Diabetes[JOURNAL]
Sun
200 papers
Diabetes Spotlight: Susan Bailey Gurley, MD, PhD-Charting Hypertension and Diabetic Nephropathy Through Mouse Models.
Page B
Diabetes · 2026 Jan · PMID 41417983 · Publisher ↗
Abstract loading — click title to view on PubMed.
Imaging Hypoxia in the Diabetic Retina: A Potential Early-Detection Imaging Biomarker Before Detectable Retinopathy in Diabetes.
Uddin MI, Dieckmann B, Burgos DE
Diabetes · 2026 Mar · PMID 41416829 · Full text
UNLABELLED: Current imaging technologies cannot detect diabetic retinopathy until there has been significant permanent damage to patients' vision. We hypothesized that hyperglycemia causes retinal hypoxia, and hypoxia ma...
UNLABELLED: Current imaging technologies cannot detect diabetic retinopathy until there has been significant permanent damage to patients' vision. We hypothesized that hyperglycemia causes retinal hypoxia, and hypoxia may lead to apoptosis of retinal cells. We performed experiments using a mouse model of streptozotocin (STZ)-induced diabetes to investigate the role of hyperglycemia in diabetic eye disease. Our experimental results indicate that diabetic retinas are significantly hypoxic compared with nondiabetic controls. Retinal hypoxia can be detected using HYPOX-4, an early-detection imaging probe, potentially before any detectable changes in the diabetic retina. In the early stages of diabetes, we did not observe any detectable changes in electroretinography response, vascular permeability in fluorescein angiography, or retinal thickness in optical coherence tomographic imaging. In addition, increased HYPOX-4 fluorescence in the diabetic retina was not associated with focal ischemia; rather, increased levels of HYPOX-4 fluorescence were observed throughout the entire diabetic retina. Moreover, hypoxia profiles in STZ-induced diabetic retinas were colocalized with TUNEL-positive apoptotic cells. To confirm the role of hyperglycemia in the diabetic retina, human retinal cells were treated under hyperglycemic conditions, and hypoxia was monitored using the pimonidazole-adduct immunostaining method. Surprisingly, retinal cells became hypoxic under hyperglycemic conditions within the first few hours. We conclude that the diabetic retina becomes hypoxic as a result of hyperglycemia in the early stage of diabetes, which could lead to the degeneration of retinal cells at later stages of the disease. In addition, HYPOX-4 could be used as a powerful early diagnostic imaging method to detect retinal hypoxia in the diabetic retina before any detectable retinopathy. ARTICLE HIGHLIGHTS: Hyperglycemia causes retinal hypoxia. Hypoxia may lead to apoptosis of retinal cells. Retinal hypoxia can be detected before any detectable changes in the diabetic retina. HYPOX-4 is a powerful early diagnostic imaging method to detect hypoxia in the diabetic retinas of living patients.
Toward Scientific Rigor: Setting Standards for Indirect Calorimetry Analysis and Reporting.
Lieu EL, Herman MA, Hartig SM
Diabetes · 2026 Mar · PMID 41405847 · Full text
Indirect calorimetry determines energy expenditure by measuring respiratory gas exchange. The approach is based on the principle that nutrient metabolism consumes O2 and produces CO2 and water in predictable ratios that...
Indirect calorimetry determines energy expenditure by measuring respiratory gas exchange. The approach is based on the principle that nutrient metabolism consumes O2 and produces CO2 and water in predictable ratios that can be compared with heat production. Due to the impracticality and high cost of direct calorimetry, indirect calorimetry is the major approach for modern metabolic studies in preclinical models. Despite the broad adoption of this method in rodent phenotyping, the field has lacked standardized methods for analyzing, representing, and sharing these data, limiting scientific progress. The recent review in Nature Metabolism by the International Indirect Calorimetry Consensus Committee (IICCC) addresses the lack of standardized methods by providing updated guidelines for data processing and representation and emphasizes the importance of shared data repositories tailored to these studies. These expert consensus standards aim to improve transparency, facilitate data sharing and archiving, and enhance cross-study comparability. We encourage authors submitting to Diabetes to adopt the IICCC guidelines to strengthen rigor and reproducibility in the field.
Mitochondrial mGPDH Modulates Fibroblast Function in Diabetic Wound Healing via the SIRT1-c-Myc-TGF-β1 Axis.
Zhou L, Hong Y, Li X … +13 more , Zhang Y, Zhang L, Peng G, Qu H, Liao X, Liao M, Yang Y, Cheng L, Leng W, Zheng Y, Zhang Y, Zheng H, Long M
Diabetes · 2026 Mar · PMID 41401074 · Full text
UNLABELLED: Fibroblasts play a pivotal role in wound healing, particularly during the proliferative and remodeling phase, where they migrate to the injury site, proliferate, and synthesize essential extracellular matrix...
