Diabetes最新文献

{"title":"Metformin Boosts Intestinal Lipid Sensing via GIP to Suppress Feeding.","authors":"Rachel Kuah, Melissa T Wang, Zeyu Yang, Grace Back, Rosa J W Li, Kyla Bruce, Jessica N LoChoy, Jacqueline L Beaudry, Daniel R Barros, Song-Yang Zhang, Tony K T Lam","doi":"10.2337/db25-0100","DOIUrl":"https://doi.org/10.2337/db25-0100","url":null,"abstract":"<p><p>An acute increase of lipids in the upper small intestine (USI) of rodents and humans triggers lipid-sensing pathways to reduce food intake. However, USI lipid sensing does not reduce feeding in high-fat (HF) fed conditions, and the underlying mechanism remains elusive. Here, we report that HF feeding in male rats impaired USI lipid infusion to stimulate glucose-dependent insulinotropic polypeptide (GIP) secretion and decrease refeeding, and the defects of USI lipid sensing were restored by metformin. Next, we found that infusion of GIP receptor (GIPR) agonist in the nucleus of the solitary tract (NTS), but not mediobasal hypothalamus or area postrema, resulted in decreased refeeding in chow-fed rats. The anorectic effect of NTS GIPR agonist remained intact in HF rats and was inhibited by a genetic knockdown of GIPR. Finally, an inhibition of NTS GIPR also negated the ability of USI lipid sensing with metformin to decrease refeeding despite an increase in plasma GIP levels in HF rats. Thus, USI lipid sensing in HF rats is enhanced by metformin to trigger an endocrine GIP to NTS GIPR axis to reduce food intake, thereby unveiling small intestinal lipid-sensing pathways as potential targets to enhance GIP action and reduce weight in obesity.</p><p><strong>Article highlights: </strong>High-fat (HF) feeding in rats impairs upper small intestine (USI) lipid sensing to increase plasma glucose-dependent insulinotropic polypeptide (GIP) levels and reduce feeding. Metformin enhances USI lipids to increase GIP and reduce feeding in HF-fed rats. GIP activates the GIP receptor (GIPR) in the nucleus of the solitary tract (NTS), which reduces food intake in HF-fed rats. GIPR in the NTS is required for small intestinal lipids with metformin to reduce feeding.</p>","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144692815","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":"High-Quality Weight Loss in Obesity: Importance of Skeletal Muscle.","authors":"Mary-Ellen Harper, Robert R M Dent, Ruth McPherson","doi":"10.2337/dbi25-0003","DOIUrl":"https://doi.org/10.2337/dbi25-0003","url":null,"abstract":"<p><strong>Article highlights: </strong>High-quality weight loss, i.e., a high proportion of fat to skeletal muscle lost during the treatment of obesity, is advantageous for metabolic and physical health. Precise and accurate determinations of skeletal muscle mass in clinical settings are often challenging. In prevention of excessive loss of skeletal muscle during weight loss, advantages include minimization of metabolic adaptation that makes it difficult to sustain weight loss, improved glucose homeostasis and metabolic flexibility, and better mobility and strength. Effective approaches to preserving skeletal muscle include sufficient dietary protein and inclusion of exercise (especially resistance exercise) during weight loss; new pharmacological approaches are under development.</p>","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144585955","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":"The Benefits of Exercise Training in Combination With Weight Loss Therapies.","authors":"Bryan C Jiang, Dennis T Villareal","doi":"10.2337/dbi25-0001","DOIUrl":"10.2337/dbi25-0001","url":null,"abstract":"<p><strong>Article highlights: </strong>The primary treatment for obesity involves calorie restriction (CR) to promote dietary weight loss achieved through interventions including behavioral modification, bariatric surgery, and antiobesity medications. In adults with obesity, CR-induced weight loss enhances physical function and improves quality of life, while also reducing the burden of various obesity-related chronic conditions, including hypertension, diabetes, obstructive sleep apnea, and atherosclerotic heart disease. However, it is also associated with a decline in lean mass and bone mineral density, which increases the risk of sarcopenia and osteoporosis. When performed alongside CR, progressive resistance training (RT) attenuates this loss of lean mass and bone mass, while the addition of aerobic training (AT) further improves cardiorespiratory fitness. The individual benefits of RT and AT are complementary, and combining both exercise training modalities during CR provides the most optimal benefits for body composition and physical function. The World Health Organization recommends that adults engage in at least 150 min of moderate-intensity or 75 min of vigorous-intensity AT weekly and participate in RT activities involving major muscle groups at least 2 days per week. While this recommendation applies to the general adult population, regular exercise training that incorporates both RT and AT is particularly crucial for adults with obesity undergoing weight loss interventions. This clinical perspective highlights the benefits of exercise training alongside current weight loss strategies, such as lifestyle changes, bariatric surgery, and pharmacotherapy, with a focus on incretin-based therapies.