Diabetes[JOURNAL]
Sun
200 papers
Hypothalamic Prostaglandins Facilitate Recovery From Severe Hypoglycemia but Exacerbate Recurrent Hypoglycemia in Mice.
Abe T, Xu S, Sugiura Y … +10 more , Arima Y, Hayasaka T, Lee ML, Ishimoto T, Araki Y, Ngurari S, Niu Z, Iijima N, Diano S, Toda C
Diabetes · 2025 Dec · PMID 41264848 · Full text
The hypothalamus monitors blood glucose levels and regulates glucose production in the liver. In response to hypoglycemia, glucose-inhibited (GI) neurons trigger counterregulatory responses (CRRs), which stimulate the re...
The hypothalamus monitors blood glucose levels and regulates glucose production in the liver. In response to hypoglycemia, glucose-inhibited (GI) neurons trigger counterregulatory responses (CRRs), which stimulate the release of glucagon, epinephrine, and cortisol to elevate blood glucose. Recurrent hypoglycemia (RH), however, reduces the effectiveness of these CRRs. This study examined the role of hypothalamic prostaglandins in glucose recovery during acute hypoglycemia and RH. Imaging mass spectrometry and liquid chromatography/mass spectrometry showed phospholipid and prostaglandin levels in the hypothalamus of C57BL mice were changed after insulin or 2-deoxy-glucose administration. Ibuprofen, a nonsteroidal anti-inflammatory drug, was infused into the ventromedial hypothalamus (VMH) to analyze its effect on glucose production during hypoglycemia, revealing that prostaglandin inhibition decreased glucagon secretion. Additionally, RH-treated mice decreased glucagon release and glucose production during hypoglycemia. Inhibiting prostaglandin production via shRNA against cytosolic phospholipase A2 (cPLA2) in the hypothalamus restored CRRs diminished by RH via increasing glucagon sensitivity. These findings suggest that hypothalamic prostaglandins play a critical role in glucose recovery from acute hypoglycemia by activating VMH neurons and are also crucial for the attenuation of CRRs during RH.
Atherosclerotic Cardiovascular Risk Before and After Type 2 Diabetes Onset and the Roles of Ectopic Fat and Ethnic Variation: The 2025 Edwin Bierman Award Lecture.
Sattar N
Diabetes · 2025 Dec · PMID 41264847 · Publisher ↗
Atherosclerotic cardiovascular disease (ASCVD) risk begins increasing years before the clinical onset of type 2 diabetes, driven in part by ectopic lipid accumulation. Many individuals predisposed to diabetes often gain...
Atherosclerotic cardiovascular disease (ASCVD) risk begins increasing years before the clinical onset of type 2 diabetes, driven in part by ectopic lipid accumulation. Many individuals predisposed to diabetes often gain weight rapidly and have limited capacity to expand subcutaneous fat, leading to central fat storage and ectopic lipid deposition-especially in the liver. Hepatic fat contributes to metabolic dysfunction and elevated triglyceride-rich lipoproteins (TRLs), which are atherogenic. Alongside higher blood pressure, these factors accelerate atherosclerosis even before hyperglycemia is evident. Although traditional cardiovascular risk factors like LDL cholesterol (LDL-C) and smoking have declined, rising obesity-particularly among younger individuals-is shifting ASCVD risk more toward pathways linked to ectopic lipid accumulation and prolonged exposure to diabetes-related metabolic disturbances. Ethnic variation plays a significant role in modifying this risk. South Asians, for example, develop type 2 diabetes at lower BMIs and tend to have higher hepatic fat and TRL levels than White individuals, contributing to their increased ASCVD burden. Conversely, people of African ancestry often have lower hepatic fat and TRL levels at similar BMIs, correlating with lower ASCVD risk despite elevated diabetes risk. Risk profiles in other ethnic groups remain understudied. These findings highlight the need for early obesity prevention and ethnically tailored strategies for ASCVD risk assessment and management. Without targeted interventions, rising global rates of obesity and type 2 diabetes, especially in low- and middle-income countries, will increase ectopic lipid accumulation, TRLs, and blood pressure, ultimately accelerating ASCVD progression and reversing prior gains made in cardiovascular prevention.
An Unexpected Journey Into Brown Fat Research for Metabolic Health: The 2025 Outstanding Scientific Achievement Award Lecture.
Kajimura S
Diabetes · 2025 Dec · PMID 41264846 · Full text
For many years, brown adipose tissue (BAT) was primarily regarded as a "heat organ" for rodents. Over the past 15 years, however, research in this field has shifted significantly toward understanding of the role of BAT i...
For many years, brown adipose tissue (BAT) was primarily regarded as a "heat organ" for rodents. Over the past 15 years, however, research in this field has shifted significantly toward understanding of the role of BAT in metabolic health, including systemic glucose homeostasis, lipid metabolism, insulin sensitivity, and protection against cardiometabolic disease. In this award lecture, I highlight key contributions from our laboratory and others that transformed brown fat research, including molecular insights into brown and beige adipocyte biogenesis and the discovery of UCP1-independent pathways through which brown and beige fat influence metabolic health beyond thermogenesis.
Genetic Variants Increasing TAS2R38 Bitter Taste Receptor Sensitivity Are Associated With Lower Postprandial Glycemia.
Gervis JE, Westerman KE, Cole JB … +3 more , Merino J, Cromer SJ, Udler MS
Diabetes · 2025 Dec · PMID 41264845 · Full text
UNLABELLED: TAS2R38 is a bitter taste receptor that influences bitter taste perception and diet and is also found in intestinal L cells that store and secrete glucagon-like peptide 1 (GLP-1). Preclinical studies have lin...