UNLABELLED: Fibroblasts play a pivotal role in wound healing, particularly during the proliferative and remodeling phase, where they migrate to the injury site, proliferate, and synthesize essential extracellular matrix (ECM) components such as collagen and fibronectin (FN). However, fibroblast functionality is compromised because of factors such as vascular dysfunction and oxidative stress in diabetic wounds, leading to chronic inflammation and delayed healing. This study investigates the role of mitochondrial glycerol-3-phosphate dehydrogenase (mGPDH), a key enzyme in energy metabolism, in regulating fibroblast function during diabetic wound healing. We demonstrate that mGPDH is overexpressed in diabetic wounds and in fibroblasts cultured under high-glucose conditions, contributing to impaired ECM repair. Importantly, the inhibition of mGPDH restores fibroblast functionality by enhancing ECM synthesis, increasing the levels of collagen IV and α-smooth muscle actin (α-SMA) proteins, and accelerating wound healing. Mechanistically, mGPDH deficiency activates the SIRT1-c-Myc-TGF-β1 signaling axis, resulting in reduced c-Myc protein stability, alleviation of its inhibitory effects on TGF-β1 signaling, and subsequent activation of ECM synthesis pathways. This study highlights the role of mGPDH in regulating fibroblast migration and ECM secretion, without affecting apoptosis or proliferation, thereby underscoring its selective regulatory role in wound healing. These findings establish mGPDH as a pivotal regulatory node in fibroblast function during diabetic wound healing, providing a foundation for the development of localized therapeutic strategies aimed at restoring fibroblast activity and improving wound healing outcomes in patients with diabetes. ARTICLE HIGHLIGHTS: Mitochondrial glycerol-3-phosphate dehydrogenase (mGPDH) is elevated in diabetic wounds; its inhibition enhances extracellular matrix production and wound closure. mGPDH deficiency activates SIRT1, deacetylating c-Myc to boost TGF-β1 and extracellular matrix production synthesis genes. Targeted mGPDH inhibition can restore fibroblast function and accelerate wound healing in diabetes.
miR-494 Deletion Improves Glucose Metabolism Independently of Obesity in Mice.
Sugawara L, Morino K, Iwasaki H … +13 more , Ohashi N, Ida S, Murata K, Yanagimachi T, Miyazawa I, Lemecha M, Imamura T, Ugi S, Mizuno S, Takahashi S, Fujita Y, Maegawa H, Kume S
Diabetes · 2026 Mar · PMID 41384877 · Publisher ↗
UNLABELLED: The browning of white adipose tissue (WAT) enhances thermogenesis and represents a promising approach for combating obesity and metabolic disorders. miRNA-494 (miR-494) acts as a suppressor of browning in cul...
UNLABELLED: The browning of white adipose tissue (WAT) enhances thermogenesis and represents a promising approach for combating obesity and metabolic disorders. miRNA-494 (miR-494) acts as a suppressor of browning in cultured adipocytes via regulation of peroxisome proliferator-activated receptor γ coactivator 1α, and its inhibition is expected to promote browning and thereby improve obesity and metabolic disorders. To assess its in vivo role and therapeutic potential, we generated miR-494-knockout (KO) mice using CRISPR/Cas9. KO mice showed increased browning of WAT and resistance to high-fat diet-induced obesity. Notably, they also exhibited improved glucose tolerance, even under normal chow feeding conditions without weight loss. Ex vivo analysis revealed enhanced β-adrenergic-stimulated oxidative phosphorylation directly induced by miR-494 deletion. Metabolomic and Seahorse analyses further suggested accelerated glucose metabolism independent of insulin secretion or sensitivity. Analysis of human adipose tissue transcriptomic data supported the association between low miR-494 expression and better glucose tolerance without weight differences. These findings suggest that suppression of miR-494 improves glucose metabolism through both insulin-dependent and insulin-independent mechanisms, independently of changes in body weight. Targeting miR-494 could represent a potential therapeutic strategy for obesity and various forms of diabetes. ARTICLE HIGHLIGHTS: Browning of white adipose tissue enhances energy expenditure and may improve metabolic health; however, it remains unclear whether inhibition of its suppressor, miRNA-494 (miR-494), can exert therapeutic effects in vivo. We investigated whether genetic deletion of miR-494 expression in vivo promotes adipocyte browning, exerts antiobesity effects, and improves glucose tolerance. miR-494-knockout mice showed resistance to high-fat diet-induced obesity and improved glucose tolerance, even under normal chow feeding conditions. miR-494 inhibition may offer a therapeutic strategy for improving glycemic control through both insulin-dependent and insulin-independent mechanisms, independently of changes in body weight.
Type 2 Diabetes Genetic Risk and Type 1 Diabetes Heterogeneity and Progression.
Triolo TM, Sosenko JM, Cuthbertson D … +13 more , Oram RA, Parikh HM, Steck AK, Sims EK, Jacobsen LM, Nathan B, Templeman EL, Onengut-Gumuscu S, Evans-Molina C, Rich SS, Atkinson MA, Redondo MJ, Type 1 Diabetes TrialNet Study Group*
Diabetes · 2026 Jan · PMID 41369591 · Full text
UNLABELLED: Insulin secretion varies widely in preclinical type 1 diabetes. To understand the pathogenesis of this metabolic heterogeneity, we asked whether genetic predisposition to type 2 diabetes, quantified by a type...
