Diabetes[JOURNAL]
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200 papers
Diabetes Spotlight: Jay M. Sosenko, MD-Diabetic Neuropathy and Prevention Strategies for Type 1 Diabetes.
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Diabetes · 2026 Feb · PMID 41627930 · Publisher ↗
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Endogenous Glucagon-Like Peptide 1 Enhanced by Vildagliptin Reduces Triglyceride Appearance During Intraduodenal Fat Infusion in Type 2 Diabetes.
Xie C, White JB, Huang W … +6 more , Horowitz M, Rayner CK, Verjans JW, Snel MF, Psaltis PJ, Wu T
Diabetes · 2026 Apr · PMID 41591292 · Publisher ↗
UNLABELLED: Glucagon-like peptide 1 (GLP-1) receptor agonists improve dyslipidemia and reduce cardiovascular risk in type 2 diabetes (T2D), but the role of endogenous GLP-1 in lipid metabolism remains unclear. We evaluat...
UNLABELLED: Glucagon-like peptide 1 (GLP-1) receptor agonists improve dyslipidemia and reduce cardiovascular risk in type 2 diabetes (T2D), but the role of endogenous GLP-1 in lipid metabolism remains unclear. We evaluated the effect of dipeptidyl peptidase 4 (DPP-4) inhibition on the response of plasma triglycerides (TGs) to intraduodenal lipid and a mixed meal, and the impact of GLP-1 receptor blockade with exendin(9-39) in T2D. Fifteen participants with T2D, managed by diet and/or metformin, were studied on three occasions in a double-blind, randomized, crossover design. Vildagliptin (50 mg) or placebo was administered orally (t = -60 min), followed by intravenous exendin(9-39) from t = -60 to 150 min on one of the two vildagliptin days or 0.9% saline on two other days. A lipid emulsion was infused intraduodenally (2 kcal/min, t = 0-120 min), followed by a mixed meal (t = 120-150 min). Plasma TG levels, quantified by liquid chromatography-tandem mass spectrometry, increased after lipid and meal, with most individual TGs corresponding to those in the lipid emulsion. Vildagliptin reduced TG(54:4) and TG(54:5) concentrations (each P < 0.01), without affecting total TGs. Blocking endogenous GLP-1 during vildagliptin treatment increased plasma total TGs (P < 0.001), associated with elevations of 10 individual TG species (P < 0.05 each). These outcomes suggest that endogenous GLP-1 contributes to the physiological modulation of postprandial TG appearance in T2D. ARTICLE HIGHLIGHTS: The contribution of endogenous glucagon-like peptide 1 (GLP-1) to postprandial lipid metabolism in type 2 diabetes (T2D) is poorly defined. The specific questions we wanted to answer were what is the effect of dipeptidyl peptidase 4 (DPP-4) inhibition on plasma triglyceride (TG) profiles during an intraduodenal lipid infusion and following a mixed meal in T2D, and how does blockage of endogenous GLP-1 signaling affect these responses? We found that plasma TGs increased after intraduodenal lipid infusion and the meal, with most species reflecting the infused lipid emulsion. Vildagliptin selectively reduced TG(54:4) and TG(54:5) species, whereas exendin(9-39) increased total TGs and 10 individual TG species. The implications of our finding are that endogenous GLP-1 plays a physiological role in the regulation of postprandial lipid handling in T2D.
Phase I Clinical Trial of Islet Antigen-Specific Plasmid Coexpressing Tolerogenic Proteins Demonstrates Safety in Adults With Type 1 Diabetes.
Greenbaum CJ, Long SA, Gitelman SE … +29 more , Gaglia JL, Daniels M, Brusko TM, Lord S, Bundy BN, Krischer JP, Haller MJ, Steck AK, DiMeglio LA, Evans-Molina C, Moran A, Prahalad P, Wilson DM, Russell WE, Sherr JL, Raskin P, Clements MA, Moore WV, Libman I, Wassermann K, von Herrath M, Bergholdt R, Hastrup H, Kobernat SE, Kus AM, Tung LW, Goland RS, Herold KC, Type 1 Diabetes TrialNet Study Group*
Diabetes · 2026 Mar · PMID 41564354 · Full text
UNLABELLED: There is significant interest in antigen-specific approaches to delaying type 1 diabetes in preclinical stages and supporting tolerance after diagnosis. We conducted a phase I trial of a nonintegrating DNA pl...
UNLABELLED: There is significant interest in antigen-specific approaches to delaying type 1 diabetes in preclinical stages and supporting tolerance after diagnosis. We conducted a phase I trial of a nonintegrating DNA plasmid constructed to secrete the type 1 diabetes antigen preproinsulin (PPI) and the immune modulatory cytokines transforming growth factor-β1 (TGF-β1), interleukin-10 (IL-10), and IL-2. In this placebo-controlled, double-masked study of 47 adults with stage 3 type 1 diabetes, we showed that the drug is safe and well tolerated, with most reported adverse events (AEs) categorized as grade 1 and with no clinically significant difference in AEs among treatment groups. There were no untoward metabolic or immune effects. We found pharmacodynamic evidence of treatment, as demonstrated by a dose-dependent type 1 interferon (IFN) signature. Plasmid DNA, representing a pharmocokinetic measure, was detected in the two highest dosing groups. We did not find global or antigen-specific immune cell changes following treatment with a DNA plasmid expressing PPI, IL-2, IL-10, and TGF-β1, and we did not detect immune changes driven by IL-2, IL-10, or TGF-β1. Our results support further trials of this novel tolerizing antigen construct. ARTICLE HIGHLIGHTS: Antigen-specific therapy is needed to induce tolerance in type 1 diabetes at early disease stages or in combination with immunotherapy. We conducted a phase I trial in type 1 diabetes of a novel plasmid construct expressing the islet antigen preproinsulin (PPI) and immunomodulatory cytokines transforming growth factor-β1 (TGF-β1), interleukin-10 (IL-10), and IL-2. The therapy was safe and well tolerated. Dose-dependent changes in DNA plasmid levels and type 1 interferon signatures were detected; however, global and antigen-specific immune changes to PPI, IL-2, IL-10, or TGF-β1 were not observed. Further trials are needed to assess efficacy.