</p>","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12418233/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144585956","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":"Liraglutide Treatment Reverses Unconventional Cellular Defects in Induced Pluripotent Stem Cell-Derived β-Cells Harboring a Partially Functional WFS1 Variant.","authors":"Silvia Torchio, Gabriel Siracusano, Federica Cuozzo, Valentina Zamarian, Silvia Pellegrini, Fabio Manenti, Riccardo Bonfanti, Giulio Frontino, Valeria Sordi, Raniero Chimienti, Lorenzo Piemonti","doi":"10.2337/db24-0720","DOIUrl":"10.2337/db24-0720","url":null,"abstract":"<p><p>Wolfram syndrome 1 (WS1) is a rare genetic disorder caused by WFS1 variants that disrupt wolframin, an endoplasmic reticulum-associated protein essential for cellular stress responses, Ca2+ homeostasis, and autophagy. Here, we investigated how the c.316-1G>A and c.757A>T WFS1 mutations, which yield partially functional wolframin, affect the molecular functions of β-cells and explored the therapeutic potential of the glucagon-like peptide 1 receptor (GLP-1R) agonist liraglutide. Pancreatic β-cells obtained from patient-derived induced pluripotent stem cells (iPSCs) carrying this WFS1 variant exhibited reduced insulin processing and impaired secretory granule maturation, as evidenced by proinsulin accumulation and decreased prohormone convertase PC1/3. Moreover, they exhibited dysregulated Ca2+ fluxes due to altered transcription of Ca2+-related genes, including CACNA1D, and significantly reduced SNAP25 levels, leading to uncoordinated oscillations and poor glucose responsiveness. Affected cells also showed increased autophagic flux and heightened susceptibility to inflammatory cytokine-induced apoptosis. Notably, liraglutide treatment rescued these defects by normalizing Ca2+ handling, enhancing insulin processing and secretion, and reducing apoptosis, likely through modulation of the unfolded protein response. These findings underscore the importance of defining mutation-specific dysfunctions in WS1 and support targeting the GLP-1/GLP-1R axis as a therapeutic strategy.</p><p><strong>Article highlights: </strong>The molecular basis of WFS1-related mutations remains poorly investigated, and no definitive therapies exist for Wolfram syndrome 1. We dissected the molecular defects associated with c.316-1G>A and c.757A>T WFS1 mutations in patient-derived induced pluripotent stem cell islets and analyzed whether they are potential therapeutic targets of the glucagon-like peptide 1 receptor agonist liraglutide. We found impaired insulin granule maturation, altered Ca2+ fluxes, increased autophagic activity, and heightened susceptibility to inflammatory apoptosis in mutated cells. Liraglutide restored critical β-cell functions suggesting a route for personalized therapy based on WFS1 mutations.</p>","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":" ","pages":"1273-1288"},"PeriodicalIF":0.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12185971/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143813245","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":"Type 1 Diabetes Depends on CD4-Driven Expression of the Transcriptional Repressor Bcl6.","authors":"Dudley H McNitt, Jonathan M Williams, Joseph G Santitoro, Jacob Kim, James W Thomas, Rachel H Bonami","doi":"10.2337/db23-0709","DOIUrl":"10.2337/db23-0709","url":null,"abstract":"<p><p>High-affinity islet autoantibodies predict type 1 diabetes in mice and humans and implicate germinal centers (GCs) in disease pathogenesis. T follicular helper (Tfh) cells are increased in individuals with type 1 diabetes and alterations in Tfh-like cells in the peripheral blood predicted individual responses to abatacept. Tfh cells support GC responses and depend on the transcriptional repressor BCL6 for their maturation. Therefore, we hypothesized that CD4-driven deletion of Bcl6 would disrupt essential T- and B-cell interactions in GCs to prevent type 1 diabetes. To test this hypothesis, we generated Bcl6fl/fl-CD4.Cre.NOD mice and found they were completely protected against diabetes. Insulitis severity and tertiary lymphoid structure organization were preserved in the pancreas of Bcl6fl/fl-CD4.Cre.NOD mice, which did not show decreases in CD4+, CD8+, and B-cell numbers in the pancreas and draining lymph nodes, relative to control Bcl6fl/fl.NOD mice. CD4-driven loss of functional BCL6 resulted in significantly reduced GC B-cell and Tfh-cell numbers in the pancreatic lymph nodes and pancreas at late prediabetic intervals. Spontaneous anti-insulin autoantibody was blunted in Bcl6fl/fl-CD4.Cre.NOD mice. These data highlight BCL6 as a novel therapeutic target in type 1 diabetes.