UNLABELLED: Insulin secretion varies widely in preclinical type 1 diabetes. To understand the pathogenesis of this metabolic heterogeneity, we asked whether genetic predisposition to type 2 diabetes, quantified by a type 2 diabetes genetic risk score (T2D-GRS), modulates β-cell function and disease progression in individuals at risk of type 1 diabetes. We analyzed 4,324 islet autoantibody–positive TrialNet Pathway to Prevention participants with genome-wide genotyping and oral glucose tolerance testing. Both T2D-GRS and the type 1 diabetes genetic risk score 2 (T1D-GRS2) differed significantly across five previously described groups defined by C-peptide area under the curve (AUC; a measure of insulin secretion). The highest C-peptide AUC group, compared with the lowest, had significantly higher T2D-GRS, lower T1D-GRS2, higher BMI z-score, greater insulin resistance, older age, and lower prevalence of male participants; multiple islet autoantibody positivity; and IA-2 or insulin autoantibody positivity. Progression to clinical (stage 3) type 1 diabetes was significantly associated with T1D-GRS2 across all groups and with T2D-GRS in all but the lowest C-peptide AUC group. In conclusion, type 2 diabetes genetic burden shapes metabolic heterogeneity and accelerates progression in preclinical type 1 diabetes. These results support the evaluation of type 2 diabetes–related mechanisms as targets to improve the prediction and prevention of type 1 diabetes. ARTICLE HIGHLIGHTS: Heterogeneity in β-cell function is a barrier to precision medicine in type 1 diabetes. We asked whether type 2 diabetes-associated genes influence insulin secretion and progression to clinical type 1 diabetes in autoantibody-positive individuals. A type 2 diabetes genetic risk score was associated with higher C-peptide area under the curve (AUC) and increased clinical type 1 diabetes risk in all but the lowest C-peptide AUC subgroup. Addressing type 2 diabetes mechanisms could improve type 1 diabetes prediction and prevention.
Phosphatidylserine Supplementation Improves Metabolic Liver Disease and Glycemic Control in the Presence of Suppressed Oxidative Glucose Metabolism.
Dong L, Lin S, Slavin J … +6 more , Gunnam S, Cheng Z, Nie S, Leeming MG, Williamson NA, Montgomery MK
Diabetes · 2026 Jan · PMID 41348177 · Publisher ↗
UNLABELLED: Type 2 diabetes and obesity are commonly accompanied by metabolic dysfunction–associated steatotic liver disease (MASLD), increasing the risk of developing metabolic dysfunction–associated steatohepatitis (MA...
UNLABELLED: Type 2 diabetes and obesity are commonly accompanied by metabolic dysfunction–associated steatotic liver disease (MASLD), increasing the risk of developing metabolic dysfunction–associated steatohepatitis (MASH) and fibrosis. The early stages of MASLD are characterized by dysfunctional lipid metabolism, including remodeling of the hepatic lipidome. In this context, reductions in hepatic phosphatidylserine (PS) have been associated with increased hepatic steatosis, inflammation, and fibrosis. In this study, we investigated the impact of dietary PS supplementation on liver function and systemic metabolic homeostasis in mice with hepatic steatosis and MASH. Taking advantage of the MUP-uPA mouse model, including wild-type mice with hepatic steatosis and MUP-uPA mice with MASH and fibrosis, we showed that PS supplementation reduces hepatic triglyceride accumulation, inflammation, and fibrosis in male MUP-uPA mice. Supporting these data, PS supplementation suppressed fibrogenic gene expression in LX-2 hepatic stellate cells. We further showed that PS supplementation improved glycemic control and insulin sensitivity in male and female mice, which was associated with enhanced insulin signaling in muscle and liver, despite a pronounced suppression of glycolysis, glucose oxidation, and glycogen breakdown in liver, muscle, and/or adipose tissue. Metabolic flux analysis suggested a shift in substrate use, favoring fatty acid metabolism, particularly in muscle, while further pointing to marked improvements in mitochondrial function and oxidative capacity. These findings indicate that PS exerts multifaceted benefits by improving both MASH and whole-body glucose homeostasis, independent of conventional oxidative glucose metabolism. Our results support further investigation into dietary PS as a potential complementary strategy for MASH and glycemic control. ARTICLE HIGHLIGHTS: The prevalence of metabolic dysfunction-associated steatohepatitis (MASH) and type 2 diabetes is increasing. We show that dietary phosphatidylserine supplementation reduces hepatic lipid accumulation, inflammation, and liver fibrosis while further improving blood glucose control and insulin sensitivity in mice with MASH and insulin resistance. Improvements in glycemic control are present despite suppression of glycolysis, glucose oxidation, and glycogen breakdown in liver, skeletal muscle, and/or adipose tissue. In contrast, oxidative lipid metabolism and overall mitochondrial function are enhanced in skeletal muscle.
Altered Molecular Regulation of TUG Is a Central Feature of Insulin-Resistant Human Adipose Tissue.
Strober JW, Ter Horst KW, Sung D … +12 more , Jongejan A, Slusher AL, Gassaway BM, Tarabra E, Paulo JA, Shuken SR, Gygi SP, Santoro N, Caprio S, Serlie MJ, Bogan JS, Vatner DF
Diabetes · 2026 Jan · PMID 41347935 · Full text
UNLABELLED: White adipose tissue (WAT) insulin resistance (IR) is a central feature of metabolic syndrome; however, data regarding defects in WAT insulin signaling in humans with IR is limited. To determine which defects...