UNLABELLED: TAS2R38 is a bitter taste receptor that influences bitter taste perception and diet and is also found in intestinal L cells that store and secrete glucagon-like peptide 1 (GLP-1). Preclinical studies have linked TAS2R38 activation to postprandial GLP-1 secretion, fueling interest in TAS2R38 as a therapeutic target for glucose regulation; however, evidence in humans remains limited. To further establish TAS2R38 actions in glucose homeostasis, we analyzed data from ∼220,000 European adults without type 2 diabetes in the UK Biobank to test whether functional variants conferring TAS2R38 sensitivity were associated with blood glucose. We found that individuals with two copies of a haplotype increasing receptor sensitivity (PAV) had significantly lower 0-2-h (i.e., postprandial) glucose than those with two copies of a nonfunctional haplotype (AVI), following a dose-response relationship per PAV haplotype. These associations were replicated in published genome-wide association studies of 2-h glucose, persisted after adjustment for diet and lifestyle behaviors related to bitter taste perception, and were not seen for variants in other bitter taste receptors without putative roles in glucose metabolism (TAS2R14 and TAS2R19). Collectively, these findings provide evidence in humans consistent with direct TAS2R38 actions in postprandial glycemia, supporting TAS2R38 as a novel therapeutic target for glucose regulation. ARTICLE HIGHLIGHTS: The TAS2R38 bitter taste receptor, recently identified within intestinal L cells, has been shown to modulate GLP-1 secretion in preclinical models; however, evidence in humans remains limited. We harnessed functional variants comprising three canonical diplotypes of TAS2R38 to study the role of TAS2R38 in glucose homeostasis in humans. In a large sample of adults without type 2 diabetes, we found that individuals with more sensitive TAS2R38 receptors had lower postprandial glucose levels, independent of diet and lifestyle habits. Our findings provide evidence in humans supporting direct TAS2R38 actions in postprandial glycemia and highlight TAS2R38 as a potential therapeutic target for impaired glucose regulation.
Diabetes Spotlight: Sylvaine You, PhD-Preventing the Progression of Type 1 Diabetes Through Immunomodulatory Therapeutics.
Page B
Diabetes · 2025 Dec · PMID 41264844 · Publisher ↗
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NUAK1 Promotes Diabetic Kidney Disease by Accelerating Renal Tubular Senescence via the ROS/P53 Axis.
Guo L, Wu P, Li Q … +16 more , Feng Q, Lin X, Luo Y, Wang Y, Wu M, Cai F, Zhang J, Hu Y, Wang H, Wang Y, Luo S, Tian L, Fan X, Wang L, Xue Y, Guan M
Diabetes · 2025 Dec · PMID 41264843 · Publisher ↗
UNLABELLED: Diabetic kidney disease (DKD) progression involves intricate interactions among senescence, oxidative stress, inflammation, and fibrosis. This study systematically investigates the regulatory role and molecul...
UNLABELLED: Diabetic kidney disease (DKD) progression involves intricate interactions among senescence, oxidative stress, inflammation, and fibrosis. This study systematically investigates the regulatory role and molecular mechanisms of NUAK1 in DKD pathogenesis. Bioinformatics analysis of Gene Expression Omnibus data sets identified NUAK1 as a differentially expressed gene, validated in human kidney proximal tubule epithelial (HK-2) cells, high-fat diet and streptozotocin-induced DKD mice, d-galactose-induced senescent mice, and human peripheral blood mononuclear cells. Functional studies demonstrated that NUAK1 inhibition via siRNA knockdown, pharmacological inhibitors, or kidney tubule-targeted adeno-associated virus serotype carrying shRNA against NUAK1 delivery attenuated reactive oxygen species-tumor protein 53 (ROS/P53) axis-mediated renal tubular senescence, oxidative stress, inflammation, and fibrosis in vitro and in vivo. Mechanistically, chromatin immunoprecipitation quantitative PCR revealed that transcription factor ETS1 directly binds to the NUAK1 promoter, driving its transcriptional activation in DKD. Furthermore, molecular docking and dynamics simulations identified Asiatic acid (AA) as a potent NUAK1 inhibitor, with a stable binding affinity. AA suppressed NUAK1 expression and downstream pathological processes, ameliorating renal injury in DKD models. These findings elucidate the role and regulatory mechanisms of NUAK1 in modulating ROS/P53 axis-driven tubular senescence and oxidative stress, providing a theoretical basis for structure optimization in drug development targeting NUAK1. ARTICLE HIGHLIGHTS: Mechanisms linking renal tubular senescence to diabetic kidney disease (DKD) progression remain poorly understood. Systematic elucidation of the regulatory role of NUAK1 in the pathogenesis of DKD and its regulatory mechanisms is provided. NUAK1 is upregulated in DKD, promoting senescence via reactive oxygen species-tumor protein 53 under transcriptional activation by E26 transformation-specific 1, while Asiatic acid (AA) directly binds NUAK1 to suppress these pathological processes. NUAK1 emerges as a therapeutic target for DKD, and AA provides a natural scaffold for NUAK1 inhibitor development, offering a strategy to combat diabetes-related renal decline.
Postprandial Glucagon Metabolism in Healthy and Type 1 Diabetes.
Ruchi FNU, Schiavon M, Pandey A … +4 more , Dalla Man C, Cobelli C, Basu R, Basu A
Diabetes · 2026 Jan · PMID 41264412 · Full text
UNLABELLED: Early postprandial glucagon concentrations are higher in type 1 diabetes (T1D) than in individuals with no diabetes (ND). To determine the cause, we infused stable [13C9, 15N1]glucagon before, during, and aft...
