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.

G protein-coupled receptor 35 (GPR35) is a poorly characterized receptor with unclear intracellular mechanisms in endothelial cells (ECs). Oxidative stress responsive kinase 1 (OXSR1) is a serine/threonine protein kinase that modulates cell morphology and has recently been found to promote angiogenesis. We hypothesized that GPR35 inhibition promotes EC angiogenesis via augmenting OXSR1 activity and accelerating wound healing in diabetes. Here, we show that active GPR35 contributed to the impaired migration and tube formation of human dermal microvascular ECs from patients with type 2 diabetes (T2D) or ECs exposed to high glucose. Proximity labeling and coimmunoprecipitation identified OXSR1 as an interacting partner of GPR35 in ECs. GPR35 suppressed OXSR1 from translocating to nuclei to activate SMAD1/5, thereby inhibiting the transcription of angiogenic factors. Furthermore, enhanced wound angiogenic response and accelerated wound closures were observed in induced T2D mice with topical application of GPR35 siRNA, or in T2D models of transgenic mice with either global or endothelial-selective GPR35 deletion. Our data suggest that GPR35 suppresses OXSR1-dependent angiogenic activity in ECs, contributing to poor angiogenesis and delayed wound healing in T2D animals. This study provides both in vitro and in vivo evidence for GPR35 as a potential therapeutic target in tissue repair in patients with diabetes.

In this month's Classics in Diabetes featured article, published in Diabetes in 1993, the description by Kahn et al. of the relationship between insulin secretion and insulin sensitivity in 93 healthy adults without diabetes provided a model for the regulation of glucose tolerance that continues to be used today. In the study, data from a large sample of individuals studied with intravenous glucose tolerance tests demonstrated that in those with normal glucose tolerance, insulin secretion and sensitivity were related by a hyperbolic curve. This relationship supports adaptability between these parameters that maintains a constant amount of insulin action, and glycemia conforming to the normal range. These findings have led to the general view that type 2 diabetes mellitus is fundamentally a failure of β-cells to adequately supply tissues such as the liver, skeletal muscle, and adipose with insulin. This simple conception remains useful for explaining diabetes pathogenesis and interpreting experimental data some 30 years after publication, with impact meriting recognition as a Diabetes classic.

Oxidative stress has a major pathogenic role in diabetic retinopathy (DR), and neuroretina dysfunction is recognized as an early and important problem. Soluble guanylate cyclase (sGC) has been implicated for its neuroprotective effects in the central nervous system, but its role in the retina remains unclear. Here, we demonstrated in healthy human and rodent retinas the expression of sGC subunits GUCY1A1 and GUCY1B1 in vascular cells and neuronal elements, including retinal ganglion, bipolar, and amacrine cells. We provided evidence using in vitro and in vivo studies that sGC function is impaired by oxidative stress-induced damage in the retina. The sGC activator runcaciguat activated sGC in multiple retinal cell types and counteracted the inhibitory effect of damage induced by oxidative stress on the retina and retinal cells. In the rat retinal ischemia-reperfusion model, runcaciguat treatment improved neuroretinal and visual function as measured by electroretinography and optokinetic tracking and resulted in retinal morphologic improvement. In the streptozotocin-induced diabetic rat model, runcaciguat significantly improved neuroretinal function and improved inner plexiform layer thickness. These studies suggest that sGC signaling is involved in neuroretinal function and vision and that diabetes negatively affects this pathway, supporting restoring sGC activation as a novel therapy for early DR.

Obesity-induced biological changes often persist after weight loss and are difficult to reverse, a phenomenon known as 'obesogenic memory'. This enduring effect is associated with metabolic inflammation, particularly in adipose tissue. In this study, we characterise a mouse model of obesogenic memory and evaluate the efficacy of the unimolecular conjugate GLP-1/Dexa, which selectively and safely delivers the anti-inflammatory drug dexamethasone to GLP-1 receptor (GLP-1R)-expressing cells. We document that this precision pharmacological approach outperforms treatment with GLP-1 or dexamethasone alone, significantly reducing body weight, food intake, adiposity and markers of adipose tissue inflammation in male mice with obesogenic memory. In addition, we identify the CCR2/CCL2 inflammatory pathway as an important mediator of glucose intolerance and adipose tissue inflammation associated with obesogenic memory. Our findings suggest that targeting inflammation via GLP-1R signalling may be a promising therapeutic strategy to alleviate obesogenic memory and improve the long-term clinical management of metabolic diseases.