UNLABELLED: White adipose tissue (WAT) insulin resistance (IR) is a central feature of metabolic syndrome; however, data regarding defects in WAT insulin signaling in humans with IR is limited. To determine which defects in WAT insulin signaling are associated with human IR, WAT was obtained from three cohorts of patients with obesity. In a bariatric surgery cohort (RESOLVE), subcutaneous WAT (n = 24) was collected before and after weight loss, and RNA sequencing was performed. In another bariatric surgery cohort (SODA), glucose- or fructose-sweetened beverages were consumed before subcutaneous and omental WAT collection, and proteomic data were collected (n = 16). In an adolescent cohort, subcutaneous WAT (n = 14) was collected before and during hyperinsulinemic clamps, and both quantitative PCR and immunoblotting were performed. The TC10–tether containing a UBX domain for GLUT4 (TUG) pathway regulates GLUT4 translocation and glucose uptake in insulin-responsive tissues. Expectedly, in the adipose tissue from all three cohorts, GLUT4 content decreased in those with IR. TUG, which traps insulin-responsive GLUT4 vesicles in intracellular pools, was increased in the setting of IR in all three cohorts. Furthermore, expression of multiple components of the TC10–TUG pathway was altered with IR. Therefore, human WAT IR is characterized by altered molecular regulation of the TC10–TUG pathway, underscoring the importance of this pathway to WAT metabolic health. ARTICLE HIGHLIGHTS: There is a paucity of data regarding defects in insulin signaling in insulin-resistant human white adipose tissue (WAT). The tether containing a UBX domain for GLUT4 (TUG) protein, which retains GLUT4 vesicles, was increased in WAT of participants with greater insulin resistance in three different cohorts with obesity. Components of the TUG regulatory signaling pathway were differentially expressed between participants with greater insulin resistance and those with greater insulin sensitivity. TUG may provide an important pharmacologic target in the treatment or prevention of metabolic dysfunction in patients with obesity.
Maternal Obesity Leads to Muscle Dysfunction via H19-Mediated Programming of Insulin-Like Growth Factor 2 Signaling.
Islam S, Li X, Hossain MN … +5 more , Kou Z, Chen LW, Deavila JM, Zhu MJ, Du M
Diabetes · 2026 Jan · PMID 41335523 · Full text
UNLABELLED: Forty-two percent of American women of childbearing age have obesity, impacting offspring muscle and metabolism. The insulin-like growth factor 2 (IGF2) pathway is vital for muscle growth, but its regulation...
UNLABELLED: Forty-two percent of American women of childbearing age have obesity, impacting offspring muscle and metabolism. The insulin-like growth factor 2 (IGF2) pathway is vital for muscle growth, but its regulation by maternal obesity (MO) remains unclear. H19, a long noncoding RNA, is reciprocally regulated with Igf2, which has multiple promoters (P0–P3). H19 interacts with EZH2, the catalytic subunit of polycomb repressive complex 2 depositing H3K27me3. We found that MO increased fetal H19 expression and investigated how H19 epigenetically regulates Igf2 in offspring muscle. C57BL/6J female mice were fed a control (10% fat) or high-fat diet (45% fat) to induce obesity before mating, continuing through pregnancy and lactation. Neonates were sampled for biochemical analysis, and 3-month-old offspring were used for assessing muscle function and metabolism. MO increased H19 expression, enhancing H19-EZH2 interaction and H3K27me3-mediated repression of Igf2 in the P3 promoter, leading to hypermethylation and impaired muscle function in offspring. In addition, offspring with myogenic cell-specific H19 overexpression were also used. Weaning offspring with H19 overexpression showed reduced muscle mass, strength, and endurance and altered structure. Primary myogenic cells from H19 overexpressing neonates showed suppressed Igf2 expression, promoter activity, and myotube formation, which were recovered upon IGF2 treatment. In C2C12 and human skeletal myoblast cells, H19 overexpression disrupted IGF2 signaling, increased EZH2 recruitment, and reduced myotube formation, while its knockdown had opposite effects. Additionally, EZH2 inhibition reduced H3K27me3 deposition and methylation in the Igf2 P3 promoter. These data show that MO impairs muscle development by disrupting IGF2 signaling through H19-EZH2 interaction, affecting offspring muscle function. ARTICLE HIGHLIGHTS: H19-mediated epigenetic modifications alter Igf2 promoter activity, leading to persistent Igf2 suppression in maternal obesity (MO) offspring, causing long-term muscle dysfunction. MO increases H19 expression and enhances EZH2 recruitment and H3K27me3 deposition in the Igf2 P3 promoter, leading to higher DNA methylation. H19-EZH2 axis provides a potential therapeutic target for mitigating MO-induced muscle dysfunction and improving offspring metabolic health.
Profiling Associations Between IGHG-FCGR Ligand-Receptor Interactions and Disease Progression From Stage 1 and 2 to Stage 3 Type 1 Diabetes.
