrations, while SGE remained unchanged within and between groups, LGE fell in participants with ND (41 vs. 31 vs. 24%) but did not change in those with T1D. Despite a numerically lower net splanchnic glucagon production in participants with T1D than in those with ND, no changes were observed with increasing glucagon concentrations within the physiological range in both groups. This is the first human study applying novel glucagon isotopes that describes regional glucagon metabolism in participants with ND and T1D. Our observations provide translational relevance for dual hormone closed-loop systems and provide tools for probing the effects of GLP-1, dual, and triple receptor agonists on pancreatic α-cell functions.

Diabetic peripheral neuropathy (DPN) poses significant clinical challenges due to progressive nerve degeneration and vascular insufficiency. To address both neural and vascular complications simultaneously, we employed an mRNA-based protein replacement therapy. In this study, leveraging mRNA template design, structure-based screening identified NGFR100W as a variant dissociating neuroprotective and nociceptive functions, demonstrating enhanced neuritogenic activity without pain sensitization. Additionally, transcriptome analysis of NGF mutants versus wild type further reveals the potential mechanism by which NGFR100W uncouples neuroprotective and nociceptive pathways. We cotransfected chemically modified NGFR100W mRNA and vascular endothelial growth factor A (VEGFA) mRNA, and the conditioned media collected from this transfection promoted endothelial cell migration, tubulogenesis, and neurite outgrowth. In a diabetic mouse model, combination therapy with lipid nanoparticle codelivery of NGFR100W and VEGFA mRNA significantly improved blood flow in the plantar region and mitigated nerve function decline compared with monotherapy. Histological analysis showed increased microvessel formation and higher intraepidermal nerve fiber density in treated mice. Our findings highlight the therapeutic potential of NGFR100W and VEGFA mRNA coadministration for DPN, suggesting that protein supplementation via mRNA could offer a novel strategy for clinical intervention in some chronic medical conditions.

Glucokinase (GK) activators (GKAs) are a long-sought therapeutic modality for the treatment of type 2 diabetes. However, GKAs have failed in clinical trials, with the recent exception of dorzagliatin (Hua Medicine). A comprehensive approach using human islet perifusions, enzyme kinetics, X-ray crystallography, and modeling studies was applied to compare the effects of dorzagliatin with those of the unsuccessful GKA MK-0941 (Merck Pharmaceuticals), which is well characterized both clinically and mechanistically. Dorzagliatin improved glucose-stimulated insulin secretion in a dose- and glucose-dependent manner, in contrast to MK-0941, which induced maximal insulin secretion at low doses and glucose concentrations. To understand these functional differences, the atomic resolution structure of the dorzagliatin-GK complex was determined and compared with the GK-MK-0941 structure. MK-0941 bound to a pocket accessible in both open and closed conformations; had a strong interaction with Y214, the mutation of which produces the most clinically severe activating mutation; and produced a high energy barrier for the open-to-closed transition. In contrast, dorzagliatin only bound favorably to the closed form of GK, interacting primarily with R63 and causing a low energy barrier for the open-to-closed transition. This provides the molecular rationale for the clinical success of dorzagliatin, which can guide the future development of next-generation allosteric activators of GK.

We aimed to identify distinct axes of obesity using advanced magnetic resonance imaging (MRI)-derived phenotypes. We used 24 MRI-derived fat distribution and muscle volume measures (UK Biobank; N = 33,122) to construct obesity axes through principal component analysis. Genome-wide association studies were performed for each axis to uncover genetic factors, followed by pathway enrichment, genetic correlation, and Mendelian randomization analyses to investigate disease associations. Four primary obesity axes were identified: 1) general obesity, reflecting higher fat accumulation in all regions (visceral, subcutaneous, and ectopic fat); 2) muscle dominant, indicating greater muscle volume; 3) peripheral fat, associated with higher subcutaneous fat in abdominal and thigh regions; and 4) lower-body fat, characterized by increased lower-body subcutaneous fat and reduced ectopic fat. Each axis was associated with distinct genetic loci and pathways. For instance, the lower-body fat axis was associated with RSPO3 and COBLL1, which are emerging as promising candidates for therapeutic targeting. Disease risks varied across axes; the general obesity axis was correlated with higher risks of metabolic and cardiovascular diseases, whereas the lower-body fat axis seemed to protect against type 2 diabetes and cardiovascular disease. This study highlights the heterogeneity of obesity through the identification of obesity axes and emphasizes the potential to extend beyond BMI in defining and treating obesity for obesity-related disease management.

Islet cell replacement therapies have evolved as a viable treatment option for type 1 diabetes complicated by problematic hypoglycemia and glycemic lability. Refinements of islet manufacturing, islet transplantation procedures, peritransplant recipient management, and immunosuppressive protocols allowed most recipients to achieve favorable outcomes. Subsequent phase 3 trials of transplantation of deceased donor islets documented the effectiveness of transplanted islets in restoring near-normoglycemia, glycemic stability, and protection from severe hypoglycemia, with an acceptable safety profile for the enrolled high-risk population. Health authorities in several countries have approved deceased donor islet transplantation for treating patients with type 1 diabetes and recurrent severe hypoglycemia. These achievements amplified academic and industry efforts to generate pluripotent stem cell-derived β-cells through directed differentiation for β-cell replacement. Preliminary results of ongoing clinical trials suggest that the transplantation of stem cell-derived β-cells can consistently restore insulin independence in immunosuppressed recipients with type 1 diabetes, thus signaling the profound progress made in generating an unlimited and a uniform supply of cells for transplant. Avoiding the risks of chronic immunosuppression represents the next frontier. Several strategies have entered or are approaching clinical investigation, including immune-isolating islets, engineering immune-privileged islet implantation sites, rendering islets immune evasive, and inducing immune tolerance in transplanted islets. Capitalizing on high-dimensional, multiomic technologies for deep profiling of graft-directed immunity and the fate of the graft will provide new insights that promise to translate into sustaining functional graft survival long-term. Leveraging these parallel progression paths will facilitate the wider clinical adoption of cell replacement therapies in diabetes care.

