Diabetes最新文献

{"title":"β-Hydroxybutyrate Improves Glucose Metabolism in Streptozotocin-Induced Type 1 Diabetes by Inhibiting Gut and Liver Glucose Transporters via GPR109A.","authors":"Shaobo Li, Jingjie Wang, Chunxiao Xin, Yiling Dong, Anqi Xie, Jing Song, Jing Wan, Jun Yin","doi":"10.2337/db25-1115","DOIUrl":"10.2337/db25-1115","url":null,"abstract":"<p><p>Ketone bodies, particularly β-hydroxybutyrate (3HB), are often elevated in type 1 diabetes (T1D); however, their physiological roles remain unclear. In a low-carbohydrate diet study, patients with insulin-deficient diabetes exhibited reduced fasting blood glucose and increased fasting blood ketone levels, negatively correlated. Another clinical study using continuous glucose and ketone monitoring confirmed inverse glucose-ketone fluctuations. To test causality, we conducted animal and cellular studies. In streptozotocin-induced T1D mice, 7-week oral 3HB administration improved glucose metabolism and alleviated glycogenic hepatopathy. Imaging with 2-deoxy-2-[18F]-fluoro-d-glucose positron emission tomography/computed tomography demonstrated reduced hepatic and intestinal glucose uptake. Western blotting confirmed 3HB suppressed glucose transporter (sodium-glucose cotransporter 1, GLUT2, GLUT5) overexpression and normalized glycogen metabolism. In vitro, 3HB dose-dependently inhibited glucose transporter expression and glucose uptake in primary hepatocytes and IEC-6 cells. G protein-coupled receptor 109A (GPR109A) serves as the primary receptor for 3HB. Mechanistic studies using the GPR109A inhibitor mepenzolate bromide, the mTOR inhibitor rapamycin, and siRNA-mediated gene silencing revealed that these effects were GPR109A dependent and linked to inhibition of the PI3K/AKT/mTOR pathway. Overall, this study provides new insights into the role of ketone bodies in T1D, establishing 3HB as a modulator of glucose homeostasis through GPR109A-mediated suppression of glucose transporters in the liver and intestine.</p><p><strong>Article highlights: </strong></p>","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":"75 7","pages":"1125-1141"},"PeriodicalIF":0.0,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13291861/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148304507","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":"Islet Autotransplant Recipients Have Elevated Proinsulin-to-C-Peptide Ratios Supporting Metabolic Stress as a Cause of Islet Attrition.","authors":"Ekram Ali, Anne Eaton, Michael R Rickels, Carmella Evans-Molina, Karthik Ramanathan, David Martin, Guru Trikudanathan, Elissa Downs, Gregory J Beilman, Melena D Bellin","doi":"10.2337/db26-0011","DOIUrl":"10.2337/db26-0011","url":null,"abstract":"<p><p>Attrition of islet function is observed over time following total pancreatectomy with islet autotransplantation (TPIAT). Metabolic stress on a suboptimal islet mass is a suspected, but unconfirmed, contributor. We measured proinsulin-to-C-peptide (PI:C) ratios as an indicator of β-cell stress in TPIAT recipients >5 years post-TPIAT. Individuals ≥16 years old with TPIAT 5-20 years prior underwent 4-h mixed-meal tolerance testing (MMTT) and assessment of ambulatory glycemia by continuous glucose monitoring (CGM). Insulin use and HbA1c were obtained. PI:C was measured from fasting and +90 min MMTT samples. PI:C ratios were compared with healthy control individuals (n = 24) and were associated with MMTT and CGM measures. PI:C ratios from 132 TPIAT (median age 48 [interquartile range 33, 55] years, 33% male, 9.4 [6.7, 11.8] years post-TPIAT, islet mass transplanted 4,022 [2,777, 5,390]) were high compared with healthy control individuals (P < 0.0001; mean PI:C two- to threefold higher). Within the TPIAT recipients, higher PI:C ratios were associated with lower islet equivalents per kilogram transplanted, partial or failed islet function, higher HbA1c, higher BMI, reduced time in range on CGM, and more time in hyperglycemia by MMTT. Overweight/obesity and low islet mass associations with PI:C ratios were only partially mediated by hyperglycemia. PI:C ratios were elevated at a median of 10 years after TPIAT. These findings support the concept that metabolic stress is a cause of islet attrition in TPIAT and that having fewer islets, poor glycemic control, or unhealthy body weight may contribute to islet function decline.</p><p><strong>Article highlights: </strong>β-Cell stress after total pancreatectomy with islet autotransplantation has been proposed an important cause of islet loss. We measured circulating proinsulin-to-C-peptide ratios, measured to determine whether total pancreatectomy with islet autotransplantation recipients exhibit β-cell stress, and whether this is associated with hyperglycemia and other clinical factors. Proinsulin-to-C-peptide ratio levels were elevated twofold or more compared with healthy control volunteers and were higher with hyperglycemia, high BMI, and low islet mass. These results support the hypothesis that metabolic stress is a cause of long-term islet attrition and suggest potential opportunity to reduce β-cell stress through maintaining healthy body weight and avoiding significant time in hyperglycemia.