Diabetic Corneal Neuropathy Precedes and Is Associated With Diabetic Retinopathy.
Liu C, Lee IXY, Xue CC … +5 more , Yu M, Anam A, Wong RKT, Cheng CY, Liu YC
Diabetes · 2026 Apr · PMID 41563729 · Full text
UNLABELLED: Diabetic corneal neuropathy (DCN) and diabetic retinopathy (DR) are microvascular complications and share common pathophysiological mechanisms. However, the relationship between them remains poorly defined. I...
UNLABELLED: Diabetic corneal neuropathy (DCN) and diabetic retinopathy (DR) are microvascular complications and share common pathophysiological mechanisms. However, the relationship between them remains poorly defined. In this cross-sectional study, we aimed to investigate the association among DCN, DR, and tear mediators in 1,654 eyes from 822 participants, comprising 634 patients with type 2 diabetes and 188 healthy participants. Our data demonstrated that compared with control participants, all patients with diabetes had significantly impaired corneal nerve metrics, increased dendritic cell length and density, and larger corneal microneuromas, even in the absence of DR. Patients with nonproliferative DR (NPDR) and proliferative DR (PDR) showed significantly reduced corneal nerve parameters compared with those with no DR. Furthermore, patients with PDR presented significantly worse ocular surface clinical manifestations than patients with no DR, patients with NPDR, and control participants. Cumulative link mixed models demonstrated that corneal sensitivity and corneal nerve parameters were significantly associated with the severity of DR. Tear substance P concentrations were significantly lower across all stages of DR compared with control participants. Tear MMP-9, substance P, and IGFBP-3 levels were significantly associated with corneal nerve and ocular surface parameters. This study demonstrates that DCN precedes the onset of DR and worsens with the severity of DR. Corneal nerve status could be an early indicator and predictor of DR. ARTICLE HIGHLIGHTS: Both diabetic corneal neuropathy (DCN) and diabetic retinopathy (DR) are microvascular complications and share common pathophysiological mechanisms. The links between them are poorly understood. We investigated the relationship between DCN and DR by studying imaging features, clinical manifestations, and tear biomarkers. Our study demonstrated that DCN precedes the onset of DR, and DCN worsens with the severity of DR stage. Corneal sensitivity and corneal nerve parameters are significantly associated with DR severity. Tear MMP-9, substance P, and IGFBP-3 were significantly altered in DR. Corneal nerve status could be an early indicator and predictor of DR.
Optimizing Single-Cell Long-Read Sequencing for Enhanced Isoform Detection in Pancreatic Islets.
Hansen MS, Hill CJ, Sussel L … +1 more , Wells KL
Diabetes · 2026 Apr · PMID 41563441 · Full text
UNLABELLED: Alternative splicing is an essential mechanism for generating protein diversity by producing distinct isoforms from a single gene. Dysregulation of splicing that affects pancreatic function and immune toleran...
UNLABELLED: Alternative splicing is an essential mechanism for generating protein diversity by producing distinct isoforms from a single gene. Dysregulation of splicing that affects pancreatic function and immune tolerance has been linked to both types 1 and 2 diabetes. Next-generation sequencing technologies, with their short read lengths, are limited in their ability to accurately detect splice variants. Long-read sequencing technologies offer the potential to overcome these limitations by providing full-length transcript information; however, their application in single-cell RNA sequencing has been hindered by technical challenges, including insufficient read lengths and higher error rates. Furthermore, cell types that produce high levels of a single transcript, such as islet endocrine cells, can obscure identification of lower-abundance transcripts. In this study, we optimized a protocol for single-cell long-read sequencing in pancreatic islets to improve read length and transcript detection. Our findings demonstrate that 5' library preparation protocols outperform 3' protocols, resulting in better transcript identification. Furthermore, we show that targeted depletion of insulin transcripts enhances the detection of informative reads, highlighting the utility of transcript-depletion strategies. This optimized protocol enables isoform-specific gene expression analysis and reveals differential transcript usage across the various cell types in pancreatic islets. By leveraging this approach, we gain deeper insights into the transcriptomic complexity and cellular heterogeneity within pancreatic islets. ARTICLE HIGHLIGHTS: This study addresses the limitations of current single-cell long-read RNA sequencing technologies in detecting full-length transcripts and isoform diversity, particularly in pancreatic islets. We demonstrate that optimizing single-cell library preparation protocols reproducibly enhances read length and transcript identification in pancreatic islets. Combined with targeted insulin depletion and extended reverse transcription, 5' capture methods significantly improved read length and isoform detection compared with standard protocols, while maximizing the number of informative reads. These improvements yield longer reads in single-cell experiments, substantially enhancing transcript identification and enabling more accurate analysis of isoform diversity.