Obesity is a growing global health threat, and inducing browning of white adipose tissue (WAT) to increase energy expenditure has become an attractive strategy for treating obesity and related metabolic complications. BRCA1-associated protein 1 (BAP1), a ubiquitin C-terminal hydrolase domain-containing deubiquitinase expressed broadly across tissues, has previously been shown to play an important role in liver carbohydrate and lipid metabolism. However, its role in the browning of inguinal WAT (iWAT) has not been studied. Our study initially found that BAP1 expression was downregulated in cold-induced mouse iWAT but upregulated in obese conditions. Furthermore, overexpression of BAP1 in the inguinal fat tissue suppressed iWAT browning and thermogenesis. Mechanistically, we found that BAP1 interacts with KDM1B and stabilizes it through deubiquitination. Subsequently, KDM1B demethylates H3K4me1/2 modifications in proximity to thermogenesis-related genes, thereby inhibiting the expression of genes essential for browning. In summary, our study shows that BAP1 negatively regulates iWAT browning via a mechanism mediated by KDM1B.

Wolfram syndrome 1 (WS1) is a rare genetic disorder caused by WFS1 variants that disrupt wolframin, an endoplasmic reticulum-associated protein essential for cellular stress responses, Ca2+ homeostasis, and autophagy. Here, we investigated how the c.316-1G>A and c.757A>T WFS1 mutations, which yield partially functional wolframin, affect the molecular functions of β-cells and explored the therapeutic potential of the glucagon-like peptide 1 receptor (GLP-1R) agonist liraglutide. Pancreatic β-cells obtained from patient-derived induced pluripotent stem cells (iPSCs) carrying this WFS1 variant exhibited reduced insulin processing and impaired secretory granule maturation, as evidenced by proinsulin accumulation and decreased prohormone convertase PC1/3. Moreover, they exhibited dysregulated Ca2+ fluxes due to altered transcription of Ca2+-related genes, including CACNA1D, and significantly reduced SNAP25 levels, leading to uncoordinated oscillations and poor glucose responsiveness. Affected cells also showed increased autophagic flux and heightened susceptibility to inflammatory cytokine-induced apoptosis. Notably, liraglutide treatment rescued these defects by normalizing Ca2+ handling, enhancing insulin processing and secretion, and reducing apoptosis, likely through modulation of the unfolded protein response. These findings underscore the importance of defining mutation-specific dysfunctions in WS1 and support targeting the GLP-1/GLP-1R axis as a therapeutic strategy.

Gestational diabetes mellitus (GDM) is one of the most common medical complications of pregnancy. It is generally defined as glucose intolerance with onset or first recognition during pregnancy. The pathogenesis of GDM has long been attributed to inadequate pancreatic β-cell compensation for the physiological insulin resistance of pregnancy. This defect is thought to resolve after pregnancy but become manifest in later life as an increased risk of diabetes. Examination of mechanisms underlying GDM does not support this commonly held picture. In this Perspective, we present evidence that, like diabetes outside of pregnancy, GDM has no single etiology. It results from multiple causes of a common physiological manifestation, inadequate β-cell function, which leads to a common clinical manifestation, elevated glucose levels. We provide evidence that GDM often represents detection of chronic and progressive β-cell dysfunction that is temporally but not mechanistically related to pregnancy. We provide detailed characterization of the β-cell defect in one high-risk group, Hispanic Americans. Finally, we address some of the clinical and research implications of these findings.

By stimulating hepatic glucose production, glucagon (released by islet α-cells) restores normal blood glucose levels when they fall below the normal range. We used optogenetics in conjunction with electrophysiology, [Ca2+]i imaging and hormone release measurements to explore the intrinsic and paracrine regulation of glucagon secretion. Many α-cells were spontaneously active at 1mM glucose. However, up to ∼50% of the α- cells were electrically silent. KATP channel blockade, amino acids and somatostatin receptor (SSTR) antagonism restored electrical activity in such α-cells. Termination of optoactivation resulted in KATP channel-dependent (tolbutamide-sensitive) membrane repolarization in active α-cells but long-lasting membrane depolarization and action potential firing in silent α-cells. The latter effect was associated with an increased cytoplasmic ATP:ADP-ratio. Optoactivation or -inhibition of somatostatin-releasing δ- cells inhibits and stimulates electrical activity in adjacent (but not distal) α-cells. There is an inverse relationship between basal glucagon secretion (a measure of the fraction active α-cells) and the relative stimulatory effects of amino acids. We conclude that islet α-cells are functionally heterogenous and that their electrical excitability and glucagon release are determined by K+ channel activity due to variable mosaic of KATP and somatostatin-sensitive K+ channels reflecting metabolic state and proximity to δ-cells, respectively.