</p>","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":" ","pages":"1210-1220"},"PeriodicalIF":0.0,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13291868/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147792838","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":"Protection Against Periodontitis by Improving Mitochondrial Function in Diabetes.","authors":"Satoru Onizuka, Takanori Shinjo, Atsushi Ishikado, I-Hsien Wu, Yujin Ohsugi, Surya Vishva Teja Jangolla, Qian Li, Kyoungmin Park, Jialin Fu, Marc Gregory Yu, Qin Li, Hatice Hasturk, Thomas E Van Dyke, George L King","doi":"10.2337/db25-0849","DOIUrl":"10.2337/db25-0849","url":null,"abstract":"<p><p>Diabetes is a major risk factor for severe periodontitis. This is partly due to impaired wound healing associated with concomitant failure to resolve inflammation and chronic infection. Studies from the Joslin Medalist Cohort, people with >50 years of type 1 diabetes, have reported that protective factors exist to delay the onset of severe retinopathy, nephropathy, and periodontitis, even with persistent hyperglycemia. Proteomic analysis of healthy gingival tissues from individuals with hyperglycemia versus those with periodontitis and good glycemic control showed substantial upregulation of oxidative phosphorylation, particularly mitochondrial complex I and II, as validated by immunoblot analysis. Diabetes reduced mitochondrial enzyme expression and function, measured by oxygen consumption rate in the gingiva, compared with nondiabetic mice, in parallel, with exacerbation of ligature-induced periodontal bone loss, elevation of inflammatory cytokines (Il-1b, Il-6, and Il-17a) and activation of osteoclasts. However, activation of pyruvate kinase M2 reversed diabetes and ligature-induced mitochondrial dysfunction, reduced levels of inflammatory cytokines, and mitigated periodontal bone loss, without affecting glycolytic function. These results suggested that enhancing mitochondrial protein expression and function can decrease periodontal inflammation and osteoclast activation in diabetes, thereby protecting against the onset of periodontitis and bone loss, suggesting a potential therapy for chronic wounds, even with persistent hyperglycemia.</p><p><strong>Article highlights: </strong>Characterization of protective factors against periodontal inflammation with long durations of diabetes. Proteomic analysis of gingival tissue from people with type 1 diabetes >50 years and poor glycemic control without periodontitis showed elevated mitochondrial enzymes and functions. These mitochondrial dysfunctions, as well as inflammatory and osteoclast activation, were validated in diabetic mouse models of periodontitis. Elevation of mitochondrial functions by pyruvate kinase 2 activation reversed diabetes-induced gingival inflammation, osteoclast activation, and periodontitis, even in the presence of hyperglycemia. Mitochondrial activation could be a potential therapy for periodontitis and, perhaps, chronic wound healing in diabetes.</p>","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":" ","pages":"1243-1255"},"PeriodicalIF":0.0,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13291857/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147950517","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":"cGAS-STING Pathway Mediates Retinal Pigmental Epithelial Dysfunction in Diabetic Retinopathy.","authors":"Zhaoqi Zhu, Aowang Qiu, Ningyu Wang, Ziyu Zhu, Wenjie Yin, Ziyun Jiao, Qinghuai Liu, Weiwei Zhang","doi":"10.2337/db25-0128","DOIUrl":"10.2337/db25-0128","url":null,"abstract":"<p><p>Diabetic retinopathy (DR) is a predominant cause of vision impairment among working-age individuals, with a subset of patients responding poorly to current treatments. This study investigated alterations in double-stranded DNA (dsDNA) levels in the aqueous humor and retinal pigment epithelium (RPE) dysfunction in DR patients, exploring the potential role of the cyclic GMP-AMP synthase (cGAS)-STING pathway in DR progression. We found that DR patients showed significantly elevated dsDNA levels in the aqueous humor compared with control individuals. Fundus autofluorescence imaging revealed an increase in high-autofluorescence spots in DR patients, indicating early RPE dysfunction. In vivo and in vitro models of DR demonstrated mitochondrial damage and dsDNA leakage in RPE cells, along with cGAS-STING pathway activation in the retina. Pharmacological inhibition of STING reduced cytoplasmic dsDNA accumulation and damaged mitochondria, alleviating inflammation in vitro. In vivo, STING inhibition ameliorated RPE dysfunction and vascular changes. These findings highlight the critical role of the cGAS-STING pathway in DR pathogenesis and suggest that STING inhibition may serve as a promising therapeutic strategy to reduce retinal inflammation and slow the progression of DR.