Integrating SMRT and Bulk RNA Sequencing With Metabolic Phenotyping to Examine Reduced Skeletal Muscle Mitochondrial Respiration in Type 2 Diabetes.
Schön M, Oehler D, Yurchenko I … +17 more , Lang A, Trinks N, Dewidar B, Mastrototaro L, Zaharia OP, Bódis KB, Karusheva Y, Toledo FGS, Burkart V, Granata C, Westenfeld R, Polzin A, Kelm M, Wagner R, Roden M, Szendroedi J, German Diabetes Study Group*
Diabetes · 2026 Mar · PMID 41563348 · Full text
UNLABELLED: Recent advances in RNA sequencing (RNA-seq) techniques allow the identification of tissue-specific alternative splicing and can thereby provide new insights into molecular mechanisms of energy metabolism. Ful...
UNLABELLED: Recent advances in RNA sequencing (RNA-seq) techniques allow the identification of tissue-specific alternative splicing and can thereby provide new insights into molecular mechanisms of energy metabolism. Full-length transcriptomics based on single-molecule real-time sequencing (SMRT-seq) enable precise detection of isoforms with 99% accuracy in an unbiased manner. In this proof-of-concept study, we integrated SMRT-seq, bulk RNA-seq, and comprehensive metabolic phenotyping to investigate reduced mitochondrial function in the skeletal muscle of individuals with type 2 diabetes. Muscle biopsies were taken from nine individuals with type 2 diabetes and nine age- and BMI-matched glucose-tolerant men. Whole-body insulin sensitivity (WBIS) was assessed by hyperinsulinemic-euglycemic clamps, and muscle mitochondrial respiration was assessed by high-resolution respirometry. In muscle samples, SMRT-seq was used to create full-length reads and isoforms, which were mapped to the genome. Short-read sequencing was used to compare isoform expression between the groups. Participants with diabetes exhibited lower WBIS and fatty acid-driven and complex I-linked respiration compared with control participants. SMRT-seq revealed ∼67,000 isoforms originating from ∼14,000 unique genes. Although isoform numbers per gene did not differ, SMRT-seq-based mapping enabled refined data set clustering compared with conventional short-read sequencing and identified four splicing variants of the ATP5F1A gene encoding a subunit for ATP synthase. Among these, two novel transcripts were expressed exclusively in control participants. This study identified splicing variants of ATP synthase that were differentially expressed between participants with type 2 diabetes and those with normal glucose tolerance, which may contribute to the reduced fatty acid oxidation in diabetes. ARTICLE HIGHLIGHTS: In our study, we developed a pipeline to integrate single-molecule real-time sequencing (SMRT-seq) with comprehensive metabolic phenotyping to examine reduced mitochondrial respiration in the skeletal muscle of individuals with type 2 diabetes. SMRT-seq revealed ∼67,000 isoforms originating from ∼14,000 unique genes; the isoform numbers per gene did not differ between participants with diabetes and matched control participants. Our data identified novel alternative splicing events, including two variants of the ATP5F1A gene encoding a subunit for ATP synthase. Among these, two novel transcripts were expressed exclusively in control participants. Our findings link transcriptomic changes to impaired mitochondrial respiration in type 2 diabetes, with the potential of providing novel therapeutic targets to improve metabolic health.
Urinary Dickkopf-3 Reveals Tubular Fibrosis and Hidden Progression in Diabetic Kidney Disease.
Lin MC, Chen SC
Diabetes · 2026 Jan · PMID 41557889 · Publisher ↗
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Downregulation of Hepatic PPA1 Protects Against Obesity by Elevating FGF21 Production via eIF2α Phosphorylation.
Sun Y, Zhang J, Su Y … +6 more , Wu T, Chen J, Yang N, Han X, Lin H, Yin Y
Diabetes · 2026 Mar · PMID 41538425 · Publisher ↗
UNLABELLED: Chronic overnutrition promotes excessive hepatic triglyceride accumulation, subsequently leading to insulin resistance and systemic metabolic dysfunction. Inorganic pyrophosphatase 1 (PPA1), an enzyme that hy...
UNLABELLED: Chronic overnutrition promotes excessive hepatic triglyceride accumulation, subsequently leading to insulin resistance and systemic metabolic dysfunction. Inorganic pyrophosphatase 1 (PPA1), an enzyme that hydrolyzes inorganic pyrophosphate, plays a key role in driving synthetic biochemical reactions. Here, we identified PPA1 as a novel regulator of systemic energy expenditure that functions by controlling hepatic production of fibroblast growth factor 21 (FGF21). FGF21 is a hormone predominantly secreted by the liver that protects against obesity by enhancing whole-body energy expenditure. Although nutritional states and various transcription factors are known to regulate hepatic FGF21 expression, the underlying mechanisms remain elusive. In this study, we demonstrate that hepatic-specific deletion of PPA1 effectively attenuates high-fat diet-induced obesity, reduces hepatic lipid deposition, and improves systemic insulin sensitivity in vivo. PPA1 ablation in the liver significantly elevates circulating FGF21 levels and increases whole-body energy expenditure by promoting adipose tissue browning and thermogenesis. Knockdown of hepatic FGF21 expression partially counteracts the protective effect conferred by PPA1 deficiency. Mechanistically, hepatic PPA1 deficiency elevates FGF21 through the GCN2/eIF2α/ATF4 pathway, a process that is dependent on the loss of its enzymatic activity. Our findings not only establish PPA1 as a critical regulator of systemic energy metabolism but also identify it as a novel modulator of FGF21, highlighting its potential as a therapeutic target for obesity and related metabolic disorders. ARTICLE HIGHLIGHTS: Pyrophosphatase 1 (PPA1) is upregulated in livers of high-fat diet-induced obese mice and metabolic dysfunction-associated steatotic liver disease patients. Hepatic PPA1 deletion protects mice against high-fat diet-induced obesity and related metabolic disorders by promoting whole-body energy expenditure. Deficiency of hepatic PPA1 expression facilitates fibroblast growth factor 21 production by activating the GCN2/eIF2α/ATF4 signaling pathway.