Zhao LP, Papadopoulos GK, Skyler JS … +10 more , Parikh HM, Kwok WW, Lybrand TP, Bondinas GP, Moustakas AK, Wang R, Pyo CW, Nelson WC, Geraghty DE, Lernmark Å
Diabetes · 2026 Jan · PMID 41335420 · Full text
UNLABELLED: The primary objective of this study was to investigate whether ligand-receptor interactions (LRIs) between IGHG and FCGR gene products are associated with progression to type 1 diabetes (T1D). Using two compl...
UNLABELLED: The primary objective of this study was to investigate whether ligand-receptor interactions (LRIs) between IGHG and FCGR gene products are associated with progression to type 1 diabetes (T1D). Using two completed clinical trials (DPT-1 and TN07), we applied next-generation targeted sequencing to genotype IGHG and FCGR genes in a cohort of 1,214 individuals and assessed LRI associations with disease progression. A Cox regression model was used to quantify LRI associations. IGHG or FCGR alone was found to have weak and sporadic associations with progression. Multiple LRIs between IGHG and FCGR gene products were found to be associated with progression, especially LRIs of IGHG2 with multiple FCGR receptors that accelerate progression and those of IGHG4 with multiple FCGR receptors (some overlapping) that delay progression. Furthermore, as several crystal structures of FcγRs complexed with distinct IgG molecules are known, application of this knowledge here was hampered by the absence of any information on the subclass distribution of each of the several T1D-related autoantibodies. It cannot be excluded that their respective state of glycosylation may influence binding affinity to various FcγRs and the function of thus-formed complexes. Our findings suggest that LRIs of the IGHG and FCGR gene products probably influence progression, shedding new insights into some of the immunological mechanisms involved in progression to T1D. Our findings potentially facilitate the search for new immunotherapeutic treatment through intervening at key steps in the progression. ARTICLE HIGHLIGHTS: This study investigated ligand-receptor interactions (LRIs) between IGHG and FCGR gene products in type 1 diabetes progression. Genes of 1,214 participants from the DPT-1 and TN07 trials were sequenced using next-generation targeted sequencing technology, and LRI associations with the progression time to type 1 diabetes were analyzed using Cox regression modeling. Weak associations were found for IGHG or FCGR variants individually, but multiple LRIs significantly impacted progression. Several IGHG2-FCGR interactions accelerated progression, while a few other IGHG4-FCGR interactions delayed it. The results may provide insights into certain immunogenetic mechanisms of T1D and suggest therapeutic potential of targeting specific LRIs.
Prolonged Semaglutide Treatment Reveals Stage-Dependent Changes to Feeding Behavior and Metabolic Adaptations in Male Mice.
Shah H, Ayala JE
Diabetes · 2026 Jan · PMID 41329075 · Full text
UNLABELLED: Glucagon-like peptide 1 receptor (GLP-1R) agonists have transformed obesity treatment, but weight loss responses to these drugs vary widely. Elucidating behavioral and metabolic phenotypes throughout GLP-1R a...
UNLABELLED: Glucagon-like peptide 1 receptor (GLP-1R) agonists have transformed obesity treatment, but weight loss responses to these drugs vary widely. Elucidating behavioral and metabolic phenotypes throughout GLP-1R agonist treatment could identify mechanisms underlying this response spectrum. We characterized food intake, meal patterns, energy expenditure (EE), and substrate oxidation during prolonged semaglutide treatment and posttreatment recovery in obese male mice at room temperature (RT) and thermoneutral temperature (TN). Semaglutide-induced weight loss and posttreatment weight regain were similar at RT and TN. Weight loss was divided into three stages at both temperatures: rapid initial weight loss, slower gradual weight loss, and weight maintenance. Initial weight loss was marked by reduced food intake, smaller and less frequent meals, and increased lipid oxidation. Food intake gradually returned to pretreatment levels through increased meal frequency, whereas meal size remained suppressed. Lipid oxidation gradually decreased, whereas carbohydrate oxidation increased. Weight-adjusted EE remained constant and elevated in semaglutide- versus vehicle-treated mice, and locomotor activity increased throughout semaglutide treatment. Mice rapidly regained weight after treatment cessation as a result of increased food intake, meal size and frequency, carbohydrate oxidation, EE, and activity. Thus, semaglutide-induced weight loss and regain after treatment cessation involve dynamic, stage-specific changes in feeding behavior, EE, and substrate oxidation. ARTICLE HIGHLIGHTS: Although many studies have demonstrated acute behavioral and metabolic effects of glucagon-like peptide 1 receptor (GLP-1R) agonists, few have assessed long-term effects of these drugs on these phenotypes. We assessed changes in various behavioral and metabolic phenotypes throughout a 21-day treatment regimen with semaglutide and posttreatment. Weight loss in response to prolonged semaglutide treatment can be divided into distinct phases, and each phase is characterized by different effects on food intake, meal patterns, energy expenditure, and substrate oxidation. Our findings suggest that differences in behavioral changes and/or metabolic adaptations may underlie the degree of weight loss responsiveness to GLP-1R agonists.
Multiorgan Fibrosis and Risk of Type 2 Diabetes: Genetic and Observational Evidence Highlighting a Causal Role of Pancreatic Fibrosis.