</p><p><strong>Article highlights: </strong>Germinal center B cells and CD4+ T follicular helper cells are implicated in the pathogenesis of type 1 diabetes and depend upon the transcriptional repressor BCL6 for their maturation. This study tests the dependence of type 1 diabetes development on BCL6 expression in CD4+ cells. Data presented here show that CD4-driven loss of Bcl6 blocks germinal center formation, spontaneous insulin autoantibody production, and type 1 diabetes in nonobese diabetic mice, despite normal tertiary lymphoid structure formation in pancreatic islets. This study highlights BCL6 as a potential immunomodulatory target in type 1 diabetes.</p>","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":" ","pages":"921-932"},"PeriodicalIF":0.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12097460/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142668942","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":"Diroximel Fumarate Acts Through Nrf2 to Attenuate Methylglyoxal-Induced Nociception in Mice and Decrease ISR Activation in DRG Neurons.","authors":"Muhammad Saad Yousuf, Marisol Mancilla Moreno, Brodie J Woodall, Vikram Thakur, Jiahe Li, Lucy He, Rohita Arjarapu, Danielle Royer, Jennifer Zhang, Munmun Chattopadhyay, Peter M Grace, Theodore J Price","doi":"10.2337/db23-1025","DOIUrl":"10.2337/db23-1025","url":null,"abstract":"<p><p>Diabetic neuropathic pain is associated with elevated plasma levels of methylglyoxal (MGO). MGO is a metabolite of glycolysis that causes pain hypersensitivity in mice by stimulating the phosphorylation of eukaryotic initiation factor 2α (p-eIF2α) and subsequently activating the integrated stress response (ISR). We first established that Zucker diabetic fatty rats have enhanced MGO signaling, engage ISR, and develop pain hypersensitivity. Since nuclear factor erythroid 2-related factor 2 (Nrf2) regulates the expression of antioxidant proteins that neutralize MGO, we hypothesized that fumarates, like diroximel fumarate (DRF), will stimulate Nrf2 signaling, and prevent MGO-induced ISR and pain hypersensitivity. DRF (100 mg/kg) treated animals were protected from developing MGO (20 ng) induced mechanical and cold hypersensitivity. Mechanistically, DRF treatment protected against MGO-induced increase in p-eIF2α levels in the sciatic nerve and reduced loss of intraepidermal nerve fiber density. Using Nrf2 knockout mice, we demonstrate that Nrf2 is necessary for the antinociceptive effects of DRF. Cotreatment of MGO (1 µmol/L) with monomethyl fumarate (10, 20, and 50 µmol/L), the active metabolite of DRF, prevented ISR in both mouse and human dorsal root ganglia neurons. Our data show that targeting Nrf2 with DRF is a strategy to potentially alleviate pain associated with elevated MGO levels.</p><p><strong>Article highlights: </strong></p>","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":" ","pages":"827-837"},"PeriodicalIF":0.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12015141/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143461277","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":"Of Mice and Men: Toward a Better Model of Diabetic Cardiomyopathy With Application in Female Animals.","authors":"Jordan S F Chan, John R Ussher","doi":"10.2337/dbi25-0010","DOIUrl":"https://doi.org/10.2337/dbi25-0010","url":null,"abstract":"","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":"74 5","pages":"689-690"},"PeriodicalIF":0.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144045100","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":"β-Cell Benchmarks: Defining Predictive Outcomes in Islet Transplantation.","authors":"Shareen Forbes","doi":"10.2337/dbi24-0054","DOIUrl":"https://doi.org/10.2337/dbi24-0054","url":null,"abstract":"","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":"74 5","pages":"685-688"},"PeriodicalIF":0.