Amino Acid Sensing by the α-Cell Mitochondrial Phosphoenolpyruvate Cycle Regulates Intracellular Ca2+ Levels Without Affecting Glucagon Secretion.
Jin E, Foster HR, Potapenko E … +4 more , Huang SM, Dong X, Hughes JW, Merrins MJ
Diabetes · 2026 Mar · PMID 41525135 · Full text
UNLABELLED: Pancreatic islet α-cells are increasingly recognized as amino acid sensors for the organism. Building on our prior work in β-cells, we sought to determine whether the mitochondrial phosphoenolpyruvate (PEP) c...
UNLABELLED: Pancreatic islet α-cells are increasingly recognized as amino acid sensors for the organism. Building on our prior work in β-cells, we sought to determine whether the mitochondrial phosphoenolpyruvate (PEP) cycle is involved in α-cell amino acid sensing. Three different methods were used to probe the PEP cycle, including pyruvate kinase activators (TEPP-46), and mice with α-cell-specific deletion (KO) of pyruvate kinase M (PKM1/2-αKO) or mitochondrial PEP carboxykinase (PCK2-αKO). The mitochondrial fuel leucine, in the presence of glutamine, antagonized alanine/arginine-stimulated Ca2+ influx and glucagon secretion under hypoglycemic conditions. Both PKM1/2 and PCK2 deletion prevented leucine from closing α-cell KATP channels. The Ca2+ response to amino acids was suppressed by pyruvate kinase activation with TEPP-46 and enhanced by α-cell deletion of PKM1/2 or PCK2-all without changing glucagon secretion. Using diazoxide/KCl to probe the pathways downstream of membrane depolarization, we identified a further role of the PEP cycle in homeostatically regulating Ca2+ levels. In sum, α-cell pyruvate kinase and the mitochondrial PEP cycle senses leucine and inhibits KATP channels similarly to β-cells, while restricting amino acid-stimulated membrane depolarization and Ca2+ influx. However, none of the amino acids tested, including alanine/arginine, regulate glucagon secretion by modulating membrane depolarization or Ca2+ influx. ARTICLE HIGHLIGHTS: Our studies identify a role for the α-cell phosphoenolpyruvate cycle in sensing amino acids under hypoglycemic conditions. Leucine, in the presence of glutamine, opposes alanine/arginine-stimulated Ca2+ influx and glucagon secretion. Pyruvate kinase and phosphoenolpyruvate carboxykinase 2 are required for leucine to close α-cell KATP channels and limit Ca2+ influx. All of the amino acids tested regulate glucagon secretion, but none do so by modulating membrane depolarization or intracellular Ca2+ levels.
GLP-1, Pancreatic β-Cells, and Insulin Secretion: What We Know and Where We Need to Go.
Vogt ÉL, Kowaltowski AJ
Diabetes · 2026 Mar · PMID 41525103 · Publisher ↗
UNLABELLED: GLP-1 receptor agonists have emerged as key pharmacological tools in the treatment of type 2 diabetes and obesity. While their anorexigenic effects are well characterized, the mechanisms by which GLP-1 modula...
UNLABELLED: GLP-1 receptor agonists have emerged as key pharmacological tools in the treatment of type 2 diabetes and obesity. While their anorexigenic effects are well characterized, the mechanisms by which GLP-1 modulates pancreatic β-cell function remain only partially understood. In this article, we argue that GLP-1 receptor agonists should be viewed as integrative regulators of β-cell function and explore the multifaceted actions of GLP-1 analogs on β-cell signaling. GLP-1 influences key secretagogues and intracellular mediators (calcium, glutamate, γ-aminobutyric acid, serotonin, and urocortin-3), with complex roles in insulin exocytosis. Additionally, we discuss the interplay between calcium and cAMP, and how GLP-1 modulates both pathways to coordinate insulin secretion. Emerging evidence suggests that GLP-1 analogs affect mitochondrial morphology and redox homeostasis. Considering the relatively low expression of classical antioxidant enzymes in β-cells, and their reliance on both glycolytic and mitochondrial metabolism to sustain insulin secretion, the influence of GLP-1 on mitochondrial dynamics and reactive oxygen species may play a central role in sustaining cell function and viability. Despite recent advances, critical gaps persist in the literature, particularly regarding organelle cross talk, intracellular calcium stores, and the modulation of vesicular content. Drawing on current evidence, we propose that three mechanistic dimensions (intracellular neurotransmitters, mitochondrial remodeling, and redox control) represent key areas where clarifying GLP-1 actions could most effectively advance the field. Further investigation into these mechanisms is essential for a comprehensive understanding of GLP-1 actions in β-cells. This knowledge may help refine current incretin-based therapies and identify novel molecular targets for the treatment of metabolic disorders. ARTICLE HIGHLIGHTS: GLP-1 and its analogs enhance insulin secretion, but the specific intracellular mechanisms in β-cells remain unclear. Key intracellular mediators including calcium, glutamate, γ-aminobutyric acid, serotonin, and urocortin-3 are modulated by GLP-1 signaling with variable and sometimes contradictory effects. GLP-1 may affect mitochondrial dynamics and redox balance in β-cells, both critical for function and survival. Gaps in knowledge remain regarding cross talk between classical secretagogues and GLP-1 pathways. Further investigation is needed to clarify how GLP-1 integrates metabolic, signaling, and organelle-based processes in insulin secretion.
