Diabetes最新文献

{"title":"Type 2 Diabetes Genetic Risk and Type 1 Diabetes Heterogeneity and Progression.","authors":"Taylor M Triolo, Jay M Sosenko, David Cuthbertson, Richard A Oram, Hemang M Parikh, Andrea K Steck, Emily K Sims, Laura M Jacobsen, Brandon Nathan, Erin L Templeman, Suna Onengut-Gumuscu, Carmella Evans-Molina, Stephen S Rich, Mark A Atkinson, Maria J Redondo","doi":"10.2337/db25-0711","DOIUrl":"10.2337/db25-0711","url":null,"abstract":"<p><p>Insulin secretion varies widely in preclinical type 1 diabetes. To understand the pathogenesis of this metabolic heterogeneity, we asked whether genetic predisposition to type 2 diabetes, quantified by a type 2 diabetes genetic risk score (T2D-GRS), modulates β-cell function and disease progression in individuals at risk of type 1 diabetes. We analyzed 4,324 islet autoantibody–positive TrialNet Pathway to Prevention participants with genome-wide genotyping and oral glucose tolerance testing. Both T2D-GRS and the type 1 diabetes genetic risk score 2 (T1D-GRS2) differed significantly across five previously described groups defined by C-peptide area under the curve (AUC; a measure of insulin secretion). The highest C-peptide AUC group, compared with the lowest, had significantly higher T2D-GRS, lower T1D-GRS2, higher BMI z-score, greater insulin resistance, older age, and lower prevalence of male participants; multiple islet autoantibody positivity; and IA-2 or insulin autoantibody positivity. Progression to clinical (stage 3) type 1 diabetes was significantly associated with T1D-GRS2 across all groups and with T2D-GRS in all but the lowest C-peptide AUC group. In conclusion, type 2 diabetes genetic burden shapes metabolic heterogeneity and accelerates progression in preclinical type 1 diabetes. These results support the evaluation of type 2 diabetes–related mechanisms as targets to improve the prediction and prevention of type 1 diabetes.</p><p><strong>Article highlights: </strong>Heterogeneity in β-cell function is a barrier to precision medicine in type 1 diabetes. We asked whether type 2 diabetes-associated genes influence insulin secretion and progression to clinical type 1 diabetes in autoantibody-positive individuals. A type 2 diabetes genetic risk score was associated with higher C-peptide area under the curve (AUC) and increased clinical type 1 diabetes risk in all but the lowest C-peptide AUC subgroup. Addressing type 2 diabetes mechanisms could improve type 1 diabetes prediction and prevention.</p>","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":" ","pages":"389-397"},"PeriodicalIF":0.0,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12823339/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145716783","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":"Phosphatidylserine Supplementation Improves Metabolic Liver Disease and Glycemic Control in the Presence of Suppressed Oxidative Glucose Metabolism.","authors":"Li Dong, Sihan Lin, John Slavin, Satya Gunnam, Zhili Cheng, Shuai Nie, Michael G Leeming, Nicholas A Williamson, Magdalene K Montgomery","doi":"10.2337/db25-0588","DOIUrl":"10.2337/db25-0588","url":null,"abstract":"<p><p>Type 2 diabetes and obesity are commonly accompanied by metabolic dysfunction–associated steatotic liver disease (MASLD), increasing the risk of developing metabolic dysfunction–associated steatohepatitis (MASH) and fibrosis. The early stages of MASLD are characterized by dysfunctional lipid metabolism, including remodeling of the hepatic lipidome. In this context, reductions in hepatic phosphatidylserine (PS) have been associated with increased hepatic steatosis, inflammation, and fibrosis. In this study, we investigated the impact of dietary PS supplementation on liver function and systemic metabolic homeostasis in mice with hepatic steatosis and MASH. Taking advantage of the MUP-uPA mouse model, including wild-type mice with hepatic steatosis and MUP-uPA mice with MASH and fibrosis, we showed that PS supplementation reduces hepatic triglyceride accumulation, inflammation, and fibrosis in male MUP-uPA mice. Supporting these data, PS supplementation suppressed fibrogenic gene expression in LX-2 hepatic stellate cells. We further showed that PS supplementation improved glycemic control and insulin sensitivity in male and female mice, which was associated with