UNLABELLED: Early postprandial glucagon concentrations are higher in type 1 diabetes (T1D) than in individuals with no diabetes (ND). To determine the cause, we infused stable [13C9, 15N1]glucagon before, during, and after a mixed meal in 16 ND and 16 T1D individuals to measure glucagon turnover. In a subcohort of 9 ND and 12 T1D individuals, we estimated [13C9, 15N1]glucagon kinetics during steady state. A linear, single-compartment model described [13C9, 15N1]glucagon kinetics and allowed precise estimation of the volume of distribution (VD) and clearance rate (CL). Model parameters were similar between groups, with the VD of [13C9, 15N1]glucagon at 42.1 ± 3.3 mL/kg, implying that [13C9, 15N1]glucagon distributes in a single compartment and with VD approximating the plasma volume and CL at 10.6 ± 0.9 mL/kg/min. Higher early (0–120 min after meal ingestion) postprandial glucagon concentrations (1,907.9 ± 373.4 vs. −93.6 ± 240.5 pg/mL · 120 min P < 0.001) observed in T1D was due to higher rates of glucagon appearance (3.39 ± 2.8 vs. −3.95 ± 2.0 ng/kg · 120 min, P < 0.04) and disappearance (2.13 ± 2.6 vs. −5.28 ± 2.1 ng/kg · 120 min, P < 0.04) compared with ND. We have determined postprandial glucagon turnover in humans and have demonstrated that changes in postprandial glucagon concentrations in T1D are due to increased rates of glucagon turnover during the early postprandial period. ARTICLE HIGHLIGHTS: This study was conducted to determine postprandial glucagon metabolism in people with and without type 1 diabetes. We wanted to determine the cause for higher early postprandial glucagon concentrations in type 1 diabetes. We found that higher early postprandial glucagon turnover is the cause of higher early postprandial glucagon concentrations in type 1 diabetes Strategies that decrease early post prandial glucagon fluxes could improve postprandial glucose concentrations in type 1 diabetes.
Neural Regulation of Blood Glucose in Acute Stress: A Report on Research Supported by Pathway to Stop Diabetes.
Stanley SA
Diabetes · 2026 Jan · PMID 41252653 · Full text
UNLABELLED: There is significant evidence that acute stress, a challenge to an organism's homeostasis, has dramatic effects on metabolic control. Acute stress impairs blood glucose control in people with both type 1 and...
UNLABELLED: There is significant evidence that acute stress, a challenge to an organism's homeostasis, has dramatic effects on metabolic control. Acute stress impairs blood glucose control in people with both type 1 and type 2 diabetes. In addition, growing evidence suggests that metabolic responses to stress in people without diabetes may be a crucial determinant of health. Acute dysregulation of blood glucose in the hospital setting, including both hyper- and hypoglycemia, predicts short- and long-term morbidity and mortality in patients with critical illnesses. Animal studies indicate that exposure to physiological and psychological stressors activates a highly conserved network of neural circuits that ultimately coordinate the functions of multiple organs to increase blood glucose. In this article, we provide an overview of the neural populations and circuits that increase blood glucose in response to acute stress, including our research funded by the American Diabetes Association Pathway to Stop Diabetes program, highlighting the impacts on clinical outcomes and opportunities for the development of therapies for diabetes. This article is part of a series of perspectives that report on research funded by the American Diabetes Association Pathway to Stop Diabetes program. ARTICLE HIGHLIGHTS: Internal and external stressors rapidly increase blood glucose, a highly conserved metabolic response. Multiple stress-modulated neural populations in the brain stem, hypothalamus, and forebrain contribute to regulation of the hypothalamo-pituitary-adrenal axis and sympathetic nervous system to elicit hyperglycemia. Exaggerated or diminished glucose responses to acute stress are associated with increased risk of type 2 diabetes and poor health outcomes. A greater understanding of the neural circuitry contributing to stress hyperglycemia and how these circuits are disrupted has the potential to provide new approaches to improve glycemic control.
Gestational Diabetes Mellitus Alters Placental Precursor mRNA Splicing.
Engal E, Gershon A, Melamed S … +14 more , Sharma A, Ner-Gaon H, Jaffe-Herman S, Nevo Y, Kirzhner A, Barak O, Vaisbuch E, Kay G, Staff AC, Dechend R, Herse F, Shay T, Salton M, Schiller T
Diabetes · 2026 Jan · PMID 41252199 · Publisher ↗
UNLABELLED: Gestational diabetes mellitus (GDM) is defined as hyperglycemia first identified during pregnancy and can lead to adverse maternal and neonatal outcomes. The molecular mechanisms leading to these outcomes are...
UNLABELLED: Gestational diabetes mellitus (GDM) is defined as hyperglycemia first identified during pregnancy and can lead to adverse maternal and neonatal outcomes. The molecular mechanisms leading to these outcomes are currently poorly understood. While transcriptomics of GDM placentas has been previously studied, the effect on precursor mRNA splicing remains largely unknown. This study explores the impact of GDM on placental splicing and identifies its regulatory mechanisms. Using RNA sequencing data from Norwegian and Chinese cohorts, we uncovered thousands of differential splicing events. Pathway enrichment analysis revealed significant associations with metabolic and diabetes-related pathways. Splicing factor motif and cross-linking and immunoprecipitation sequencing analyses highlighted serine/arginine-rich splicing factor 10 (SRSF10) as a key regulator in this process, with its binding enriched at misspliced exons. Silencing SRSF10 in placental cells mirrored GDM-associated missplicing in key genes. These findings underscore splicing dysregulation as a critical process in GDM pathogenesis, suggesting that targeting SRSF10 could be a potential therapeutic approach to mitigate the deleterious effects of GDM. ARTICLE HIGHLIGHTS: Gestational diabetes mellitus (GDM) causes hyperglycemia during pregnancy and adverse maternal and neonatal outcomes. Bulk placental gene expression has been reported largely unchanged. RNA sequencing of Norwegian and Chinese GDM placentas reveals hundreds of differential splicing events enriched for metabolic- and diabetes-related pathways. Motif enrichment and cross-linking and immunoprecipitation sequencing integration identify serine/arginine splicing factor 10 as a key regulator of GDM-associated missplicing. Silencing serine/arginine splicing factor 10 in placental models recapitulates the GDM-associated missplicing program.
Cerebrospinal Fluid Fatty Acids, Hypothalamic Inflammation, and Weight Loss in Human Obesity: A Longitudinal Study.