Uchida M, Yamazaki H, Han S … +7 more , Huang BZ, Ariyoshi S, Hirayama Y, Matsushita S, Horitani R, Wagner R, Heni M
Diabetes · 2026 Jan · PMID 41324495 · Publisher ↗
UNLABELLED: Pancreatic fibrosis has been proposed as a contributor to type 2 diabetes (T2D) by impairing islet function, but whether it plays a causal role remains unclear. We investigated this question using two complem...
UNLABELLED: Pancreatic fibrosis has been proposed as a contributor to type 2 diabetes (T2D) by impairing islet function, but whether it plays a causal role remains unclear. We investigated this question using two complementary approaches. First, we performed a computed tomography–based retrospective case-control study (T2D case patients: n = 58; control participants: n = 58) assessing extracellular volume fraction as a marker of fibrosis in the pancreas, liver, and myocardium. Greater pancreatic fibrosis was associated with T2D (adjusted odds ratio [OR] per 1 [SD] increase: 1.64; 95% CI 1.00–2.68), independent of age, sex, BMI, liver fibrosis, and myocardial fibrosis. Second, we conducted a Mendelian randomization analysis using genome-wide association study (GWAS) data on multiorgan fibrosis derived from MRI in the UK Biobank (n = 43,881), along with T2D GWAS data from the Diabetes Genetics Replication and Meta-analysis (DIAGRAM) consortium (n = 242,283 T2D case patients and 1,569,734 control participants). Genetically predicted pancreatic fibrosis levels were associated with an increased T2D risk (OR per 1-SD increase: 1.43; 95% CI 1.09–1.89), whereas liver and myocardial fibrosis levels showed no associations. These findings support a potential causal and organ-specific role of pancreatic fibrosis in the pathogenesis of T2D, highlighting pancreatic fibrosis as a mechanistically plausible and potentially targetable target in diabetes prevention. ARTICLE HIGHLIGHTS: Pancreatic, but not liver or myocardial, fibrosis is specifically and independently linked to type 2 diabetes. Mendelian randomization analysis reveals a causal role of pancreatic fibrosis in diabetes development. Pancreatic fibrosis might be a potential therapeutic target to preserve β-cell function and prevent diabetes.
Effects of Marked Weight Loss Induced by Gastric Bypass Surgery or Low-Calorie Diet Alone on Postprandial Glucose Disposal in Type 2 Diabetes.
Mittendorfer B, Patterson BW, Eagon JC … +2 more , Yoshino M, Klein S
Diabetes · 2026 Jan · PMID 41296546 · Full text
UNLABELLED: We used a dual (intravenous and oral) glucose tracer protocol to evaluate rates of glucose appearance in the circulation, insulin-mediated glucose disposal (IMGD), and noninsulin-mediated glucose disposal (NI...
UNLABELLED: We used a dual (intravenous and oral) glucose tracer protocol to evaluate rates of glucose appearance in the circulation, insulin-mediated glucose disposal (IMGD), and noninsulin-mediated glucose disposal (NIMGD) for 4 h after consumption of a mixed meal in people with obesity and type 2 diabetes before and after marked (∼20%) weight loss, induced by behavioral diet therapy (BDT, n = 11) or Roux-en-Y gastric bypass (RYGB) surgery (n = 9). Total postprandial glucose appearance rate was lower after compared with before weight loss in both the BDT and RYGB groups because of a decrease in endogenous glucose production, without a difference between groups. However, the decreases in total and incremental postprandial plasma glucose concentration areas under the curve were greater in the BDT group than the RYGB group because IMGD doubled in the BDT group but did not change in the RYGB group. These results demonstrate that the improvement in postprandial glycemia is greater after marked, matched weight loss induced by BDT compared with RYGB in people with obesity and type 2 diabetes, because of increased IMGD after BDT but not RYGB. Nonetheless, these findings do not diminish the potent therapeutic effect of RYGB surgery on glycemic control and even achieving remission of type 2 diabetes. ARTICLE HIGHLIGHTS: In people with obesity and diabetes, marked (∼20%) weight loss induced by behavioral diet therapy (BDT) causes a greater decrease in postprandial plasma glucose area under the curve than matched weight loss after Roux-en-Y gastric bypass (RYGB), even though insulin sensitivity and postprandial plasma insulin area under the curve are the same in both groups. We studied the effects of marked weight loss after BDT or RYGB on insulin-mediated glucose disposal (IMGD) and non-insulin-mediated glucose disposal. Weight loss induced by BDT, but not RYGB, increased IMGD. Postprandial glycemia improves more after marked weight loss induced by BDT than by RYGB because of increased IMGD after BDT but not RYGB.
Adipose TGR5 Deletion Promotes Hepatic Steatosis Through Decreasing Adiponectin Secretion in Mice.
Li J, Liu Q, Xiong Y … +12 more , Xu Y, Zhang J, Xia Y, Jing X, Zhang Z, Pang J, Huang C, Song H, Zhang A, Li Y, Tang Q, He J
Diabetes · 2026 Jan · PMID 41296511 · Full text
UNLABELLED: Metabolic dysfunction–associated steatotic liver disease (MASLD) has emerged as a global epidemic, yet its underlying molecular mechanisms remain elusive, and therapeutic options are limited. The interorgan c...