Identifying Insulin Autoantibodies With Differential Risk in Type 1 Diabetes With a Novel Bridging ELISA.
Jia X, Zhang C, Waugh K … +4 more , Miao D, Michels AW, Rewers MJ, Yu L
Diabetes · 2026 Mar · PMID 41525084 · Full text
UNLABELLED: Insulin autoantibodies (IAAs) are commonly measured by radiobinding assays (RBAs), which detect both high- and low-affinity binding. Improved assays that preferentially detect high-affinity IAA are likely to...
UNLABELLED: Insulin autoantibodies (IAAs) are commonly measured by radiobinding assays (RBAs), which detect both high- and low-affinity binding. Improved assays that preferentially detect high-affinity IAA are likely to provide greater specificity and thereby increase the diagnostic accuracy of IAA for early-stage type 1 diabetes (T1D). This study aimed to develop and validate a novel bridging ELISA for IAA detection. The bridging ELISA detects IAAs by their bivalent cross-linking of two proinsulin moieties in fluid phase. Validation was performed by using samples from 227 patients with newly diagnosed stage 3 T1D and 1,021 control participants. Additionally, 202 children positive for IAA by RBA from general population screening were tested by the bridging ELISA and electrochemiluminescence (ECL) assay. At 99.5% specificity, ELISA detected IAA in 65.2% of patients with stage 3 T1D vs. 60.8% by RBA. Among children identified as having RBA-positive IAA in general population screening, 80.3% of those with multiple islet autoantibodies and 48.1% of those with a single IAA had ELISA-IAA positive findings (P < 0.0001). For children with a single IAA by RBA, ELISA detected 78.9% of those with ECL-IAA-positive findings vs. 27.9% of those with ECL-IAA negative findings (P < 0.0001). Samples that were IAA negative by ELISA showed lower antibody affinity. The ELISA-IAA assay demonstrates high sensitivity and specificity and could become a practical tool for T1D population screening and clinical diagnosis across laboratories. ARTICLE HIGHLIGHTS: In global type 1 diabetes (T1D) population screening studies, there is an urgent need for a highly sensitive and specific insulin autoantibody (IAA) assay that can be implemented across multiple laboratories. This study aimed to develop and characterize a novel ELISA-based platform for IAA detection. We established a new bridging ELISA for IAA and validated it in cohorts of patients with stage 3 T1D, children positive for multiple and single islet antibodies, and control children negative for islet autoantibodies. The bridging ELISA-IAA assay demonstrates excellent sensitivity and specificity, preferentially identifies high-risk individuals, and offers a practical, scalable solution for T1D population screening and clinical diagnosis across laboratories.
Paracrine Hormonal Signals From Islet α-Cells Regulate Microtubule Dynamics in β-Cells to Promote Insulin Secretion in Mouse and Human Islets.
Ho KH, Barmaver SN, Gibson SE … +7 more , Hu R, Yagan M, Ahmed HK, Balamurugan AN, Jacobson DA, Kaverina I, Gu G
Diabetes · 2026 Mar · PMID 41511443 · Full text
UNLABELLED: The microtubule network in β-cells attenuates insulin secretion by pulling insulin secretory granules away from the plasma membrane. Thus, high-glucose-induced microtubule remodeling is required for robust gl...
UNLABELLED: The microtubule network in β-cells attenuates insulin secretion by pulling insulin secretory granules away from the plasma membrane. Thus, high-glucose-induced microtubule remodeling is required for robust glucose-stimulated insulin secretion. We now demonstrate that hormones secreted by α-cells regulate microtubule dynamics in β-cells through receptors for glucagon (GcgR) and glucagon-like peptide 1 (GLP-1R). Activation of GcgR or GLP-1R destabilizes microtubules in β-cells, accompanied by increased insulin secretion. In contrast, inhibiting these receptors attenuates high-glucose-induced microtubule destabilization and decreases secretion. Supporting the physiological significance of this regulation, β-cells in islets with a higher α-cell-to-β-cell ratio exhibit more dynamic microtubules than those with a lower ratio, and a high-fat diet challenge in mice, which can compromise β-cell secretion, attenuates this effect in their islets. Within individual islets, β-cells located near α-cells show faster microtubule remodeling upon glucose stimulation than those more distant from α-cells. Consequently, islets with a higher α-cell-to-β-cell ratio secrete more insulin in response to glucose stimulation and plasma membrane depolarization, results recapitulated by exogenous glucagon stimulation or chemically induced microtubule destabilization in islets with lower α-cell-to-β-cell ratios. These combined results suggest that α-cells use glucagon-mediated and/or GLP-1-mediated paracrine signaling to fine-tune β-cell secretion via microtubule remodeling. ARTICLE HIGHLIGHTS: Glucagon/glucagon-like peptide 1 sensitizes glucose-induced microtubule remodeling in β-cells. Microtubule density in islets inversely correlates with the α-cell-to-β-cell ratio. Glucose-stimulated insulin secretion levels in single islets positively correlate with their α-cell-to-β-cell ratio. Glucagon and microtubule destabilization mobilize the same granule pool.