enhanced insulin signaling in muscle and liver, despite a pronounced suppression of glycolysis, glucose oxidation, and glycogen breakdown in liver, muscle, and/or adipose tissue. Metabolic flux analysis suggested a shift in substrate use, favoring fatty acid metabolism, particularly in muscle, while further pointing to marked improvements in mitochondrial function and oxidative capacity. These findings indicate that PS exerts multifaceted benefits by improving both MASH and whole-body glucose homeostasis, independent of conventional oxidative glucose metabolism. Our results support further investigation into dietary PS as a potential complementary strategy for MASH and glycemic control.</p><p><strong>Article highlights: </strong>The prevalence of metabolic dysfunction-associated steatohepatitis (MASH) and type 2 diabetes is increasing. We show that dietary phosphatidylserine supplementation reduces hepatic lipid accumulation, inflammation, and liver fibrosis while further improving blood glucose control and insulin sensitivity in mice with MASH and insulin resistance. Improvements in glycemic control are present despite suppression of glycolysis, glucose oxidation, and glycogen breakdown in liver, skeletal muscle, and/or adipose tissue. In contrast, oxidative lipid metabolism and overall mitochondrial function are enhanced in skeletal muscle.</p>","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":" ","pages":"273-287"},"PeriodicalIF":0.0,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145679820","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":"Altered Molecular Regulation of TUG Is a Central Feature of Insulin-Resistant Human Adipose Tissue.","authors":"Jordan W Strober, Kasper W Ter Horst, Daeun Sung, Aldo Jongejan, Aaron L Slusher, Brandon M Gassaway, Elena Tarabra, Joao A Paulo, Steven R Shuken, Steven P Gygi, Nicola Santoro, Sonia Caprio, Mireille J Serlie, Jonathan S Bogan, Daniel F Vatner","doi":"10.2337/db25-0488","DOIUrl":"10.2337/db25-0488","url":null,"abstract":"<p><p>White adipose tissue (WAT) insulin resistance (IR) is a central feature of metabolic syndrome; however, data regarding defects in WAT insulin signaling in humans with IR is limited. To determine which defects in WAT insulin signaling are associated with human IR, WAT was obtained from three cohorts of patients with obesity. In a bariatric surgery cohort (RESOLVE), subcutaneous WAT (n = 24) was collected before and after weight loss, and RNA sequencing was performed. In another bariatric surgery cohort (SODA), glucose- or fructose-sweetened beverages were consumed before subcutaneous and omental WAT collection, and proteomic data were collected (n = 16). In an adolescent cohort, subcutaneous WAT (n = 14) was collected before and during hyperinsulinemic clamps, and both quantitative PCR and immunoblotting were performed. The TC10–tether containing a UBX domain for GLUT4 (TUG) pathway regulates GLUT4 translocation and glucose uptake in insulin-responsive tissues. Expectedly, in the adipose tissue from all three cohorts, GLUT4 content decreased in those with IR. TUG, which traps insulin-responsive GLUT4 vesicles in intracellular pools, was increased in the setting of IR in all three cohorts. Furthermore, expression of multiple components of the TC10–TUG pathway was altered with IR. Therefore, human WAT IR is characterized by altered molecular regulation of the TC10–TUG pathway, underscoring the importance of this pathway to WAT metabolic health.</p><p><strong>Article highlights: </strong>There is a paucity of data regarding defects in insulin signaling in insulin-resistant human white adipose tissue (WAT). The tether containing a UBX domain for GLUT4 (TUG) protein, which retains GLUT4 vesicles, was increased in WAT of participants with greater insulin resistance in three different cohorts with obesity. Components of the TUG regulatory signaling pathway were differentially expressed between participants with greater insulin resistance and those with greater insulin sensitivity. TUG may provide an important pharmacologic target in the treatment or prevention of metabolic dysfunction in patients with obesity.