Diabetes最新文献

{"title":"Metabolite Erythritol in 24-Hour Urine Is Associated With Higher Intrahepatic Lipid Content: The Maastricht Study.","authors":"Amée M Buziau, Anke Wesselius, Evan Yi-Wen Yu, Irene M L W Körver-Keularts, Dennis Visser, Laura K M Steinbusch, Pomme I H G Simons, Marleen M J van Greevenbroek, Pieter C Dagnelie, M Eline Kooi, Simone J P M Eussen, Ilja C W Arts, Carla J H van der Kallen, Casper G Schalkwijk, Martijn C G J Brouwers","doi":"10.2337/db25-0881","DOIUrl":"10.2337/db25-0881","url":null,"abstract":"<p><p>The pentose phosphate pathway (PPP) furnishes NADPH for hepatic de novo lipogenesis, driving intrahepatic lipid (IHL) accumulation. The aim of the current study was to examine the association between the PPP, proxied by 24-h urinary erythritol, and IHL content at the population level. We used cross-sectional data from the Maastricht Study, a population-based cohort study (N = 1,494; mean ± SD age 59 ± 8 years; 49% women). We first assessed the relationship between 24-h urinary erythritol and IHL content (quantified with 3T Dixon MRI), with adjustment for age, sex, type 2 diabetes, proxies of socioeconomic status/lifestyle, MRI lag time, BMI, and intake of erythritol-containing food items. Second, we performed a genome-wide association study (GWAS) for 24-h urinary erythritol (N = 2,000) and Mendelian randomization (MR) study using common variants in genes associated with erythritol in relation to IHL content. In the fully adjusted model, 24-h urinary erythritol levels were associated with higher (10log) IHL content. The GWAS identified one genome-wide significant locus (rs72686491; TESK2) and replicated two previously reported genetic variants at nominal significance. MR analysis, using these three genetic instruments, did not reveal a statistically significant association between genetically predicted erythritol levels and IHL content. The findings of this population-based study show that higher PPP flux is associated with higher IHL content, a well-established risk factor for type 2 diabetes. An active role for erythritol per se was excluded by MR analysis.</p><p><strong>Article highlights: </strong>The role of the pentose phosphate pathway (PPP) in the pathogenesis of intrahepatic lipid (IHL) accumulation has not been studied before in humans. Is the PPP, proxied by 24-h urinary erythritol, associated with IHL content at the population level? In the fully adjusted model, 24-h urinary erythritol levels were associated with higher IHL content. Furthermore, genetically predicted erythritol levels were not associated with liver fat, suggesting that erythritol per se is not responsible for the former observation. Findings of the current study suggest that 1) the PPP is associated with IHL content at the population level, and 2) erythritol could potentially serve as a urinary biomarker for IHL content.</p>","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":" ","pages":"762-771"},"PeriodicalIF":0.0,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147446419","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mesenchymal Stem Cell and Secretome Treatments Inhibit the mTOR-NOX4 Pathway in Diabetic Kidney Disease.","authors":"Rachel Njeim, Sahar Alkhansa, Sarah Almoussawi, Amani Slika, Sarah Hamade, Ghaith Al Danaf, Batoul Dia, Leonard Lawandos, Ali H Eid, Hala Kfoury Kassouf, Frederic Harb, Antoine Abou Fayad, Fuad N Ziyadeh, Fadlo R Khuri, Assaad A Eid","doi":"10.2337/db25-1036","DOIUrl":"10.2337/db25-1036","url":null,"abstract":"<p><p>Diabetic kidney disease (DKD) is a major complication of diabetes characterized by progressive renal dysfunction driven by oxidative stress and inflammation involving mammalian target of rapamycin (mTOR) and NADPH oxidase (NOX) pathways. Mesenchymal stem cells (MSCs) have gained attention for their regenerative and immunomodulatory properties in attenuating DKD, but the mechanisms behind their protective effects are still being explored. Moreover, concerns regarding tumorigenic risks hinder their direct clinical use. In this study, we compared MSCs and their conditioned media (MSCs-CM; secretome) in a type 1 diabetic rodent model, demonstrating that both treatments attenuated glomerular injury, preserved podocyte integrity, reduced NOX4 expression and activity, and tempered inflammation, by inhibiting mTORC1 and mTORC2 signaling. Importantly, MSCs-CM replicated the renoprotective effects of MSCs, indicating that soluble factors mediate these benefits. To our knowledge, this is the first study to directly compare MSCs and their conditioned media (MSCs-CM) in DKD, revealing that MSCs-CM delivers equivalent therapeutic efficacy while circumventing the safety concerns inherent to cell-based therapies. These findings identify the mTOR/NOX axis as a therapeutic target and support MSCs-CM as a promising, safer, cell-free alternative for DKD treatment, potentially advancing regenerative strategies to mitigate diabetic renal injury.