Long Duration of Type 2 Diabetes Drives Erythrocyte-Induced Vascular Endothelial Dysfunction: A Link to miRNA-210-3p.
Kontidou E, Collado A, Humoud R … +9 more , Manickam K, Tengbom J, Jiao T, Alvarsson M, Yang J, Mellbin L, Mahdi A, Pernow J, Zhou Z
Diabetes · 2026 Mar · PMID 41508879 · Publisher ↗
UNLABELLED: Type 2 diabetes increases cardiovascular risk, with endothelial dysfunction playing a key role. Prolonged disease duration exacerbates cardiovascular risk, but the underlying mechanisms remain unclear. We pre...
UNLABELLED: Type 2 diabetes increases cardiovascular risk, with endothelial dysfunction playing a key role. Prolonged disease duration exacerbates cardiovascular risk, but the underlying mechanisms remain unclear. We previously demonstrated that red blood cells (RBCs) from individuals with type 2 diabetes impair endothelial function via reduced miRNA (miR)-210-3p. We investigated whether disease duration influences RBC-induced endothelial dysfunction and its link to miR-210-3p. RBCs were isolated from diabetic db/db mice of various ages and from humans with newly diagnosed (<1 year) or long-lasting type 2 diabetes (>7 years). Endothelial-dependent relaxation (EDR), miR-210-3p levels, its target protein glycerol-3-phosphate dehydrogenase 2 (GPD2), and oxidative stress marker 4-hydroxynonenal (4-HNE) were assessed. RBCs from 14- and 22-week-old, but not 7-week-old, db/db mice impaired EDR. These RBCs showed similarly reduced miR-210-3p levels and increased vascular GPD2 and 4-HNE expression. RBCs from individuals with long-lasting type 2 diabetes, but not from the newly diagnosed group, impaired EDR. After ≥7 years, RBCs from initially newly diagnosed individuals impaired EDR, which was rescued by miR-210-3p mimic transfection. In contrast, RBCs from healthy subjects did not impair EDR after follow-up. These findings underscore the pivotal role of disease duration for RBC-mediated vascular dysfunction, linked to miR-210-3p downregulation. RBC miR-210-3p may serve as a biomarker for diabetes-related vascular disease. ARTICLE HIGHLIGHTS: Red blood cells (RBCs) from older (representing longer duration of diabetes) but not young diabetic mice induce endothelial dysfunction. Protective miRNA-210-3p levels in RBCs are reduced in older diabetic mice compared with young ones. RBCs from individuals with long-lasting (>7 years) but not newly diagnosed type 2 diabetes (<1 year) induce endothelial dysfunction. RBCs from individuals with newly diagnosed type 2 diabetes induce endothelial dysfunction at a >7-year follow up, which is rescued by miRNA-210-3p mimic.
Angiotensin II-Induced Ferroptosis in Epithelial Cells Contributes to Kidney Injury via SP1-DPEP1-Mediated SLC3A2 Degradation.
Tian Y, Yang G, Zhang Q … +7 more , Dong C, Li Y, Lv S, Li S, Zhang H, Jiang X, Xin Y
Diabetes · 2026 Mar · PMID 41490187 · Full text
UNLABELLED: Angiotensin II (AngII) activation, a key driver of diabetes pathogenesis and associated complications, induces kidney injury by promoting oxidative stress and inflammation. Ferroptosis is an iron-dependent re...
UNLABELLED: Angiotensin II (AngII) activation, a key driver of diabetes pathogenesis and associated complications, induces kidney injury by promoting oxidative stress and inflammation. Ferroptosis is an iron-dependent regulated cell death, playing a crucial role in kidney injury. This study aimed to explore the contribution of ferroptosis to AngII-induced kidney injury and its regulatory mechanisms. Our findings reveal that chronic AngII stimulation leads to renal dysfunction, characterized by elevated serum creatinine levels, increased urinary protein-to-creatinine ratio, and tubular injury. These changes are associated with ferroptosis in renal tubular epithelial cells (TECs) and a marked upregulation of dipeptidase 1 (DPEP1) expression. Notably, the ferroptosis inhibitor ferrostatin-1 (Fer-1) effectively reversed ferroptosis in TECs, restored tubular integrity, and improved renal function. DPEP1 gene silencing and the DPEP1 inhibitor cilastatin significantly inhibited AngII-induced ferroptosis in TECs. Mechanistically, AngII upregulated DPEP1 expression via the transcription factor SP1. Elevated DPEP1 enhanced ubiquitination of SLC3A2, a key cystine/glutathione transporter. Furthermore, inhibiting DPEP1 with cilastatin in a mouse model effectively reversed ferroptosis and alleviated kidney injury. These findings highlight ferroptosis' key role in AngII-induced kidney injury and suggest DPEP1 targeting as a therapeutic strategy against AngII-driven renal damage. ARTICLE HIGHLIGHTS: This study investigated the role of ferroptosis in angiotensin II (AngII)-induced kidney injury, addressing a critical gap in understanding AngII-mediated nephropathy mechanisms. We asked whether dipeptidase 1 (DPEP1)-mediated SLC3A2 degradation drives ferroptosis and renal damage under AngII activation. AngII upregulates DPEP1 via SP1, promoting SLC3A2 ubiquitination and glutathione depletion, ultimately triggering tubular ferroptosis. DPEP1 inhibition rescues renal function. Targeting the SP1-DPEP1-SLC3A2 axis offers a novel therapeutic strategy against ferroptosis-dependent kidney injury in hypertension and metabolic disorders.