</p><p><strong>Article highlights: </strong>The retinal pigment epithelium (RPE) serves as the outer blood-retinal barrier, protecting the neural retina from systemic changes. We aimed to preserve RPE integrity through early intervention and inhibit DR progression. Our study focused on determining whether the involvement of the cyclic GMP-AMP synthase-STING pathway and mitochondrial damage drive RPE dysfunction. We found that mitochondrial dysfunction in the RPE under diabetic conditions triggers activation of the cyclic GMP-AMP synthase-STING pathway, leading to disruption of RPE and retinal vascular instability. Targeting this pathway restored RPE function and limited retinal deterioration. These findings highlight a promising therapeutic approach for preventing disease progression.</p>","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":" ","pages":"1285-1297"},"PeriodicalIF":0.0,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13291859/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147965596","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":"Sex-Dependent Diabetes Impact of Acute Grp78 Deletion in β-Cells of Adult Mice.","authors":"Joshua J N Burton, Thalia A Castro, Alison A Juray, Hibo A Hassan, Hillary Diaz Mosquea, Rohit B Sharma, Laura C Alonso","doi":"10.2337/db25-0809","DOIUrl":"10.2337/db25-0809","url":null,"abstract":"<p><p>GRP78/BiP/HSPA5 is a widely expressed endoplasmic reticulum (ER) chaperone that also performs the critical role of regulating the unfolded protein response, an adaptive mechanism that maintains ER homeostasis. As the exclusive source of circulating insulin, pancreatic β-cells are prone to ER stress due to proinsulin synthesis workload. GRP78 is important for the ER stress response, but it is unknown whether β-cells require GRP78 in the absence of metabolic stress. Here, we report the impact of genetic deletion of GRP78 in β-cells of healthy adult mice during normal metabolic conditions. Glucose intolerance occurred in both sexes, mildly in females but profoundly in males, concomitant with weight loss. Islet size and β-cell mass were reduced only in males. Both sexes showed similar increases in β-cell death and residual α-cell proportion, but females more robustly showed increased β-cell proliferation. Intriguingly, dedifferentiation was prominent in males, both in vivo and ex vivo, and male islet cells showed hyperactive induction of ATF6 target genes during ex vivo Grp78 deletion compared with female. We conclude that GRP78 is essential for β-cell health, even in resting conditions, and that sex differences exist in the β-cell ER stress response.</p><p><strong>Article highlights: </strong>We investigated the consequence of reducing GRP78 abundance in pancreatic β-cells of adult mice in normal physiological conditions. Genetic Grp78 reduction caused β-cell failure and diabetes in male mice, with weight loss, hyperglycemia, glucose intolerance, β-cell mass reduction, and β-cell dedifferentiation. Male and female mice showed similar increases in β-cell death, but proliferation was more profoundly increased in females. Ex vivo Grp78 deletion led to hyperactivation of ATF6 target genes in male islet cells compared with female. Preserving β-cell GRP78 abundance may reduce the likelihood of diabetes, especially in males.</p>","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":" ","pages":"1176-1188"},"PeriodicalIF":0.0,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13291860/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147446428","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":"Activation of Intestinal Type 3 Innate Lymphoid Cells and Regulatory T Cells Through Free Fatty Acid Receptor 2 Ameliorates Type 1 Diabetes in Mice.","authors":"Ivan Koprivica, Natalija Jonić, Mirjana Dimitrijević, Bojan Jevtić, Dragica Mićanović, Goran Stegnjaić, Milica Lazarević, Suzana Stanisavljević, Ivan Pilipović, Nataša Radulović, Tamara Saksida, Danijela Mišić, Vera Zdravković, Graeme Fraser, Đorđe Miljković, Ivana Stojanović","doi":"10.2337/db25-0742","DOIUrl":"10.2337/db25-0742","url":null,"abstract":"<p><p>Reduction in intestinal type 3 innate lymphoid cells (ILC3) frequency is associated with type 1 diabetes (T1D) pathogenesis in humans and in animal models. The current study showed that, after T1D induction by multiple-low-dose streptozotocin in male C57BL/6 mice, ILC3 were reduced in both