Pané A, Videla L, Calvet-Mirabent À … +15 more , Castro-Barquero S, Viaplana J, Vaqué-Alcázar L, Ibarzabal A, Rozalem-Aranha M, Bejanin A, Moize V, Vidal J, de Hollanda A, Ortega E, Barroeta I, Camacho V, Chiva-Blanch G, Fortea J, Jiménez A
Diabetes · 2026 Jan · PMID 41247745 · Publisher ↗
UNLABELLED: Preclinical studies show that dietary or central administration of monounsaturated fatty acids (MUFAs) and polyunsaturated fatty acids (PUFAs) can reduce food intake, enhance energy expenditure, and attenuate...
UNLABELLED: Preclinical studies show that dietary or central administration of monounsaturated fatty acids (MUFAs) and polyunsaturated fatty acids (PUFAs) can reduce food intake, enhance energy expenditure, and attenuate hypothalamic inflammation (HI), whereas saturated fatty acids (SFAs) promote weight gain, HI, and neuronal injury. However, whether hypothalamic exposure to different fatty acids similarly influences HI and body weight in humans remains unclear. In this longitudinal study, we compared cerebrospinal fluid (CSF) free fatty acid (FFA) profiles between 19 normal-weight control participants and 44 individuals with obesity, both at baseline and 1 year after bariatric surgery (BS). We also examined associations between CSF FFA composition, MRI-based markers of HI (i.e., increased hypothalamic mean diffusivity [MD] and volume), and postoperative weight loss. At baseline, individuals with obesity had similar CSF concentrations of total FFA, SFA, and MUFA compared with control participants but significantly lower PUFA levels, mainly due to reduced docosahexaenoic acid (DHA) levels. BS did not substantially alter CSF FFA profiles. Lower baseline CSF DHA levels were associated with higher hypothalamic MD and independently predicted less weight loss at 1 year. Postoperative increases in CSF DHA levels correlated with reductions in hypothalamic MD. These findings suggest brain DHA level may influence hypothalamic microstructure and contribute to body weight regulation in human obesity. ARTICLE HIGHLIGHTS: Whether hypothalamic exposure to free fatty acid (FFA) species contributes to obesity and hypothalamic inflammation (HI) in humans is not yet defined. We compared cerebrospinal fluid FFA profiles between normal-weight control participants and individuals with obesity, before and after bariatric surgery (BS), and examined their associations with postoperative weight trajectories and neuroimaging biomarkers of HI. Individuals with obesity had reduced cerebrospinal fluid levels of docosahexaenoic acid (DHA) before and after BS. Lower cerebrospinal fluid DHA levels correlated with biomarkers of HI and were independently associated with less weight loss after BS. The findings highlight the potential of DHA in modulating hypothalamic function.
Baseline Insulin Secretion Determines Response to Abatacept in Stage 1 Type 1 Diabetes.
Galderisi A, Carr ALJ, Taylor P … +15 more , Bonet J, Cuthbertson D, Sosenko J, Sims EK, Evans-Molina C, Dalla Man C, Ismail HM, Nathan B, Petrelli A, Senior P, Sherr JL, Herold KC, Russell WE, Moran A, Dayan C
Diabetes · 2026 Jan · PMID 41237315 · Full text
UNLABELLED: Abatacept, a cytotoxic T lymphocyte–associated protein 4 immunoglobulin that inhibits T-cell costimulation, was evaluated for 12 months in stage 1 type 1 diabetes (T1D) to delay disease progression. Despite m...
UNLABELLED: Abatacept, a cytotoxic T lymphocyte–associated protein 4 immunoglobulin that inhibits T-cell costimulation, was evaluated for 12 months in stage 1 type 1 diabetes (T1D) to delay disease progression. Despite modest preservation of area under the curve C-peptide at 12 months, the primary end point was not met. We adopted the oral minimal model (OMM) to assess β-cell function over 48 months and explored how baseline insulin secretion (ϕtotal) modified treatment response. Using the OMM, ϕtotal was computed from oral glucose tolerance tests conducted at baseline and every 6 months. Participants were stratified into high- and low-secretor groups depending on baseline ϕtotal ≥33rd or <33rd centile, respectively. A sensitivity analysis was performed to validate threshold choice. Among 203 participants (abatacept n = 96; 107 placebo n = 107), 39% receiving abatacept and 47% receiving placebo experienced progression to stage 2 or 3 within 96 months. High secretors receiving abatacept gained 15.8 progression-free months (95% CI 4.85, 26.68; P = 0.005) and had a 54% lower hazard of progression versus those receiving placebo (hazard ratio [HR] 0.46; 95% CI 0.25, 0.84; P = 0.012). Treatment effect differed significantly by secretor status (interaction HR 2.92; 95% CI 1.23, 6.96; P = 0.015). A subgroup of responders to 12 months of abatacept was identified by ϕtotal, providing the first evidence that an immune intervention in stage 1 T1D may delay disease progression. ARTICLE HIGHLIGHTS: We sought to investigate whether baseline insulin secretion (ϕtotal), quantified using the oral minimal model assessing β-cell function, could identify a subgroup of responders to abatacept (a cytotoxic T lymphocyte-associated protein 4 immunoglobulin that inhibits T-cell costimulation) among those with stage 1 type 1 diabetes (T1D). Abatacept preserved ϕtotal during and up to 1 year after treatment cessation; high baseline secretors treated with abatacept gained ∼16 months of progression-free survival and had a 54% lower hazard of progression versus those receiving placebo, whereas no benefit was observed in low secretors. This is the first evidence of an immune intervention delaying disease progression in those with stage 1 T1D. Continued treatment may result in a greater delay in progression.
Development and Validation of a Type 1 Diabetes Multi-Ancestry Polygenic Score.