Adipocyte Leptin Signaling Regulates Glycemia and Cardiovascular Function by Enhancing Brown Adipose Tissue Thermogenesis in Obese Male Mice.
Ono Y, Kennard S, Wall BT … +2 more , Ma J, Belin de Chantemèle EJ
Diabetes · 2026 Mar · PMID 41490102 · Full text
UNLABELLED: Although control of metabolism by leptin is primarily viewed as centrally mediated, leptin has also been shown to directly regulate adipocyte function. However, the impact of the peripheral effects of leptin...
UNLABELLED: Although control of metabolism by leptin is primarily viewed as centrally mediated, leptin has also been shown to directly regulate adipocyte function. However, the impact of the peripheral effects of leptin on systemic metabolism, especially in the context of obesity, remains unclear. To address this question, we selectively restored adipocyte leptin receptor (LEPR) expression in obese male and female LEPR-conditional knockout mice. Adipocyte LEPR restoration did not affect body weight but selectively increased brown adipose tissue (BAT) mass in male mice. This was associated with increased energy expenditure, smaller BAT adipocytes, lower triglycerides content, and increased markers of browning and lipolysis exclusively in males. Additionally, adipocyte LEPR restoration enhanced the expression of markers of endothelial cells and angiogenesis in male mouse BAT, supporting increased local vascularization. Improved BAT function in males was also associated with lower HbA1c, better insulin sensitivity, reduced systolic blood pressure, decreased arterial stiffness, and improved endothelial function. Lastly, adipocyte LEPR restoration lowered circulating proinflammatory cytokines and reduced tissue inflammation in the aorta and heart, again in males only. These findings reveal a critical role for adipocyte leptin signaling in regulating BAT function and emphasize its importance in maintaining glycemic and cardiovascular health in males with obesity. ARTICLE HIGHLIGHTS: Leptin is known to enhance brown adipose tissue (BAT) activity through sympathetic stimulation. However, in vitro studies suggest leptin could also act directly on adipocytes to promote lipolysis. Whether these peripheral effects of leptin are relevant to systemic metabolic control in obesity remains unclear. We addressed this question by selectively restoring leptin receptor (LEPR) expression in adipocytes of obese LEPR-conditional knockout mice. LEPR restoration selectively enhanced BAT activity in male mice, which led to improved glycemic control and cardiovascular function. These findings reveal a crucial role for BAT leptin signaling in regulating energy expenditure and glycemic and cardiovascular health, primarily in males.
Activating Muscarinic Receptor Signaling in Intrapancreatic Neurons Is Required for Parasympathetic Cholinergic Control of Pancreatic Cell Function.
Levi NJ, Tamayo Garcia A, Sokolov M … +2 more , Barro-Soria R, Caicedo A
Diabetes · 2026 Mar · PMID 41489908 · Full text
UNLABELLED: The parasympathetic nervous system modulates hormone and digestive enzyme secretion from the pancreas. However, the mechanisms of neuroeffector transmission within the final parasympathetic pathway in the pan...
UNLABELLED: The parasympathetic nervous system modulates hormone and digestive enzyme secretion from the pancreas. However, the mechanisms of neuroeffector transmission within the final parasympathetic pathway in the pancreas have not been elucidated. Here, we demonstrate that intrapancreatic cholinergic neurons are bona fide postganglionic neurons that functionally couple vagal input to target cells in the pancreas. In living pancreatic slices from various mice expressing genetically encoded sensors and actuators, we found that intrapancreatic neurons responded to cholinergic input via nicotinic and muscarinic M1 acetylcholine receptors. However, only muscarinic receptor signaling was necessary and sufficient to elicit responses in exocrine and endocrine target cells. We established that muscarinic receptor signaling in intrapancreatic neurons is linked to the potassium M-current, thus producing the sustained reverberating activity required to efficiently modulate insulin and glucagon secretion and elicit oscillatory responses in acinar cells. Whereas intrapancreatic neurons triggered responses in acinar cells without additional stimulation, they only primed and amplified hormone secretion already stimulated by changes in glucose levels. This mechanistic insight into how intrapancreatic neurons regulate pancreas function challenges canonical models of parasympathetic neurotransmission and is critical to understanding autonomic control of the pancreas. ARTICLE HIGHLIGHTS: Neurotransmission mechanisms at the final parasympathetic pathway in the pancreas have not been elucidated. We manipulated and recorded neuronal and target cell responses in living pancreatic slices to assess how intrapancreatic neurons affect pancreatic cell function. Activating muscarinic receptor signaling in intrapancreatic neurons was required to trigger exocrine cell activity and modulate endocrine cell secretion. Our findings revise conventional models of parasympathetic neuronal control of pancreatic function.