</p>","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":" ","pages":"341-350"},"PeriodicalIF":0.0,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12823340/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145679725","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":"Dickkopf 3 in Urine: A Help for Prioritizing Management of Kidney Disease in Type 2 Diabetes.","authors":"Peter Rossing","doi":"10.2337/dbi25-0045","DOIUrl":"10.2337/dbi25-0045","url":null,"abstract":"","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":"75 1","pages":"17-18"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12716603/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145795695","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":"Microvascular Homeostasis Is Compromised in Pancreatic Islets in a Mouse Model of β-Cell Loss and Low-Grade Inflammation.","authors":"Luciana Mateus Gonçalves, Isha Shirvaikar, Konstandina Sideris, Elizabeth Pereira, Marjan Slak Rupnik, Joana Almaça","doi":"10.2337/db25-0368","DOIUrl":"10.2337/db25-0368","url":null,"abstract":"<p><p>Vascular dysfunction is considered a consequence of diabetes. However, in pancreatic islets, some hemodynamic changes occur before the onset of symptoms. The underlying mechanisms driving islet vascular abnormalities have not been fully characterized, but islet pericyte dysfunction seems to be an early event in the pathogenesis of type 1 diabetes in humans. It remains to be investigated, however, how abnormal pericyte physiology affects their ability to regulate islet blood flow and vascular permeability. To address this issue, we treated mice with multiple subdiabetogenic doses of the β-cell toxin streptozotocin (STZ; 50 mg/kg) and recorded islet vascular responses when animals developed glucose intolerance but were still not diabetic (average fed glycemia <200 mg/dL). At this stage, pericyte coverage of islet capillaries was abnormal, with capillaries either lacking pericytes or being covered by dysfunctional mural cells, which compromised islet vasomotor responses recorded ex vivo in living pancreas slices. These functional defects interfered with proper regulation of blood flow and compromised islet vascular integrity, because large fluorescent dextrans (500 kDa) could leak from peripheral islet vessels in the exteriorized pancreas of STZ-treated mice. Our study supports that the loss of functional pericyte coverage of islet capillaries is part of a pathogenic process occurring in islets before diabetes onset, associated with a loss of functional β-cell mass and inflammation.</p><p><strong>Article highlights: </strong>Pericyte dysfunction is an early event in type 1 diabetes in humans, but how it affects islet microvascular homeostasis in vivo is unknown. We sought to determine whether vascular integrity and blood flow regulation in islets were impaired in a model of partial β-cell loss and inflammation. Islet capillaries lost functional pericyte coverage shortly after low-dose streptozotocin, compromising vascular stability and local control of blood flow. Strategies that preserve vascular niches in islets could be of important therapeutic potential.</p>","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":" ","pages":"70-84"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12716606/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145395724","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":"Strategic Reduction of Hybrid Insulin Peptide Formation Significantly Delays Diabetes Onset in NOD Mice.","authors":"Jason Groegler, Kaitlin Mangold, Kelli Nicholson, Mylinh Dang, Janet Wenzlau, K Scott Beard, Anita Hohenstein, Roger Powell, Rocky Baker, Kathryn Haskins, Jennifer Matsuda, Thomas Delong","doi":"10.2337/db25-0324","DOIUrl":"10.2337/db25-0324","url":null,"abstract":"<p><p>Type 1 diabetes (T1D) is characterized by autoimmune destruction of insulin-producing β-cells. Recent evidence has implicated hybrid insulin peptides (HIPs) as targets of autoreactive CD4 T cells in human T1D patients and as critical autoantigens recognized by diabetogenic T cells in nonobese diabetic (NOD) mice. HIPs form within pancreatic islets through cross-linking reactions between proinsulin fragments and various β-cell peptides. In the NOD mouse model, highly pathogenic CD4 T cells specifically target HIPs generated through transpeptidation mediated by cathepsin D (CatD). These disease-relevant HIPs consistently incorporate a C-peptide fragment terminating in a critical leucine