Deutsch AJ, Bell AS, Michalek DA … +17 more , Burkholder AB, Nam S, Kreienkamp RJ, Sharp SA, Huerta-Chagoya A, Mandla R, Nanjala R, Luo Y, Oram RA, Florez JC, Onengut-Gumuscu S, Rich SS, Ng MCY, Motsinger-Reif AA, Manning AK, Mercader JM, Udler MS
Diabetes · 2026 Jan · PMID 41236419 · Full text
UNLABELLED: Polygenic scores strongly predict type 1 diabetes risk, but most scores were developed in European-ancestry populations. In this study, we leveraged recent multiancestry genome-wide association studies to cre...
UNLABELLED: Polygenic scores strongly predict type 1 diabetes risk, but most scores were developed in European-ancestry populations. In this study, we leveraged recent multiancestry genome-wide association studies to create a Type 1 Diabetes Multi-Ancestry Polygenic Score (T1D MAPS). We trained the score in the Mass General Brigham (MGB) Biobank (372 individuals with type 1 diabetes) and tested the score in the All of Us program (86 individuals with type 1 diabetes). We evaluated the area under the receiver operating characteristic curve (AUC), and we compared the AUC to two published single-ancestry scores for European (EUR) and African (AFR) populations: T1D Genetic Risk Score 2 (GRS2EUR) and T1D GRSAFR. We also developed an updated score (T1D MAPS2) that combines T1D GRS2EUR and T1D MAPS. Among individuals with non-European ancestry, the AUC of T1D MAPS was 0.90, significantly higher than T1D GRS2EUR (0.82) and T1D GRSAFR (0.82). Among individuals with European ancestry, the AUC of T1D MAPS was slightly lower than T1D GRS2EUR (0.89 vs. 0.91). However, T1D MAPS2 performed equivalently to T1D GRS2EUR in European ancestry (0.91 vs. 0.91) and performed better in non-European ancestry (0.90 vs. 0.82). Overall, these findings advance the accuracy of type 1 diabetes genetic risk prediction across diverse populations. ARTICLE HIGHLIGHTS: Type 1 diabetes polygenic scores are highly predictive of disease risk, but their performance varies based on genetic ancestry. Can we develop a polygenic score that accurately predicts type 1 diabetes risk across diverse populations? Our novel polygenic score performs similar to existing scores in European populations, and it demonstrates superior performance in non-European populations. This polygenic score will improve prediction of type 1 diabetes risk in genetically diverse populations.
Protection Against Type 1 Diabetes Development in Mice With 4E-BP2 Deletion.
Pita-Grisanti V, Peçanha FLM, Louzada RA … +5 more , Blandino-Rosano M, Jaramillo C, Arenas N, Bayer A, Bernal-Mizrachi E
Diabetes · 2026 Jan · PMID 41236207 · Full text
UNLABELLED: Type 1 diabetes (T1D) is an autoimmune disease characterized by β-cell destruction promoted by autoreactive T cells. Eukaryotic translation initiation factor 4E (eIF4E)–binding protein 1 (4E-BP1) and 4E-BP2 a...
UNLABELLED: Type 1 diabetes (T1D) is an autoimmune disease characterized by β-cell destruction promoted by autoreactive T cells. Eukaryotic translation initiation factor 4E (eIF4E)–binding protein 1 (4E-BP1) and 4E-BP2 are translational repressors and downstream targets of mammalian target of rapamycin complex 1 (mTORC1). Activation of the 4E-BP2/eIF4E pathway by 4E-BP2 deletion promotes translation initiation, inducing β-cell expansion and proliferation and regulating adaptive immunity. However, the involvement of 4E-BP2 in T1D remains unexplored. This study aimed to determine the role of 4E-BP2/eIF4E signaling in T1D prevention. We used the NOD mouse model of T1D and generated mice with global 4E-BP2 deletion in the NOD background (Eif4ebp2−/−). We assessed T1D development, glucose homeostasis, pancreas morphometry, and immune responses in Eif4ebp2−/− and littermate control mice. We found that Eif4ebp2−/− male mice exhibited reduced diabetes incidence, which did not occur in female mice, as well as preserved β-cell mass, improved insulin secretion in vitro, and comparable insulitis. Characterization of T-cell compartments showed decreased splenic CD8+ cytotoxic T-cell proliferation and increased pancreatic regulatory T-cell infiltration in Eif4ebp2−/− mice, potentially resulting from increased proliferation and suppressive capacity. Adoptive transfer studies demonstrated that Eif4ebp2−/− male lymphocytes were less diabetogenic than those of controls. In conclusion, activation of 4E-BP2/eIF4E by 4E-BP2 deletion protected against T1D, supporting 4E-BP2 as a potential therapy target. ARTICLE HIGHLIGHTS: Mammalian target of rapamycin complex 1 (mTORC1) signaling is essential to β-cell mass, function, and adaptive immunity; however, its specific downstream mediators in type 1 diabetes (T1D) remain poorly defined. We investigated eukaryotic translation initiation factor 4E-binding protein 2 (4E-BP2), a major translational regulator downstream of mTORC1, by using global 4E-BP2-knockout mice on the NOD background. Loss of 4E-BP2 protected male NOD mice from T1D through preservation of β-cell mass and function, coupled with attenuation of autoimmune responses. These findings identify 4E-BP2 as a novel immunometabolic node, highlighting its potential as a therapeutic target for T1D prevention and treatment.
Obstructive Sleep Apnea, Resting Heart Rate, and Glycemic Variability in Adults With Maturity-Onset Diabetes of the Young.
Arosemena M, Chopra K, Salguero MV … +5 more , Reyes D, Naylor RN, Wroblewski K, Tasali E, Philipson LH
Diabetes · 2026 Jan · PMID 41232044 · Full text
UNLABELLED: Obstructive sleep apnea (OSA) is a common condition strongly linked to increased cardiovascular risk and poor glycemic control. Little is known about OSA, cardiovascular risk, and glycemia in maturity-onset d...