Cluster Analysis of Younger-Onset Type 2 Diabetes in an Asian Cohort Reveals Distinct Subgroups With Differential Pathophysiology and Outcomes.
Tan CSH, Kee KX, Zheng H … +7 more , Wong KWS, Chan WTL, Song Y, Ang K, Subramaniam T, Sum CF, Lim SC
Diabetes · 2026 Mar · PMID 41467878 · Publisher ↗
UNLABELLED: Younger-onset type 2 diabetes (T2D) (onset <40 years) represents a growing global health challenge, characterized by heterogenous pathophysiology and accelerated complications. Current one-size-fits-all treat...
UNLABELLED: Younger-onset type 2 diabetes (T2D) (onset <40 years) represents a growing global health challenge, characterized by heterogenous pathophysiology and accelerated complications. Current one-size-fits-all treatment approaches may be inadequate for this population. To address this heterogeneity, we performed clinical variable-based clustering using BMI, onset age, HbA1c, and HOMA2 indices in 717 participants across discovery and validation cohorts. Three distinct subgroups were identified: mild obesity-related diabetes (MOD), severe insulin-deficient diabetes (SIDD), and severe insulin-resistant diabetes with insulin insufficiency (SIRD-II). Over median follow-up of 2.8 years, SIRD-II demonstrated 11-fold increased risk of progressive chronic kidney disease, while both SIDD and SIRD-II showed threefold increased risk for progressive albuminuria compared with MOD. SIRD-II also demonstrated 3.5-fold and 2.3-fold higher 10-year cardiovascular risk compared with SIDD and MOD respectively. Metabolomic analysis revealed distinct signatures: SIDD exhibited lower levels of lipids, amino acids, and inflammatory markers, while SIRD-II demonstrated elevated glucose, lipids, and branched-chain amino acids, suggesting glucolipotoxicity. Proteomics analysis validated previously reported biomarkers (IGFBP1, RTN4R, PLXNB2) and identified additional molecules (CDHR2, ERBB4, DPP6) that may shed light on disease mechanisms. In conclusion, younger-onset T2D exhibits distinct subgroups with differential pathobiology, molecular signatures, and clinical outcomes, suggesting the need for personalised precision diabetes care. ARTICLE HIGHLIGHTS: To understand the heterogeneity of younger-onset type 2 diabetes (T2D), clinical data-driven clustering was performed, which identified three distinct subgroups that were replicated in an independent cohort. Compared with the mild obesity-related diabetes (MOD) subgroup, both severe insulin-deficient diabetes (SIDD) and severe insulin-resistant diabetes with insulin insufficiency (SIRD-II) subgroups had higher risk of developing diabetes-related complications. Differential molecular signatures confirmed the biological distinctiveness of younger-onset T2D subgroups and highlight potential mechanisms, such as glucolipotoxicity stress that may drive complications in the SIRD-II subgroup. Proteomic analyses validated previously reported biomarkers and identified novel candidates, providing a foundation for future mechanistic studies.
Integrating Polygenic Scores and Family History for Type 2 Diabetes Prediction in an East Asian Population: Insights From the Taiwan Biobank.
Liao WL, Cheng CW, Chang YW … +5 more , Lin MC, Cheng CF, Tsai SF, Hsu CC, Wang SH
Diabetes · 2026 Mar · PMID 41467856 · Publisher ↗
UNLABELLED: Type 2 diabetes is a complex disease influenced by both genetic and environmental factors. Although polygenic risk scores (PRS) and family history (FH) are established predictors, their combined utility in Ea...
UNLABELLED: Type 2 diabetes is a complex disease influenced by both genetic and environmental factors. Although polygenic risk scores (PRS) and family history (FH) are established predictors, their combined utility in East Asian populations remains unclear. In this study, we analyzed 111,899 unrelated participants from the Taiwan Biobank with linkage to nationwide health registry data. We constructed transancestry, East Asian-specific, and European-derived PRS and assessed their associations with type 2 diabetes. The transancestry PRS improved the explained variance in disease risk compared with ancestry-specific PRS and FH. FH, particularly sibling history, also showed a strong association with type 2 diabetes. When combined, PRS and FH contributed independently and additively, improving predictive performance. These findings demonstrate that PRS and FH are independent yet complementary risk indicators and support the application of transancestry PRS models in East Asian populations. Incorporating both genetic and familial risk factors may enhance early detection and facilitate more personalized prevention strategies for type 2 diabetes. ARTICLE HIGHLIGHTS: Type 2 diabetes is influenced by genetic and environmental factors. Although polygenic risk scores (PRS) and family history (FH) are established predictors, their combined utility in East Asian populations is unclear. We evaluated the predictive performance of PRS and the independent and joint effects of PRS and FH on diabetes risk in an East Asian population. The transancestry PRS explained more variance than ancestry-specific PRS and FH. PRS and FH were independently predictive, and their combination improved prediction, with stronger effects in men. Sibling history showed the strongest familial association. Integrating PRS and FH may enhance diabetes risk prediction in East Asian populations.
ABCC8 Missense Variants and Disease: Loss or Gain? This Is the Question.
Barbetti F, Thornton P
Diabetes · 2026 Jan · PMID 41417985 · Publisher ↗
Abstract loading — click title to view on PubMed.
Dickkopf 3 in Urine: A Help for Prioritizing Management of Kidney Disease in Type 2 Diabetes.
Rossing P
Diabetes · 2026 Jan · PMID 41417984 · Full text
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