Glycated hemoglobin has shown disagreements with other glycemic indices; termed the glycation gap. The glycation gap can be influenced by nonglycemic factors, such as protein deglycation, through the fructosamine-3-kinase (FN3K) enzyme. This cross-sectional study aimed to examine whether single nucleotide polymorphisms (SNPs) in the FN3K gene can explain the glycation gap. Among the 826 participants, 79.8% were female, 22.3% presented with diabetes, and the median age was 53 years. The results suggest that genetic polymorphisms in the FN3K gene may influence the glycation gap in individuals with diabetes. With the SNP rs1056534 analysis, the CC genotype was associated with a negative glycation gap (all P < 0.02), whereas the GG genotype was associated with a positive glycation gap (all P < 0.03) in the adjusted models. Similarly, with the SNP rs2256339, the TT genotype was associated with a negative glycation gap (P < 0.08), whereas the TA genotype was associated with a positive glycation gap (all P < 0.05) in the adjusted models. The studied genotypes are associated with protein glycation, contributing to differences in measures of glycemic control. Future studies are needed to explore the clinical implications of these findings.

Intrahepatic islet transplantation is followed by islet loss due to the instant blood-mediated inflammatory response (IBMIR) in which platelet activation plays a key role. The KEATSTF-fragment (KF7), a newly discovered platelet inhibitor that interferes with the formation of the 14-3-3ζ-c-Src-integrin-β3 complex, holds significant potential in inhibiting IBMIR without causing significant bleeding. This study introduces a novel surface modification technique using 3,4-dihydroxy-l-phenylalanine (L-DOPA) conjugated with KF7 to enhance the engraftment of transplanted islets in a syngeneic marginal mass model. KF7 loaded with L-DOPA (L-DOPA-KF7) formed a protective coating on the surface of islets without interfering with their viability and functionality. Islets coated with L-DOPA-KF7 restored normoglycemia in diabetic mice, and survival time was significantly longer compared with the control group. Transplantation of L-DOPA-KF7-coated islets was associated with reduced blood clot formation and decreased infiltration of CD11b+ cells and platelets. In conclusion, a composite L-DOPA-KF7 coating significantly prolongs the survival of transplanted islets by providing a robust IBMIR isolation barrier, thereby enhancing the overall success of islet transplantation in preclinical models.

Pathologic signaling via the receptor for advanced glycation end products (RAGE) is critical to diabetic kidney disease (DKD) development, whereas RAGE deletion is renoprotective. Noncoding RNAs (ncRNAs), including miRNAs, also play key roles in DKD, including in renal fibrosis. However, the involvement of ncRNAs in RAGE signaling remains unclear. This study investigated the regulation of ncRNAs by RAGE and assessed renal expression of ncRNAs, miRNAs, and fibrotic/inflammatory markers in diabetic RAGE-knockout and wild-type (WT) mice as well as in mesangial cells (MCs) obtained from these mice. Diabetes induction in both RAGE-/- and WT mice was associated with elevated renal expression of miR-214 and its host ncRNA, Dnm3os. miR-214 and Dnm3os levels were remarkably higher in RAGE-/- MCs compared with WT MCs. Overexpression of miR-214 in WT MCs reduced fibrotic/inflammatory gene expression, whereas its inhibition increased these markers. Human DKD tissue demonstrated higher DNM3os expression compared with controls. Notably, miR-214 targeted the RAGE signaling mediator protein diaphanous homolog 1 (DIAPH1), whereas Dnm3os had an opposite effect, enhancing fibrosis and inflammation. miR-214 administration in a DKD mouse model significantly reduced renal fibrosis. These findings suggest a novel mechanism by which miR-214 and Dnm3os act as negative and positive regulators of fibrosis via the RAGE-DIAPH1 axis.