UNLABELLED: Obstructive sleep apnea (OSA) is a common condition strongly linked to increased cardiovascular risk and poor glycemic control. Little is known about OSA, cardiovascular risk, and glycemia in maturity-onset diabetes of the young (MODY), an inherited form of diabetes, which is different than both type 1 and type 2 diabetes. We assessed OSA, resting heart rate (RHR), an important prognostic marker of cardiovascular disease, and glycemic variability among the most common subtypes of MODY, glucokinase (GCK)-MODY, and transcription factor (TF)-related MODY (HNF1A, HNF4A, and HNF1B). Adults with GCK-MODY (n = 63) and TF-related MODY (n = 60) and control adults without diabetes (n = 65) were screened for OSA by home sleep test. Glycemic variability (continuous glucose monitoring) and RHR (wearable sleep-activity tracker) were concomitantly assessed for 2 weeks at home. Data from 188 individuals (2,853 recorded days) were analyzed. Individuals with TF-related MODY, compared with those with GCK-MODY or control individuals, had more OSA (48.3%, 27.0%, and 30.8%, respectively; P = 0.033), higher RHR (72.8 ± 10.8, 65.2 ± 7.9, and 67.3 ± 7.7 bpm, respectively; P < 0.001), and higher glycemic variability (coefficient of variation of glucose 31.6 ± 6.0%, 17.3 ± 4.5%, and 17.5 ± 4.0%, respectively; P < 0.001). Greater severity of OSA and higher RHR were associated with higher glycemic variability. These findings may have important clinical implications for cardiovascular risk assessment in MODY. ARTICLE HIGHLIGHTS: Obstructive sleep apnea (OSA) has been strongly linked to increased cardiovascular risk and poor glycemic control in the general population. Resting heart rate (RHR) is a prognostic marker of cardiovascular morbidity and mortality and has been linked to dysglycemia. Little is known about OSA, RHR, and glycemia in maturity-onset diabetes of the young (MODY), an inherited form of diabetes with discrete clinical features. Adults with transcription factor-related MODY (HNF1A, HNF4A, and HNF1B) had more OSA and higher RHR and greater glycemic variability compared with those with glucokinase-MODY or control adults without diabetes, which may have important clinical implications for future cardiovascular risk.
Killing of Human β-Cells by CD8+ T Cells Triggers Inflammatory Paracrine Signaling and Neighboring β-Cell Dysfunction.
Oshima M, Halliez C, Kobaisi F … +7 more , Modé N, Fouque A, Brandao B, Mayeur O, Balboa D, Mallone R, Scharfmann R
Diabetes · 2026 Jan · PMID 41218919 · Publisher ↗
UNLABELLED: Type 1 diabetes is a progressive autoimmune disease characterized by the selective destruction of insulin-producing β-cells by CD8+ T cells. Although the mechanisms of antigen-specific β-cell killing are well...
UNLABELLED: Type 1 diabetes is a progressive autoimmune disease characterized by the selective destruction of insulin-producing β-cells by CD8+ T cells. Although the mechanisms of antigen-specific β-cell killing are well established, the broader consequences of this targeted destruction on neighboring β-cells that escape direct T-cell receptor (TCR)-mediated attack remain poorly understood. Here, we developed a coculture model of HLA-A2-expressing human β-cells cultured as pseudoislets and CD8+ T cells specific for the INS15-24 epitope. Using this new in vitro model, we demonstrate that 1) β-cell death induced by CD8+ T cells strictly depends on TCR-HLA class I interactions and 2) neighboring β-cells that evade direct T-cell contact do not alter β-cell identity or glucose-stimulated insulin secretion. However, they exhibit increased expression of inflammatory markers, reduced insulin content, and impaired protein translation. The robust, versatile, and readily applicable model described here represents a strong basis to further address paracrine signaling that extend beyond direct cytotoxicity. ARTICLE HIGHLIGHTS: In type 1 diabetes, CD8+ T cells destroy pancreatic β-cells. Since most β-cells avoid direct T-cell contact, we asked whether bystander effects drive their dysfunction and loss. We asked whether CD8+ T cells can damage β-cells indirectly via bystander inflammation. By developing and using a chimeric pseudoislet model, we show that β-cell killing requires direct CD8+ T-cell contact, contact-free β-cells are impacted by inflammation, that these effects are reproduced using conditioned medium from activated CD8+ T cells, and that insulin secretion is preserved with reduced storage and impaired protein translation. Our model provides a platform to dissect type 1 diabetes pathogenesis and test therapies to preserve β-cells.
miR-432 Exacerbates Obesity-Induced Dysregulation of Glucose and Lipid Homeostasis.
Wang C, Hou Y, Zhang M … +7 more , Wang J, Chu X, Liang M, Sun C, Xie J, Zhang J, Wang CY
Diabetes · 2026 Jan · PMID 41218910 · Full text
UNLABELLED: miRNAs are key regulators of metabolic homeostasis, yet their role in obesity-associated dysfunction remains incompletely understood. Here, we identify miR-432 as a driver of systemic metabolic dysregulation....