residue that binds to other β-cell peptides. In vitro experiments demonstrated that substituting isoleucine for this leucine residue in human C-peptide inhibited CatD-mediated HIP formation. To investigate the in vivo significance of this finding, we engineered NOD mice carrying a leucine-to-isoleucine mutation in the insulin 2 gene (NOD INS2I/I). Mass spectrometric analysis revealed significantly reduced HIP formation in islets from NOD INS2I/I mice. Significantly decreased activation of HIP-reactive T cells to islets from these mice was also observed. Furthermore, the NOD INS2I/I mice showed significantly delayed diabetes onset, with 43% remaining disease-free at 1 year compared with only 10% of wild-type NOD controls. These findings implicate HIPs as key mediators in T1D pathogenesis and demonstrate that targeted disruption of HIP formation significantly alters disease progression. Inhibiting CatD-mediated transpeptidation represents a promising therapeutic approach for preventing or delaying T1D onset in genetically susceptible individuals.</p><p><strong>Article highlights: </strong>Hybrid insulin peptides (HIPs) have been identified as targets of autoreactive T cells in type 1 diabetes, although their causal role in disease pathogenesis has remained unclear. We demonstrated that a single leucine-to-isoleucine substitution in insulin C-peptide significantly disrupts cathepsin D-mediated HIP formation in nonobese diabetic (NOD) mouse islets. NOD mice engineered with this precise modification (NOD INS2I/I) showed significantly reduced HIP content, decreased T-cell reactivity, and significantly delayed diabetes onset (43% disease-free at 1 year vs. 10% in controls). These findings establish a mechanistic link between HIP formation and disease progression, revealing cathepsin D-mediated transpeptidation as a potential therapeutic target for intervention in at-risk individuals.</p>","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":" ","pages":"115-123"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12707259/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145350779","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":"Gut Microbiota-Decanoic Acid-Interleukin-17A Axis Orchestrates Hyperglycemia-Induced Osteoporosis in Male Mice.","authors":"Tao Jiang, Changkun Li, Zhengcan Pan, Yizhu Wang, Xiaojing Chen, Jiaxi Song, Kecheng Zhu, Yuying Yang, Yanfang Hou, Lihao Sun, Hongyan Zhao, Jianmin Liu, Yanyun Gu, Bei Tao","doi":"10.2337/db25-0471","DOIUrl":"10.2337/db25-0471","url":null,"abstract":"<p><p>Hyperglycemia (HG) is a well-established risk factor for secondary osteoporosis, primarily due to suppressed osteoblast activity. While gut microbiota (GM) dysbiosis has been implicated in various diseases, its role in HG-induced osteoporosis remains poorly understood. Here, we demonstrate that HG mice develop low-turnover osteoporosis accompanied by reduced GM diversity. Fecal microbiota transplantation (FMT) from HG mice (GMHG-FMT) induced osteoporosis in recipient mice, independent of blood glucose levels. A depletion of Bifidobacterium pseudolongum was associated with bone loss, whereas supplementation with either microbiota of normoglycemic mice or B. pseudolongum alleviated osteoporosis in HG mice. Both HG and GMHG-FMT recipient mice exhibited elevated serum interleukin-17A (IL-17A) levels, and anti-IL-17A antibody treatment mitigated osteoporosis in the GMHG-FMT model. Furthermore, decanoic acid levels were elevated in the feces of HG mice and the serum of GMHG-FMT recipients. Decanoic acid promoted the differentiation of naive CD4+ T cells into T helper17 cells, leading to increased IL-17A production. These findings reveal a microbiome dysbiosis-driven decanoic acid/IL-17A axis in HG-induced osteoporosis and highlight the therapeutic potential of microbiome-associated targets.</p><p><strong>Article highlights: </strong>This study investigated the role of gut microbiota dysbiosis in hyperglycemia-induced osteoporosis, a condition with unclear mechanisms. We explored whether gut microbiota dysbiosis drives bone loss in hyperglycemia and identified key microbial and molecular pathways. Hyperglycemic mice showed disturbed gut microbiota symbiosis, decreased Bifidobacterium pseudolongum, and elevated decanoic acid, which promoted T helper 17 differentiation and interleukin-17A (IL-17A) production, leading to osteoporosis. Fecal microbiota transplantation from control mice, B. pseudolongum supplementation, and IL-17A blockade alleviated bone loss, highlighting both B. pseudolongum supplementation and IL-17A inhibition as potential therapeutic strategies for hyperglycemia-induced osteoporosis.