</p><p><strong>Article highlights: </strong>Despite advances in diabetes management, diabetic kidney disease (DKD) remains a leading cause of end-stage renal disease. We investigated whether mesenchymal stem cells (MSCs) and their conditioned medium, containing the MSC-derived secretome, protect against DKD by modulating the mammalian target of rapamycin (mTOR)/NADPH oxidase (NOX) pathway. MSCs and MSCs-conditioned medium both reduced kidney injury, podocyte structural integrity, oxidative stress, and inflammation by inhibiting mTORC1/mTORC2 and NOX4. MSCs-conditioned medium offers a safe, secretome-based, cell-free approach for DKD therapy.</p>","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":" ","pages":"840-851"},"PeriodicalIF":0.0,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147438445","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Distinct Enterovirus Antigen Landscape in Children With Islet Autoimmunity.","authors":"Beatriz Delgado-Corrales, Legana Fingerhut, Preston Leung, Cynthia S A Yau, Charles S P Foster, Emily J Ward, Dylan B Foskett, Aakash Annadurai, Simon C Barry, Peter G Colman, Jennifer J Couper, Elizabeth A Davis, Emma E Hamilton-Williams, Leonard C Harrison, Aveni Haynes, Tony Huynh, Kelly J McGorm, Grant Morahan, Helena Oakey, Megan A S Penno, Georgia Soldatos, Rebecca L Thomson, Jason A Tye-Din, Peter J Vuillermin, John M Wentworth, Marc R Wilkins, Jutta E Laiho, Heikki Hyöty, William D Rawlinson, Maria E Craig, Ki Wook Kim","doi":"10.2337/db25-0805","DOIUrl":"10.2337/db25-0805","url":null,"abstract":"<p><p>Enteroviruses (EVs) have long been implicated in the development of islet autoimmunity (IA) and type 1 diabetes. However, given the ubiquity of EV infections in children, disease susceptibility is likely driven by host-specific immune responses rather than viral exposure alone. To investigate the host antibody response to EVs, we used virome-wide serological profiling (VirScan) to compare the EV antigen landscapes in IA-positive case children versus IA-negative control children across two independent pediatric cohorts separated by 12 years, using samples collected at the time point of seroconversion. We identified a reproducible and distinct EV-specific antibody signature in IA-positive case samples, with an enriched immunogenic hotspot localized within a highly conserved region in the 3D RNA-dependent RNA polymerase. Additionally, IA-positive male children exhibited significantly heightened antibody responses against a motif in the VP1 capsid protein compared with IA-negative male children (risk ratio 1.24; 95% CI 1.02, 1.52; P = 0.03). Our findings provide paradigm-shifting evidence that differential antiviral humoral responses, rather than the specific types of EV infection, play a central role in IA development, highlighting the need for an updated framework to study host-virus interactions in autoimmune pathogenesis.</p><p><strong>Article highlights: </strong>Children positive for islet autoimmunity (IA) in two different Australian cohorts showed a distinct enterovirus (EV) antibody signature against specific regions of the EV genome polyprotein. A specific motif in the 3D region of the EV polyprotein was consistently enriched across cohorts and sexes, making it a potential marker for IA onset. Anti-VP1 motif antibody levels varied by sex, with significantly elevated levels in male children linked to early IA onset, highlighting possible sex-specific antiviral immunity. Findings support that host immune responses against EVs drive IA development, calling for a new framework to study host-virus interactions in IA.</p>","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":" ","pages":"738-747"},"PeriodicalIF":0.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13007209/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146151592","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Endogenous Glucagon-Like Peptide 1 Enhanced by Vildagliptin Reduces Triglyceride Appearance During Intraduodenal Fat Infusion in Type 2 Diabetes.","authors":"Cong Xie, Jake B White, Weikun Huang, Michael Horowitz, Christopher K Rayner, Johan W Verjans, Marten F Snel, Peter J Psaltis, Tongzhi Wu","doi":"10.2337/db25-0980","DOIUrl":"10.2337/db25-0980","url":null,"abstract":"<p><p>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.</p><p><strong>Article highlights: </strong>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.</p>","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":" ","pages":"630-635"},"PeriodicalIF":0.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146055516","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Optimizing Single-Cell Long-Read Sequencing for Enhanced Isoform Detection in Pancreatic Islets.","authors":"Maria S Hansen, Christopher J Hill, Lori Sussel, Kristen L Wells","doi":"10.2337/db25-0424","DOIUrl":"10.2337/db25-0424","url":null,"abstract":"<p><p>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.</p><p><strong>Article highlights: </strong>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.</p>","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":" ","pages":"606-616"},"PeriodicalIF":0.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13007207/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146013655","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pericytes Are Not Merely Accessory Cells in Pancreatic Islets.","authors":"Luciana Mateus Gonçalves, Joana Almaça","doi":"10.2337/dbi26-0006","DOIUrl":"10.2337/dbi26-0006","url":null,"abstract":"","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":"75 4","pages":"e5-e6"},"PeriodicalIF":0.