UNLABELLED: Metabolic dysfunction–associated steatotic liver disease (MASLD) has emerged as a global epidemic, yet its underlying molecular mechanisms remain elusive, and therapeutic options are limited. The interorgan communication between liver and adipose tissue plays a crucial role in maintaining hepatic lipid homeostasis. This study investigates the role of G-protein–coupled bile acid receptor 1 (TGR5) in adipose tissue-liver communication and its impact on hepatic lipid metabolism during the progression of MASLD. We observed that TGR5 expression in white adipose tissue was significantly upregulated under both fasting and high-fat diet (HFD) conditions, whereas its levels in brown adipose tissue remained unchanged. Notably, mice with adipocyte-specific TGR5 deletion exhibited exacerbated fasting/HFD-induced hepatic steatosis and impaired hepatic fatty acid oxidation. Mechanistically, adipose tissue TGR5 deficiency reduced adiponectin secretion, which in turn suppressed hepatic fatty acid oxidation and aggravated hepatic lipid accumulation; conversely, restoration of circulating adiponectin rescued these metabolic abnormalities. Collectively, our findings highlight a critical role for adipose tissue TGR5 in promoting adiponectin secretion, thereby enhancing hepatic fatty acid oxidation and protecting against hepatic steatosis. ARTICLE HIGHLIGHTS: Systemic G-protein-coupled bile acid receptor 1 (TGR5) is involved in modulating hepatic triglyceride accumulation, but whether adipose-derived TGR5 regulates hepatic lipid metabolism remains undefined. We investigated whether fasting or a high-fat diet (HFD) altered TGR5 levels in adipose tissue and the effect of TGR5 ablation in adipose tissue on hepatic lipid metabolism. We found that TGR5 protein expression was upregulated in white adipose tissue upon fasting or HFD. Adipose-specific TGR5 deficiency decreased adiponectin secretion, which ultimately suppressed hepatic fatty acid oxidation and exacerbated intrahepatic lipid deposition. Given the limited therapeutic options for metabolic dysfunction-associated steatotic liver disease (MASLD), our findings highlight the therapeutic potential of targeting adipocyte TGR5 for MASLD intervention.
MODY Is Prevalent in Later-Onset Diabetes and Has Potential for Targeted Therapy but Is Challenging to Identify.
Sharp LN, Mirshahi UL, Colclough K … +8 more , Hall TS, Haley JS, Cannon SJ, Laver TW, Weedon MN, Hattersley AT, Carey DJ, Patel KA
Diabetes · 2026 Jan · PMID 41288518 · Full text
UNLABELLED: Maturity-onset diabetes of the young (MODY) can present after the age of 40 years, but its prevalence and clinical characteristics, and the utility of simple clinical features for selecting cases in this age...
UNLABELLED: Maturity-onset diabetes of the young (MODY) can present after the age of 40 years, but its prevalence and clinical characteristics, and the utility of simple clinical features for selecting cases in this age group, remain poorly defined. We analyzed whole-exome and clinical data from 51,619 individuals with diabetes diagnosed after age 40 years from one U.K. and one U.S. cohort. The prevalence of MODY due to a pathogenic variant in the 10 most common MODY genes was 1 in 191 (0.52%) in the U.K. cohort and 1 in 633 (0.16%) in the U.S. cohort. For subtypes with treatment implications (i.e., GCK, HNF1A, HNF4A, ABCC8, KCNJ11), prevalence was 1 in 234 and 1 in 935 in the U.K. and U.S. cohorts, respectively. GCK-MODY was most common, followed by HNF4A and the lower-penetrance RFX6-MODY. Clinical features of MODY largely overlapped with non-MODY diabetes either treated with insulin from diagnosis or not. Only BMI, HbA1c and HDL values were statistically different between patients with MODY and those with non-MODY diabetes in both cohorts (P < 0.0018 for all). Applying strict clinical criteria (i.e., BMI <25, noninsulin treated, and parent with diabetes) only increased the MODY diagnosis to 2.64% and 0.87% in the respective cohorts but missed >86% of cases. MODY is prevalent in later-onset diabetes and has potential for targeted therapy but is challenging to identify. ARTICLE HIGHLIGHTS: Maturity-onset diabetes of the young (MODY) can present later in life, and diagnosis can enable precision treatment. However, individuals with later-onset diabetes are rarely tested. How common is MODY in people diagnosed with diabetes after age 40 years? Can they be identified clinically? MODY affects 1 in 191-633 individuals with diabetes onset after 40 years, but clinical features alone cannot reliably identify them. MODY is relatively common in later-onset diabetes but difficult to detect clinically, limiting routine genetic testing in this group.
B Lymphocytes Impede Tregs to Erode Islet Tolerance in Type 1 Diabetes.
Wilson CS, Stocks BT, Falk AC … +1 more , Moore DJ
Diabetes · 2026 Jan · PMID 41288499 · Full text
UNLABELLED: B lymphocytes are thought to drive β-cell destruction in type 1 diabetes (T1D) by activating anti-islet T cells. However, the observation that autoreactive T-cell activation and disease progression can occur...