The identification of a "rundlichen Häuflein" by Paul Langerhans more than 150 years ago marked the initiation of a global effort to unravel the mysteries of pancreatic islets, an intricate system of nutrient-sensing, hormone-secreting, and signaling cells. In type 1 diabetes, this interconnected network is vulnerable to malfunction and immune attack, with strategies to prevent or repair islet damage still in their infancy. In 2014, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) established the Human Islet Research Network (HIRN) to accelerate our understanding of the molecular and cellular basis of type 1 diabetes development. In this article, investigators from the HIRN detail pioneering advances, technologies, and systems that contextualize insulin-producing β-cells and other related cells within their physiological environment. Disease models, devices, and therapies are evaluated by the HIRN in light of promising functional and mechanistic data. Collaborative relationships and opportunities within this network are emphasized as a means of enhancing the quality of innovative research and talent in science. Topics are developed through a series of questions, achievements, and milestones, with the 75th anniversary of the NIDDK as an opportunity to reflect on the past, present, and future of type 1 diabetes research.

Cardiovascular disease (CVD) is a leading cause of morbidity and mortality in individuals with diabetes. Individuals with type 1 diabetes have a two- to fourfold higher risk of CVD in comparison with the general population, driven by an earlier onset and increased lifetime incidence of CVD events and mortality. Similarly, type 2 diabetes confers two- to threefold increased CVD risk, usually alongside metabolic syndrome, obesity, and hypertension. Despite advancements in methods for achieving glycemic control, the CVD burden remains disproportionately high in diabetes. The mechanisms driving elevated risk are complex and variably multifactorial, involving hyperglycemia, insulin resistance, dyslipidemia, inflammation, and a hypercoagulable state. Unfortunately, critical gaps in understanding persist on how these factors interact to promote CVD in type 1 versus type 2 diabetes, particularly across disease stages and age. Addressing these knowledge gaps is essential to developing targeted therapies that can effectively mitigate CVD risk. To meet this need, the National Institute of Diabetes and Digestive and Kidney Diseases, in partnership with the National Heart, Lung, and Blood Institute, recently formed the Cardiovascular Repository for Type 1 Diabetes (CaRe-T1D) program. Its mission is to elucidate the molecular and cellular pathways linking diabetes with CVD through the provision of high-quality human tissues for investigator-led analyses using cutting-edge technologies and collaborative data sharing to advance precision medicine and reduce the global burden of diabetes-associated cardiovascular complications.

In the last two decades, significant progress has been made toward understanding the genetic basis of type 2 diabetes. An important supporter of this research has been the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), most recently through the Accelerating Medicines Partnership Program for Type 2 Diabetes (AMP T2D) and Accelerating Medicines Partnership Program for Common Metabolic Diseases (AMP CMD). These public-private partnerships of the National Institutes of Health, multiple biopharmaceutical and life sciences companies, and nonprofit organizations, facilitated and managed by the Foundation for the National Institutes of Health, were designed to improve understanding of therapeutically relevant biological pathways for type 2 diabetes. On the occasion of NIDDK's 75th anniversary, we review the history of NIDDK support for these partnerships, which saw the convergence of research directions prioritized by academic consortia, the pharmaceutical industry, and government funders. Although the NIDDK was not the sole originator or funder of these efforts, its support and leadership have been pivotal to the partnerships' success and have enabled their research to be broadly accessible through the AMP Common Metabolic Diseases Knowledge Portal (CMDKP) and the AMP Common Metabolic Diseases Genome Atlas (CMDGA). Findings from AMP CMD align with NIDDK's mission to conduct research and share results with the goal of improving health and quality of life.

This year marks the 75th anniversary of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health. NIDDK's long history of research and innovation includes support of four types of collaborative research centers focused on diabetes, endocrinology, and metabolic diseases. The Diabetes Research Centers promote basic and clinical diabetes research, while the Centers for Diabetes Translation Research conduct diabetes research across the translation science spectrum. The Mouse Metabolic Phenotyping Center (MMPC)-Live program provides the research community with standardized phenotyping services for mouse models of diabetes and obesity, and the Cystic Fibrosis Research and Translation Centers advance basic, preclinical, and clinical research for cystic fibrosis. These centers have evolved over time in response to new scientific opportunities and to expand their reach to be an asset to the larger scientific community. Looking to the future, NIDDK will continue to ensure that these centers enhance the research community, foster novel and synergistic scientific collaborations, and promote career development of scientists in the early stages of their careers. We will also ensure that our centers align with NIDDK's goal of improving health outcomes for all people with and at risk for diseases, within our mission.