</p>","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":" ","pages":"154-165"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145380586","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":"Flt3L-Derived Antigen-Presenting Cell Transfer in Neonatal NOD Mice Reduces the Incidence of Type 1 Diabetes.","authors":"Stephanie Orozco, Nouf Aljobaily, Hayley M Reynolds, Georgina A Oceguera, Thomas Lee, Maria Bettini, Matthew L Bettini","doi":"10.2337/db25-0055","DOIUrl":"10.2337/db25-0055","url":null,"abstract":"<p><p>Type 1 diabetes (T1D) is an autoimmune disease characterized by progressive stages culminating in T-cell-mediated destruction of the β-cells at the islets of Langerhans. The immune mechanisms that initiate T1D are not fully resolved but likely involve an interaction between proinflammatory antigen-presenting cells (APCs) and autoreactive T cells that initiate immune infiltration and activation. Previous studies have tested the use of tolerogenic APCs in adult female NOD mice to delay or prevent T1D with only slight to intermediate success. Moreover, immune infiltration begins as early as age 4 weeks; therefore, targeting autoreactive T cells with tolerogenic APCs in adult mice may not impact later stages of diabetes. Thus, we hypothesize that the transfer of tolerogenic APCs at the neonatal stage prior to priming and immune infiltration will result in effective protection from autoimmunity. Our studies demonstrate that immature APCs travel to the pancreatic draining lymph nodes, alter the cytokine milieu in young mice, divert autoreactive CD4+ T cells to anergy, and drastically decrease proliferation and function of cytotoxic lymphocytes in adult prediabetic mice, leading to a significant reduction in the incidence of T1D.</p><p><strong>Article highlights: </strong>Neonatal transfer of immature dendritic cell-enriched Flt3L splenocytes significantly reduces the incidence of type 1 diabetes in female NOD mice. Early time points are associated with accumulation of anergic T cells. In adult mice, there is a reduction in CD4 T helper 1 cells and reduced proliferation and perforin of CD8 T cells. Our work demonstrates how targeting the neonatal window of tolerance alters autoimmunity outcome.</p>","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":" ","pages":"133-143"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12716620/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145461055","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":"Maternal Obesity Programs Glucose Intolerance in Pregnant Female Offspring.","authors":"Liping Qiao, Cindy Lu, Sarah Saget, Jianhua Shao","doi":"10.2337/db25-0603","DOIUrl":"10.2337/db25-0603","url":null,"abstract":"<p><p>Maternal obesity is a known risk factor for metabolic dysfunction in offspring; however, its effect on metabolism during pregnancy in female offspring remains unclear. This study investigated how maternal obesity, induced by high-fat (HF) feeding in C57BL/6J mice, affects the metabolic adaptation to pregnancy in female offspring. Dams were fed an HF diet (60% fat) or chow for 3 months before and during pregnancy. Offspring of HF diet-fed dams (OF-HFD) exhibited reduced fetal growth, followed by rapid postnatal catch-up and increased adult adiposity, compared with offspring of chow-fed dams (OF-CD), despite having similar baseline glucose and insulin levels. During pregnancy, OF-HFD exhibited diminished increases in maternal body fat, blood triglycerides, and insulin concentrations, accompanied by glucose intolerance. In cultured islets, glucose-stimulated insulin secretion was markedly reduced in pregnant OF-HFD, despite unchanged β-cell mass or proliferation. Hepatic triglyceride secretion was decreased, whereas liver insulin signaling was enhanced, suggesting alterations in lipid and glucose metabolism. Feeding OF-HFD an HF diet before and during pregnancy further impaired fetal growth. These findings indicate that maternal obesity impairs the metabolic adaptation to pregnancy in female offspring, characterized by insulin insufficiency and disrupted lipid homeostasis. This may initiate a transgenerational cycle of metabolic dysfunction, potentially increasing the risk of gestational diabetes in subsequent generations. Our findings underscore the need for more research to explore these mechanisms in humans and develop strategies to reduce the long-term effects of maternal obesity.