Since little is known about the disposition index (DI) in autoantibody-positive individuals, we have assessed whether DI has a similar association between insulin secretion and sensitivity to the association observed in other populations. In TrialNet Pathway to Prevention (TNPTP; n = 6,620) and Diabetes Prevention Trial-Type 1 (DPT-1; n = 704) study participants, two secretion-sensitivity pairs, each representing a DI, were analyzed cross-sectionally at baseline: area under the curve (AUC) C-peptide/AUC glucose (AUC ratio) and Matsuda index (MI) from TNPTP oral glucose tolerance tests (oral DI), first-phase insulin response (FPIR), and 1 / fasting insulin (1/FI) from DPT-1 from intravenous glucose tolerance tests (DI). Participants were followed for progression to type 1 diabetes (T1D). Within the normal and diabetes glucose ranges, associations of AUC ratio with MI in TNPTP and FPIR with 1/FI in DPT-1 had inverse curvilinear patterns with convexities to the origin. After logarithmic transformations to linearize the secretion and sensitivity measures, the inverse slope was steeper for the diabetes range (P < 0.0001). In a Cox regression model including the AUC ratio and MI as variables and another model including FPIR and 1/FI, the interaction terms of secretion × sensitivity (i.e., the DI/oral DI) predicted stage 3 T1D in both (P < 0.0001). The DI remained significantly predictive (P < 0.0001) when the DPT-1 risk score was added as a covariate in regression models. In autoantibody-positive populations, insulin secretion is inversely related to sensitivity in a quasi-hyperbolic relationship in normal and diabetes ranges of glucose. The DI can be represented by a statistical and physiologic interaction between secretion and sensitivity that is predictive of stage 3 T1D.

Activation of GPR119 receptors, expressed on enteroendocrine and pancreatic islet cells, augments glucagon counterregulatory responses to hypoglycemia in preclinical models. We hypothesized that MBX-2982, a GPR119 agonist, would augment counterregulatory responses to experimental hypoglycemia in participants with type 1 diabetes (T1D). To assess this, we designed a phase 2a, double-masked, crossover trial in 18 participants (age 20-60 years) with T1D. Participants were randomized to treatment with 600 mg MBX-2982 or placebo daily for 14 days, with a 2-week washout between treatments. Counterregulatory responses to hypoglycemia during a hyperinsulinemic euglycemic-hypoglycemic clamp and hormonal responses during a mixed-meal test (MMT) were measured. The maximum glucagon response, glucagon area under the curve (AUC), and incremental AUC were not significantly different during MBX-2982 versus placebo treatment. MBX-2982 did not alter epinephrine, norepinephrine, pancreatic polypeptide, free fatty acid, or endogenous glucose production responses to hypoglycemia compared with placebo. However, glucagon-like peptide 1 (GLP-1) response during the MMT was 17% higher with MBX-2982 compared with placebo treatment. In conclusion, GPR119 activation with MBX-2982 did not improve counterregulatory responses to hypoglycemia in people with T1D. Increases in GLP-1 during the MMT are consistent with GPR119 target engagement and the expected pharmacodynamic response from L cells.

G protein-coupled receptor 119 (GPR119) is predominantly expressed in pancreatic β-cells, enteroendocrine cells, and the liver. It is a novel therapeutic for dyslipidemia and type 2 diabetes. DA-1241, a GPR119 agonist, improves glucose tolerance by inhibiting gluconeogenesis and enhancing insulin secretion. It mitigates hepatic inflammation by inhibiting NFκB signaling. However, the mechanism by which DA-1241 ameliorates nonalcoholic fatty liver disease (NAFLD) remains unknown. We hypothesized that DA-1241 improves liver steatosis by inducing autophagy in a transcriptional factor EB (TFEB)-dependent manner. It induced autophagy and TFEB nuclear translocation, and decreased lipid content in liver cell lines. Lysotracker staining and DQ-Red BSA assay revealed it increased lysosomal activity. Furthermore, DA-1241 increased the colocalization of mRFP-LC3 and lipid droplets, which were completely abolished by GPR119 knockdown. DA-1241 treatment improved glucose tolerance and insulin sensitivity, reduced liver enzymes activity and hepatic triglyceride levels, and decreased the NAFLD activity score, accompanied by an increased number of autophagosomes and lysosomes in high-fat diet-fed mice. Despite DA-1241 treatment, lysosomal activity and subsequent lipid content reduction were not induced in tfeb knockout HeLa cells. DA-1241 treatment failed to produce favorable metabolic effects, including reduced hepatic triglyceride levels, in liver-specific Tfeb knockout mice. Thus, DA-1241 attenuates hepatic steatosis through TFEB-mediated autophagy induction.