UNLABELLED: miRNAs are key regulators of metabolic homeostasis, yet their role in obesity-associated dysfunction remains incompletely understood. Here, we identify miR-432 as a driver of systemic metabolic dysregulation. Serum miRNA profiling revealed a positive correlation between miR-432 expression and obesity/type 2 diabetes mellitus. Functionally, adipose-specific miR-432 exacerbated high-fat diet-induced obesity and insulin resistance. Similarly, hepatic-specific miR-432 aggravated hepatic steatosis and systemic glucose dysregulation, while skeletal muscle-specific miR-432 disrupted glucose homeostasis without affecting body composition. Mechanistically, miR-432 disrupted insulin sensitivity by inhibiting the PIK3R3/AKT pathway and perturbed lipid homeostasis by suppressing the PIK3R3/PPAR-α axis. Notably, obesity-induced miR-432 upregulation was predominantly localized in adipocytes and driven by the CDK5/PPAR-γ axis. Furthermore, adipocyte-derived exosomal miR-432 was identified as a mediator of systemic metabolic dysfunction, facilitating intertissue cross talk in obesity. Collectively, our data demonstrate that miR-432 exacerbates obesity-induced dysregulation of glucose and lipid metabolism. ARTICLE HIGHLIGHTS: miR-432 overexpression in adipose tissue, liver, and skeletal muscle exacerbates high-fat diet-induced disruption of metabolic homeostasis. miR-432 impairs glucose homeostasis by suppressing the PIK3R3/AKT pathway and disrupts lipid homeostasis via inhibition of the PIK3R3/PPAR-α axis or directly suppressing PPAR-α. Obesity-induced elevation of miR-432 is predominantly localized in adipocytes and driven by the CDK5/PPAR-γ axis. Adipocyte-derived exosomal miR-432 mediates systemic metabolic dysfunction, establishing an intertissue regulatory network.
β-Hydroxybutyrylation Links Ketone Metabolism to Mitochondrial Remodeling in Diabetic Cardiomyopathy.
Jing H, Shi M, Wang Y … +5 more , Cao R, Li X, Zhong X, Dong S, Wei C
Diabetes · 2026 Jan · PMID 41213123 · Publisher ↗
UNLABELLED: Diabetic cardiomyopathy (DbCM) is characterized by metabolic remodeling and energetic stress independent of coronary artery disease. Increased reliance on fatty acid and ketone body metabolism has been observ...
UNLABELLED: Diabetic cardiomyopathy (DbCM) is characterized by metabolic remodeling and energetic stress independent of coronary artery disease. Increased reliance on fatty acid and ketone body metabolism has been observed in DbCM, but the regulatory mechanisms linking altered substrate use to myocardial dysfunction remain poorly understood. In particular, lysine β-hydroxybutyrate (Kbhb), a ketone body-derived, posttranslational modification, has emerged as a potentially critical regulator but has not been fully investigated. We conducted a comprehensive multiomics study integrating metabolomics, transcriptomics, proteomics, and Kbhb-specific proteomics on myocardial tissues in a well-established mouse model of DbCM. Kbhb-modified proteins were systematically mapped and quantified, followed by motif, subcellular localization, and protein-protein interaction analyses. DbCM cardiac tissue exhibited coordinated upregulations of fatty acid β-oxidation, ketone metabolism, and tricarboxylic acid cycle activity at the transcriptomic, proteomic, and metabolomic levels. Kbhb profiling revealed extensive mitochondrial protein modification, with Atp5f1a-K239 identified as a key modification site strongly correlated with β-hydroxybutyrate and isocitric acid concentrations. This study identifies Kbhb as a potential metabolic-epigenetic modifier linking ketone body availability to the regulation of mitochondrial proteins in DbCM. Our findings provide novel insights into metabolic-epigenetic cross talk and identify potential therapeutic targets for interventions to restore mitochondrial function in alleviating diabetic heart disease. ARTICLE HIGHLIGHTS: We performed a multiomics study to better understand dysfunctions in diabetic cardiomyopathy (DbCM) and specifically identify links between lysine β-hydroxybutyrylation (Kbhb), a ketone body-derived, posttranslational modification, and cardiac dysfunction. DbCM cardiac tissue exhibited coordinated upregulations of fatty acid β-oxidation, ketone metabolism, and tricarboxylic acid cycle activity at the transcriptomic, proteomic, and metabolomic levels. Mitochondrial proteins showed that high Kbhb modification and modification of the Atp5f1a-K239 site were strongly correlated with high β-hydroxybutyrate and isocitric acid concentrations. This study identifies Kbhb modification of mitochondrial proteins as a potential mechanism linking ketone body availability to mitochondrial function in DbCM.
Additive Effects of Dorzagliatin and Glucagon-Like Peptide 1 Receptor Agonism in a Novel Mouse Model of GCK-MODY and in Obese db/db Mice.
Salazar S, Delgadillo-Silva LF, Carapeto P … +12 more , Kenfaoui MM, Dakessian K, Melhem R, Provencher-Girard A, Ostinelli G, Turgeon J, Kaci I, Migneault F, Huising MO, Hébert MJ, Chaker-Margot M, Rutter GA
Diabetes · 2026 Jan · PMID 41196662 · Full text
UNLABELLED: Glucokinase (GK) catalyzes the key regulatory step in glucose-stimulated insulin secretion (GSIS). Correspondingly, hetero- and homozygous mutations in human GCK cause maturity-onset diabetes of the young (GC...
UNLABELLED: Glucokinase (GK) catalyzes the key regulatory step in glucose-stimulated insulin secretion (GSIS). Correspondingly, hetero- and homozygous mutations in human GCK cause maturity-onset diabetes of the young (GCK-MODY) and permanent neonatal diabetes mellitus, respectively. To explore the possible utility of GK activators (GKAs) and of glucagon-like peptide 1 (GLP-1) receptor agonists in these diseases, we have developed a novel hypomorphic Gck allele in mice encoding an aberrantly spliced mRNA. In islets from homozygous knock-in (GckKI/KI) mice, GK immunoreactivity was reduced by >85%, and GSIS eliminated. Homozygous GckKI/KI mice displayed frank diabetes (fasting blood glucose >18 mmol/L; HbA1c ∼108 mmol/mol), ketosis, and nephropathy. Heterozygous GckKI/+ mice were glucose intolerant (HbA1c ∼37 mmol/mol). Abnormal glucose-stimulated Ca2+ dynamics in GckKI/+ islets were completely reversed by the GKA dorzagliatin, which was largely inactive in homozygous GckKI/KI mouse islets. The GLP-1 receptor agonist exendin-4 improved glucose tolerance in male GckKI/+ mice, an action potentiated by dorzagliatin. Sex-dependent additive effects of these agents were also observed on insulin secretion in vitro. Similar additive effects of the drugs were observed in obese hyperglycemic db/db mice. Combined treatment with GKA and incretin mimetics may thus be useful in GCK-MODY and in more common forms of type 2 diabetes. ARTICLE HIGHLIGHTS: Glucokinase (GK) deficiency can drive maturity-onset diabetes of the young (GCK-MODY) in heterozygotes and permanent neonatal diabetes in homozygotes. We describe a hypomorphic Gck allele that results in aberrant splicing in islets and liver lowering GK activity by ∼85%. Whereas heterozygous mutant mice are mildly hyperglycemic, homozygotes have frank diabetes but survive to adulthood. Dorzagliatin potentiates the effects of glucagon-like receptor-1 receptor activation sex dependently in heterozygous Gck mice and in obese hyperglycemic db/db mice. Combined use of these drugs may be useful in some forms of GCK-MODY and in obesity-related type 2 diabetes.