UNLABELLED: B lymphocytes are thought to drive β-cell destruction in type 1 diabetes (T1D) by activating anti-islet T cells. However, the observation that autoreactive T-cell activation and disease progression can occur without B cells challenges this view. Still, preclinical and clinical studies have shown that B-cell depletion alleviates β-cell destruction, suggesting a critical role for B cells in T1D. Our findings propose an alternative function for B cells, impairing regulatory T cells (Tregs) that would otherwise protect islets. In the NOD islet transplant model, we show that B-cell absence enables transplant tolerance, allowing Tregs to become responsive to immune therapy and confer allograft protection. Extending this to spontaneous diabetes, we have found that insulin-reactive Tregs are reduced in NOD mice in proportion to insulin-reactive B cells, while effector T cells remain unaffected. Moreover, Tregs from B-cell–deficient NOD mice better restrained β-cell destruction than those from B-cell–sufficient environments. Together, these findings indicate that autoreactive B cells primarily erode immune regulation by culling islet-protective Tregs. Thus, therapies that mobilize Tregs could be more effective when combined with B-cell–targeting strategies in islet transplant or T1D prevention. ARTICLE HIGHLIGHTS: This study expands the role of B lymphocytes in type 1 diabetes by demonstrating how B cells influence the development and function of regulatory T cells (Tregs) during islet transplant and autoimmune progression. This study was done to explain how B lymphocytes regulate the progression of anti-islet immunity, even when they appear dispensable for effector cell activation. B-cell deficiency (using NOD.μMT mice) enables durable islet transplant tolerance, enhances the expansion of Helios+ Tregs, increases the ratio of insulin-reactive Tregs to effector T cells, and enhances islet-protective Treg function. These findings indicate that B lymphocytes accelerate destructive immunity by negatively regulating Treg development and function. Targeting the harmful B-cell-Treg interactions, particularly in the thymic environment, may offer new, more selective therapeutic strategies to prevent anti-islet immunity.
Urinary Branched-Chain Amino Acid Excretion and Chronic Kidney Disease Progression in Patients With Type 2 Diabetes.
Liu JJ, Liu S, Zheng H … +11 more , Wang CP, Debnath S, Lee J, Lee LS, Ching J, Tham MS, Ang K, Gurung RL, Coffman TM, Sharma K, Lim SC
Diabetes · 2026 Jan · PMID 41270208 · Publisher ↗
UNLABELLED: Preclinical studies suggest that activating branched-chain amino acid (BCAA) catabolism may improve chronic kidney disease (CKD). In this prospective clinical study, we sought to examine the association betwe...
UNLABELLED: Preclinical studies suggest that activating branched-chain amino acid (BCAA) catabolism may improve chronic kidney disease (CKD). In this prospective clinical study, we sought to examine the association between urinary BCAA excretion and risk of CKD progression in patients with type 2 diabetes. Baseline urinary BCAAs were measured by mass spectrometry in 1,868 outpatients with type 2 diabetes. The study outcome was a composite of end-stage kidney disease (estimated glomerular filtration rate <15 mL/min/1.73 m2, dialysis, or death resulting from renal causes) or doubling of serum creatinine. During a median of 7.2 years of follow-up, 203 renal events were identified. One SD increment in urinary valine, leucine, and isoleucine concentration was associated with 1.29-fold (95% CI 1.11–1.51), 1.31-fold (1.11–1.55) and 1.29-fold (1.09–1.53) increased risk, respectively, of the composite renal outcome after adjustment for clinical risk factors. Mediation analysis showed that urinary MCP-1 mediated 57%, 47%, and 58% of the effects of valine, leucine, and isoleucine on the renal outcome, respectively. High levels of urinary BCAAs were also independently associated with an increased risk of CKD progression in the Chronic Renal Insufficiency Cohort in the U.S. Our data suggest that dysregulation of BCAA metabolism in the kidneys may be involved in intrarenal inflammation and drive CKD progression. ARTICLE HIGHLIGHTS: Restoration of branched-chain amino acid (BCAA) catabolism improves kidney pathology in animal models, but clinical data on the relationship between urinary BCAA excretion and kidney outcomes are scarce. Are urinary BCAA levels associated with CKD progression independent of clinical risk factors in patients with type 2 diabetes? High levels of urinary BCAAs predicted an increased risk of renal events independent of cardiorenal risk factors, with urinary MCP-1 mediating over 50% of the association. Activating intrarenal BCAA catabolism may potentially improve kidney function in patients with diabetes.
Beyond the Classical Axis: Metabolic "Pressure" on the Adrenal Gland?
Isidori AM, Pofi R, Fleseriu M
Diabetes · 2025 Dec · PMID 41264851 · Full text
Abstract loading — click title to view on PubMed.
The Dark Proteome: "Not Everything That Counts Can Be Counted".
van Tienhoven R, Zaldumbide A
Diabetes · 2025 Dec · PMID 41264850 · Publisher ↗
Abstract loading — click title to view on PubMed.
From Methylation to Metabolism: Linking Molecular Layers in Diabetes Risk.
Nguyen CM, Seldin M
Diabetes · 2025 Dec · PMID 41264849 · Publisher ↗
Abstract loading — click title to view on PubMed.
About
- Frequency
- Sun
- Papers found
- 200
- RSS feed
- Subscribe