Mechanisms underlying the differential susceptibility of pancreatic β- and α-cells to diabetogenic stress remain unclear. We investigated whether replication, repair fidelity, and developmental epigenetic programs determine the vulnerability of postnatal β- and α-cells to DNA damage, a key driver of β-cell failure in diabetes. Replication introduces DNA damage vulnerability in both neonatal β- and α-cells, yet β-cells resolve damage more efficiently. Loss of DNA methyltransferase 3a in pancreatic progenitors selectively heightens β-cell DNA damage vulnerability that persists into adulthood. Moreover, diabetogenic stress preferentially compromises β-cell repair fidelity. These findings reveal how developmental programs shape β-cell resilience and may influence lifelong diabetes risk.

The clinical success of dual glucagon-like peptide 1/glucose-dependent insulinotropic polypeptide (GIP) receptor agonists has renewed interest in the pharmacological actions of GIP in type 2 diabetes (T2D), although its metabolic and cardiovascular effects remain incompletely understood. The study evaluated the effects of a pharmacological GIP infusion on glucose homeostasis and cardiovascular responses during hyperglycemia in individuals with T2D. GIP stimulated insulin secretion and increased whole-body glucose disposal during hyperglycemia while modestly attenuating glucagon suppression and impairing insulin sensitivity. GIP also augmented heart rate and reduced blood pressure. Our findings demonstrate that GIP remains biologically active in T2D and pharmacological doses modulate glucose metabolism and cardiovascular function.

Type 1 diabetes (T1D) impacts more than 9 million individuals globally. Despite a century since the isolation and clinical introduction of insulin, exogenous insulin injections remain the primary form of treatment for T1D. While continuous glucose monitoring systems and optimized insulin delivery reduce life-threatening hypoglycemic events, they do not provide a permanent cure. Transplantation of pancreatic islets offers a potential long-term solution. Recent advances in stem cell-derived islets (SC-islets) have shown remarkable promise in both clinical and research settings. This article highlights recent clinical reports in the use of SC-islets to restore islet function and their versatility as a platform for disease modeling and drug screening while emphasizing current strategies aimed at overcoming their limitations and enhancing their therapeutic potential. We also discuss exciting emerging approaches that expand investigations beyond pancreatic endocrine cells to encompass nonendocrine cell types in the pancreas, offering a unique bird's-eye view into pancreatic biology and insights into cellular cross talk in health and disease. Our aim is for this article to serve as a resource for up-to-date advances in SC-islet research and to highlight novel platforms for studying diabetes pathogenesis in unprecedented ways, accelerating progress toward a permanent cure.

Pancreatic perivascular adipose tissue (PVAT) is a potentially important but understudied fat depot surrounding vessels supplying the pancreas, and its role in type 2 diabetes mellitus (T2DM) remains unclear. We aimed to quantify pancreatic PVAT automatically on routine abdominal computed tomography (CT) scans and assess whether PVAT-derived imaging biomarkers are associated with T2DM and future T2DM risk. PVAT biomarkers were associated with T2DM and were informative predictors in multivariable models. Exploratory analyses showed similar findings for incident T2DM (disease onset within 4 years of follow-up). PVAT may represent a novel CT-based biomarker for early metabolic dysfunction and T2DM risk stratification.

NAD+ is an essential cofactor for many metabolic reactions. Nicotinamide phosphoribosyltransferase (NAMPT) is an important enzyme in NAD+ biosynthesis, and diminished adipocyte NAD+ and NAMPT have been implicated in metabolic dysfunction. Mice with adipocyte NAMPT overexpression (ANOV) were protected from diet-induced metabolic dysfunction, including adipose tissue inflammation, glucose intolerance, and hepatic steatosis. Extracellular vesicles from ANOV mice improved glucose tolerance in obese mice. Compared with wild-type mice, adipose tissue extracellular vesicles from ANOV mice exhibited marked changes in lipid and metabolite cargoes.

Female C57BL/6 J mice are relatively resistant to weight gain, which complicates the study of sex-specific metabolic responses. So, we used ob/ob mice to examine semaglutide-induced weight loss in both sexes. We wanted to determine whether semaglutide-induced weight loss produces sex-specific effects on skeletal muscle mass and function in ob/ob mice. Semaglutide had minimal effects on skeletal muscle mass and strength in ob/ob mice. In particular, females were completely resistant to loss of muscle mass. These findings reveal that semaglutide exerts sex-specific effects, highlighting a need for further research into the molecular mechanisms driving these distinct protective outcomes.