</p><p><strong>Article highlights: </strong>Maternal high-fat (HF) diet induces adiposity in first-generation (F1) female offspring, impairing metabolic adaptations during pregnancy. F1 offspring from HF diet-fed dams show diminished fat gain and reduced serum triglycerides, disrupting nutrient availability for fetal growth. Impaired insulin production in F1 pregnancy leads to glucose intolerance, driven by reduced insulin secretion despite normal β-cell mass. Unlike male offspring, F1 females exhibit resistance to fat expansion under HF diet challenge, suggesting sex-specific programming. These findings underscore a transgenerational cycle of metabolic dysfunction, highlighting the need for interventions against maternal obesity.</p>","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":" ","pages":"51-62"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12716618/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145380562","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":"Additive Effects of Dorzagliatin and Glucagon-Like Peptide 1 Receptor Agonism in a Novel Mouse Model of GCK-MODY and in Obese db/db Mice.","authors":"Shadai Salazar, Luis Fernando Delgadillo-Silva, Priscila Carapeto, Mohamed Mourad Kenfaoui, Karen Dakessian, Rana Melhem, Audrey Provencher-Girard, Giada Ostinelli, Julie Turgeon, Imane Kaci, Francis Migneault, Mark O Huising, Marie-Josée Hébert, Malik Chaker-Margot, Guy A Rutter","doi":"10.2337/db25-0520","DOIUrl":"10.2337/db25-0520","url":null,"abstract":"<p><p>Glucokinase (GK) catalyzes the key regulatory step in glucose-stimulated insulin secretion (GSIS). Correspondingly, hetero- and homozygous mutations in human GCK cause maturity-onset diabetes of the young (GCK-MODY) and permanent neonatal diabetes mellitus, respectively. To explore the possible utility of GK activators (GKAs) and of glucagon-like peptide 1 (GLP-1) receptor agonists in these diseases, we have developed a novel hypomorphic Gck allele in mice encoding an aberrantly spliced mRNA. In islets from homozygous knock-in (GckKI/KI) mice, GK immunoreactivity was reduced by >85%, and GSIS eliminated. Homozygous GckKI/KI mice displayed frank diabetes (fasting blood glucose >18 mmol/L; HbA1c ∼108 mmol/mol), ketosis, and nephropathy. Heterozygous GckKI/+ mice were glucose intolerant (HbA1c ∼37 mmol/mol). Abnormal glucose-stimulated Ca2+ dynamics in GckKI/+ islets were completely reversed by the GKA dorzagliatin, which was largely inactive in homozygous GckKI/KI mouse islets. The GLP-1 receptor agonist exendin-4 improved glucose tolerance in male GckKI/+ mice, an action potentiated by dorzagliatin. Sex-dependent additive effects of these agents were also observed on insulin secretion in vitro. Similar additive effects of the drugs were observed in obese hyperglycemic db/db mice. Combined treatment with GKA and incretin mimetics may thus be useful in GCK-MODY and in more common forms of type 2 diabetes.</p><p><strong>Article highlights: </strong>Glucokinase (GK) deficiency can drive maturity-onset diabetes of the young (GCK-MODY) in heterozygotes and permanent neonatal diabetes in homozygotes. We describe a hypomorphic Gck allele that results in aberrant splicing in islets and liver lowering GK activity by ∼85%. Whereas heterozygous mutant mice are mildly hyperglycemic, homozygotes have frank diabetes but survive to adulthood. Dorzagliatin potentiates the effects of glucagon-like receptor-1 receptor activation sex dependently in heterozygous Gck mice and in obese hyperglycemic db/db mice. Combined use of these drugs may be useful in some forms of GCK-MODY and in obesity-related type 2 diabetes.</p>","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":" ","pages":"99-114"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12716621/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145461053","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}