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13007205/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147492438","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exofacial Epitope-Specific Antibodies Detect GLUT4 Translocation in Adult Human, Rat, and Mouse Skeletal Muscle.","authors":"Kaspar W Persson, Casper Fjeldsøe, Lukas W Frandsen, Jonas R Knudsen, SeongEun Kwak, Haiyan Wang, Christian T Voldstedlund, Magnus R Leandersson, Carol A Witczak, Jørgen F P Wojtaszewski, Erik A Richter, Gregory D Cartee, Thomas E Jensen","doi":"10.2337/db25-0567","DOIUrl":"10.2337/db25-0567","url":null,"abstract":"<p><p>Skeletal muscle glucose transporter 4 (GLUT4) translocation to the plasma membrane determines glucose uptake in response to insulin and exercise and is disrupted in insulin resistance, making its experimental measurement critical. Confocal light microscopy is widely used for this purpose because of its ability to provide quantitative, high-resolution spatial information from small tissue amounts. However, conventional immunofluorescence colocalization microscopy lacks sensitivity and specificity in the detection of GLUT4 translocation. We validated the use of exofacial epitope-specific GLUT4 antibodies to quantify sarcolemmal GLUT4 translocation in fixed, nonpermeabilized adult human and rodent muscle fibers. Across human, mouse, and rat muscles, these antibodies sensitively detected stimulus-induced GLUT4 translocation, and labeling was abolished in muscle-specific GLUT4-knockout muscle, confirming specificity. Importantly, this study includes the first unambiguous visualization of endogenous GLUT4 translocation in intact human skeletal muscle fibers after insulin stimulation and exercise. In TBC1D4-knockout rats, insulin-stimulated GLUT4 translocation was absent despite wild-type-level GLUT4 expression, confirming an essential role for TBC1D4 in this process. Thus, exofacial GLUT4 antibodies provide a straightforward, sensitive, and specific approach to quantify endogenous GLUT4 translocation in fixed adult skeletal muscle.</p><p><strong>Article highlights: </strong>Reliable quantification of glucose transporter 4 (GLUT4) translocation in intact skeletal muscle is essential for understanding insulin and exercise responses but remains technically challenging. We aimed to test whether exofacial GLUT4 antibodies can specifically detect sarcolemmal GLUT4 translocation in fixed, nonpermeabilized muscle fibers from humans and rodents. GLUT4 translocation in response to insulin, AMPK activation, and exercise was detectable in human and rodent muscles. Insulin-stimulated translocation correlated with 2-deoxyglucose uptake and was abolished in TBC1D4-knockout muscle. Exofacial GLUT4 antibodies enable straightforward, specific quantification of endogenous GLUT4 translocation in rodent and human muscles in healthy and insulin-resistant states.</p>","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":" ","pages":"617-629"},"PeriodicalIF":0.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13007217/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146183893","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Distinct Host Responses to Enterovirus in Children With Islet Autoimmunity Provide a New Framework for the Role of Infections in Type 1 Diabetes.","authors":"Alberto Pugliese","doi":"10.2337/dbi25-0052","DOIUrl":"10.2337/dbi25-0052","url":null,"abstract":"","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":"75 4","pages":"603-605"},"PeriodicalIF":0.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147492429","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Diabetic Corneal Neuropathy Precedes and Is Associated With Diabetic Retinopathy.","authors":"Chang Liu, Isabelle Xin Yu Lee, Can Can Xue, Mingyi Yu, Ansa Anam, Regina Kay Ting Wong, Ching-Yu Cheng, Yu-Chi Liu","doi":"10.2337/db25-0590","DOIUrl":"10.2337/db25-0590","url":null,"abstract":"<p><p>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.</p><p><strong>Article highlights: </strong>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.</p>","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":" ","pages":"683-695"},"PeriodicalIF":0.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13007213/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146013676","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cluster Analysis of Younger-Onset Type 2 Diabetes in an Asian Cohort Reveals Distinct Subgroups With Differential Pathophysiology and Outcomes.","authors":"Clara Si Hua Tan, Kai Xiang Kee, Huili Zheng, Kay Wye Sabrina Wong, Wan Ting Lovynn Chan, Yuzhen Song, Keven Ang, Tavintharan Subramaniam, Chee Fang Sum, Su Chi Lim","doi":"10.2337/db25-0871","DOIUrl":"10.2337/db25-0871","url":null,"abstract":"<p><p>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.</p><p><strong>Article highlights: </strong>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.</p>","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":" ","pages":"526-537"},"PeriodicalIF":0.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145859683","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}