Impaired cognitive function caused by insulin-induced hypoglycemia is a complication of type 1 diabetes mellitus (T1DM) for which no protective strategies are currently available. In this first-in-human mechanistic study using magnetic resonance spectroscopy, the direct contribution of the infused ketone β-hydroxybutyrate (BHB) to brain metabolism during clamped hypoglycemia was greater in participants with T1DM than healthy participants. In a randomized dietary intervention trial of participants with T1DM and recurrent hypoglycemia, receiving medium-chain triglycerides (MCTs) as a dietary ketone precursor was associated with higher working memory performance and greater regional brain activation during clamped hypoglycemia compared with an isocaloric standard diet. Counterregulatory hormone responses to hypoglycemia were not affected by MCT supplementation. We conclude that ketone bodies are well suited to support brain metabolism in persons with T1DM experiencing insulin-induced hypoglycemia. Dietary MCT supplementation raising BHB may represent a novel strategy to prevent hypoglycemia-induced brain injury in this vulnerable patient population.

Challenging the view that elevated circulating adenosine deaminase (ADA) is merely a secondary phenomenon, this study defines its pathogenic role in linking dyslipidemia to β-cell failure and establishes adenosine (ADO) homeostasis restoration as a disease-remitting therapy. We identify tissue-specific compensatory ADA upregulation that paradoxically fails to prevent systemic ADO accumulation, with elevated adenosine selectively inducing apoptosis in immune and pancreatic β-cells. We establish a novel systemic clearance-local decompression therapeutic mechanism in which exogenous ADA reduces circulating ADO, normalizes compensatory tissue ADA hyperactivity, and rescues islet function. This work redefines plasma ADA from a diagnostic marker to a therapeutic target, providing the rationale for an ADA-based therapy that uniquely combines immune modulation with metabolic correction to halt β-cell failure progression.

This study identifies the carbohydrate-responsive element-binding protein as the direct transcriptional activator of TXNIP in vascular smooth muscle cells under conditions of hyperglycemia. Aorta-specific TXNIP knockdown demonstrates therapeutic potential by alleviating arterial stiffness and attenuating atherosclerotic plaque in diabetic mice. Pharmacologic inhibition of TXNIP or activation of AKT ameliorates the senescent phenotype, highlighting a druggable pathway in diabetic vasculopathy.

Diabetic retinopathy (DR) is a major cause of irreversible vision loss driven primarily by retinal vascular damage, yet its mechanisms remain incompletely understood. Here, we identify calnexin (Canx) as a critical suppressor of pathological angiogenesis in DR. We demonstrate that hyperglycemia synergizes with TNF-α to downregulate Canx in mouse retinal microvascular endothelial cells. This loss of Canx activates Nox4, leading to hyperactivation of the Ire1α/Xbp1s branch of the unfolded protein response. Consequently, endoplasmic reticulum stress is amplified, pathological Vegfa transcription is upregulated, and the inner blood-retinal barrier is disrupted. In streptozotocin-induced diabetic mouse models, Canx deficiency exacerbated endothelial dysfunction and retinal vascular pathology. Conversely, both adalimumab treatment and adeno-associated virus-mediated Canx overexpression in vivo suppressed the Nox4/Ire1α/Xbp1s/Vegfa cascade, significantly reduced vascular leakage and acellular capillary formation, attenuated retinal thinning, and normalized endothelial cell functions (proliferation, migration, tube formation). Collectively, our findings establish Canx as a key upstream regulator of Vegfa-mediated vascular injury in DR. Our study suggests that targeting Canx, either genetically or via repurposing adalimumab, represents a source-specific strategy to halt DR progression by blocking pathological Vegfa production at its origin.

Ketone bodies, particularly β-hydroxybutyrate (3HB), are often elevated in type 1 diabetes (T1D); however, their physiological roles remain unclear. In a low-carbohydrate diet study, patients with insulin-deficient diabetes exhibited reduced fasting blood glucose and increased fasting blood ketone levels, negatively correlated. Another clinical study using continuous glucose and ketone monitoring confirmed inverse glucose-ketone fluctuations. To test causality, we conducted animal and cellular studies. In streptozotocin-induced T1D mice, 7-week oral 3HB administration improved glucose metabolism and alleviated glycogenic hepatopathy. Imaging with 2-deoxy-2-[18F]-fluoro-d-glucose positron emission tomography/computed tomography demonstrated reduced hepatic and intestinal glucose uptake. Western blotting confirmed 3HB suppressed glucose transporter (sodium-glucose cotransporter 1, GLUT2, GLUT5) overexpression and normalized glycogen metabolism. In vitro, 3HB dose-dependently inhibited glucose transporter expression and glucose uptake in primary hepatocytes and IEC-6 cells. G protein-coupled receptor 109A (GPR109A) serves as the primary receptor for 3HB. Mechanistic studies using the GPR109A inhibitor mepenzolate bromide, the mTOR inhibitor rapamycin, and siRNA-mediated gene silencing revealed that these effects were GPR109A dependent and linked to inhibition of the PI3K/AKT/mTOR pathway. Overall, this study provides new insights into the role of ketone bodies in T1D, establishing 3HB as a modulator of glucose homeostasis through GPR109A-mediated suppression of glucose transporters in the liver and intestine.