Flt3L-Derived Antigen-Presenting Cell Transfer in Neonatal NOD Mice Reduces the Incidence of Type 1 Diabetes.
Orozco S, Aljobaily N, Reynolds HM … +4 more , Oceguera GA, Lee T, Bettini M, Bettini ML
Diabetes · 2026 Jan · PMID 41196654 · Full text
UNLABELLED: Type 1 diabetes (T1D) is an autoimmune disease characterized by progressive stages culminating in T-cell-mediated destruction of the β-cells at the islets of Langerhans. The immune mechanisms that initiate T1...
UNLABELLED: Type 1 diabetes (T1D) is an autoimmune disease characterized by progressive stages culminating in T-cell-mediated destruction of the β-cells at the islets of Langerhans. The immune mechanisms that initiate T1D are not fully resolved but likely involve an interaction between proinflammatory antigen-presenting cells (APCs) and autoreactive T cells that initiate immune infiltration and activation. Previous studies have tested the use of tolerogenic APCs in adult female NOD mice to delay or prevent T1D with only slight to intermediate success. Moreover, immune infiltration begins as early as age 4 weeks; therefore, targeting autoreactive T cells with tolerogenic APCs in adult mice may not impact later stages of diabetes. Thus, we hypothesize that the transfer of tolerogenic APCs at the neonatal stage prior to priming and immune infiltration will result in effective protection from autoimmunity. Our studies demonstrate that immature APCs travel to the pancreatic draining lymph nodes, alter the cytokine milieu in young mice, divert autoreactive CD4+ T cells to anergy, and drastically decrease proliferation and function of cytotoxic lymphocytes in adult prediabetic mice, leading to a significant reduction in the incidence of T1D. ARTICLE HIGHLIGHTS: Neonatal transfer of immature dendritic cell-enriched Flt3L splenocytes significantly reduces the incidence of type 1 diabetes in female NOD mice. Early time points are associated with accumulation of anergic T cells. In adult mice, there is a reduction in CD4 T helper 1 cells and reduced proliferation and perforin of CD8 T cells. Our work demonstrates how targeting the neonatal window of tolerance alters autoimmunity outcome.
Lysyl Oxidase Promotes Actin-Dependent Neutrophil Activation and Cytotoxicity Toward Retinal Endothelial Cells in Diabetes.
Agarwal M, Chandrakumar S, Santiago Tierno I … +4 more , Lessieur EM, Bollinger ZR, Kern TS, Ghosh K
Diabetes · 2026 Jan · PMID 41187296 · Full text
UNLABELLED: Activated neutrophils contribute to retinal endothelial cell (EC) death and capillary degeneration associated with early diabetic retinopathy (DR), a major vision-threatening complication of diabetes. However...
UNLABELLED: Activated neutrophils contribute to retinal endothelial cell (EC) death and capillary degeneration associated with early diabetic retinopathy (DR), a major vision-threatening complication of diabetes. However, the factors and mechanisms driving neutrophil activation and cytotoxicity in diabetes remain insufficiently understood. Here, we show that lysyl oxidase (LOX), a matrix cross-linking and stiffening enzyme that increases retinal EC susceptibility to activated neutrophils, simultaneously activates neutrophils in its soluble form. Specifically, treatment of diabetic mice with LOX inhibitor β-aminopropionitrile (BAPN) prevented the diabetes-induced increase in neutrophil activation (extracellular release of neutrophil elastase and superoxide) and cytotoxicity toward cocultured mouse retinal ECs. Mouse neutrophils and differentiated (neutrophil-like) human HL-60 cells treated with recombinant LOX alone exhibited significant activation and cytotoxicity. Mechanistically, this LOX-induced neutrophil activation was associated with biphasic F-actin remodeling, with the initial and rapid (∼10 min) F-actin depolymerization followed by a significant increase in F-actin polymerization and polarization. Preventing the initial F-actin depolymerization blocked LOX-induced neutrophil activation and cytotoxicity toward cocultured retinal ECs. Finally, this biphasic F-actin remodeling was found to be essential for LOX-induced membrane aggregation of azurophilic granule marker CD63 and NADPH organizer p47phox, which are associated with extracellular release of neutrophil elastase and superoxide, respectively. By revealing a previously unrecognized causal link between LOX and actin-dependent neutrophil activation in diabetes, these findings provide fresh mechanistic insights into the proinflammatory role of LOX in early DR that goes beyond its canonical matrix-stiffening effects. ARTICLE HIGHLIGHTS: Activated neutrophils kill retinal endothelial cells (ECs) in early diabetic retinopathy, but how neutrophils become activated in diabetes is not well understood. We found that lysyl oxidase (LOX), whose matrix-localized form activates retinal ECs, can also directly activate neutrophils in its soluble form. LOX-induced release of neutrophil elastase and superoxide is mediated by actin remodeling and membrane aggregation of azurophilic granules. The dual ability of LOX to activate neutrophils (in its soluble form) and retinal ECs (in its matrix-localized form) implicates it as a key proinflammatory target for early diabetic retinopathy.
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