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12012584/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144046148","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":"Differential Effects of Retinol-Binding Protein 3 and Anti-VEGF Antibodies on Retinal Dysfunctions in Diabetic Retinopathy.","authors":"Qin Li, Satoru Onizuka, Kyoungmin Park, Mingming Ma, Ward Fickweiler, Hyunseok Park, Qian Li, Fabricio Simao, Jared Boisclair, Maha Sharawy, I-Hsien Wu, Marc Gregory Yu, Lloyd P Aiello, Jennifer K Sun, George L King","doi":"10.2337/db24-0822","DOIUrl":"10.2337/db24-0822","url":null,"abstract":"<p><p>Anti-vascular endothelial growth factor (anti-VEGF) therapies are effective treatment for severe diabetic retinopathy (DR) and macular edema, but a significant subset of people had inadequate response to anti-VEGF intervention. Because elevation or overexpression of retinol binding protein 3 (RBP3) decreases risks for retinal pathologies and progression to severe DR, we compared the therapeutic profiles of RBP3 and anti-VEGF antibody to normalize retinal dysfunctions induced by diabetes. Intravitreous injection of recombinant human RBP3 (rhRBP3) and anti-VEGF antibody (namely, bevacizumab) inhibited retinal vascular permeability in Lewis rats induced by VEGF-A or after 2 months of diabetes induced by streptozotocin, in parallel with reductions of retinal VEGF and VEGF receptor 2 expressions and tyrosine phosphorylation of VEGF receptor. Only rhRBP3 ameliorated diabetes-induced reduction of neural retinal function, measured by electroretinogram. Furthermore, rhRBP3 reduced retinal expressions of inflammatory cytokines (TNF-α and IL-6) in retinal pigmented epithelial and Müller cells exposed to hyperglycemia. Metabolic studies, using a Seahorse flux analyzer, showed only rhRBP3 normalized retinal glycolytic rates in diabetic rats. Thus, both intravitreous anti-VEGF antibody and RBP3 injections normalized retinal vascular dysfunctions caused by diabetes. Only RBP3 targeted both neural and vascular retina to reduce glycolytic rates, reverse neural-retinal dysfunctions, and reduce inflammatory cytokines induced by diabetes, to delay early changes of DR.</p><p><strong>Article highlights: </strong></p>","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":" ","pages":"787-797"},"PeriodicalIF":0.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12015138/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143401006","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":"Padi4-Dependent NETosis Enables Diet-Induced Gut Hyperpermeability, Translating Dysbiosis Into Systemic Inflammation and Dysmetabolism.","authors":"Mattia Albiero, Ludovica Migliozzi, Carlotta Boscaro, Anna Rodella, Stefano Ciciliot, Francesco Ivan Amendolagine, Valentina Scattolini, Laura Treu, Roberta Cappellari, Paola Lanuti, Annica Barizza, Gaia Codolo, Alessandra Giannella, Giulio Ceolotto, Tatiana Varanita, Luca Prevedello, Mirto Foletto, Sara Bogialli, Stefano Campanaro, Angelo Avogaro, Gian Paolo Fadini","doi":"10.2337/db24-0481","DOIUrl":"10.2337/db24-0481","url":null,"abstract":"<p><p>Microbial signals trigger the release of neutrophil extracellular traps (NETs) through peptidyl arginine deiminase 4 (PADI4). In turn, NETosis can propagate inflammation to distant tissues. We hypothesize that PADI4 mediates the interactions between diet-modified microbiota and host metabolism. We report that in the adipose tissue of individuals with obesity, NETosis was associated with dysglycemia. In mice, high-fat diet (HFD) induced not only dysmetabolism and metainflammation but also local and systemic signs of NETosis. Deleting Padi4 in hematopoietic cells (Padi4KO) blunted liver and adipose inflammation and improved metabolism under HFD. While NETs were able to disrupt gut epithelial integrity, abrogating NETosis preserved intestinal barrier function and mitigated metabolic endotoxemia due to HFD. Padi4 deletion did not prevent diet-induced dysbiosis, but Padi4KO mice were protected from intestinal hyperpermeability and metabolic impairment due to the transfer of HFD-modified microbiota. As Padi4KO did not blunt the dysmetabolic effects of lipopolysaccharide, we concluded that NETosis operates at the microbiota-intestinal interface, inducing hyperpermeability and the systemic spillover of bacterial-derived products, paving the way to the metabolic consequences of HFD. Finally, pharmacologic PADI4 inhibition recapitulated findings obtained in Padi4KO mice on metabolism and liver steatosis, thereby uncovering a druggable role for PADI4 in mediating the metabolic effects of unhealthy microbiota.</p><p><strong>Article highlights: </strong></p>","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":" ","pages":"705-719"},"PeriodicalIF":0.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143411817","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}