blood and pancreas and produced less IL-22 and IL-2, and a decreased proportion expressed the gut-homing α4β7 integrin in the pancreas. Additionally, T1D induction in ILC3-impaired mice produced exacerbated hyperglycemia. To activate ILC3, Compound 1 (Cpd1), a synthetic selective free fatty acid receptor 2 (FFAR2) agonist, was administered orally in a prophylactic regimen, at early therapeutic stages, or during established disease, resulting in significant amelioration of T1D symptoms. Cpd1 upregulated ILC3 and activated regulatory T cells (Treg) within the small intestine lamina propria and the pancreas, enhanced intestinal barrier integrity, and increased microbial diversity. Cpd1 also reduced α4β7-expressing inflammatory cells in the pancreas while promoting the accumulation of gut-imprinted ILC3. IL-22 was important for this anti-inflammatory response, as treatment efficacy was inhibited when mice were additionally given neutralizing anti-IL-22 antibodies. Of note, NOD mice receiving Cpd1 exhibited postponed disease initiation, but the incidence of disease was similar to that of the control group. Overall, activation of intestinal ILC3 and Treg via FFAR2 engagement, and translation of these anti-inflammatory effects to the pancreas, provided significant benefit in a mouse T1D model.</p><p><strong>Article highlights: </strong>Modulating the adaptive immune response alone is insufficient for effective type 1 diabetes treatment. This study investigates targeting intestinal type 3 innate lymphoid cells as a novel therapeutic approach for type 1 diabetes. A synthetic free fatty acid receptor 2 agonist, Compound 1, activates intestinal IL-2+ and IL-22+ type 3 innate lymphoid cells and thereby reduces pancreatic inflammation, stabilizes intestinal barrier, and improves clinical outcomes in a type 1 diabetes mouse model. Compound 1 demonstrates therapeutic potential and may serve as a candidate for future clinical trials in type 1 diabetes.</p>","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":" ","pages":"1221-1232"},"PeriodicalIF":0.0,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13291856/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147966292","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":"Effects of Dietary Carbohydrate Amount and Glycemic Index on Blood Lipidomic Signatures and Diurnal Postprandial Glucose Responses: The OmniCarb Trial.","authors":"Yoriko Heianza, Qi Sun, Lawrence J Appel, Frank M Sacks, Lu Qi","doi":"10.2337/db25-0713","DOIUrl":"10.2337/db25-0713","url":null,"abstract":"<p><p>We investigated whether lowering dietary carbohydrate content and glycemic index (GI) levels altered deep lipidomic profiles and whether these changes were associated with improved diurnal postprandial glucose response (PPGR). In the OmniCarb trial, 59 adults completed 5-week controlled feeding interventions (low carbohydrate/low GI vs. high carbohydrate/high GI) and 12-h meal tests. Comprehensive lipidomic profiling was performed to measure lipid species and lipid class-specific fatty acids (FAs) at the end of each intervention. We found that lowering carbohydrate content and GI levels significantly decreased triacylglycerols (TAGs) and phosphatidylcholines, while increasing lactosylceramides and phosphatidylethanolamines (PEs). Of 731 lipid species analyzed, 521 (71%) were significantly modified, including TAGs (n = 398), PEs (n = 45), and ceramides. Of 199 FAs analyzed across and within lipid classes, 89 showed significant changes (false discovery rate-adjusted P < 0.05), including decreases in saturated FAs (total and TAG FA12:0 and FA14:0) and palmitoleic acid and increases in very-long-chain saturated FAs, when lowering carbohydrate and GI levels. Between-diet changes in six total FAs and 17 lipid class-specific FAs were associated with half-day PPGR changes; greater decreases in joint FA score changes were linked to improved PPGRs. Our study suggests the potential importance of dietary carbohydrate-responsive lipidomic signatures in explaining individual variability in half-day PPGRs and may encourage future intervention studies to target these signatures.</p><p><strong>Article highlights: </strong>Carbohydrate diets with high glycemic index (GI) increase postprandial glucose response (PPGR) and diabetes risk; however, the pathways underlying individual variability in diurnal PPGRs to diets differing in carbohydrate content and GI remain unclear. We examined the effect of lowering dietary carbohydrate content and GI levels on comprehensive lipidomic pathways and tested whether these changes were associated with improved half-day PPGRs. Five-week controlled feeding interventions altered multiple lipid species and lipid class-specific fatty acids toward more favorable profiles, and composite fasting blood fatty acid scores derived from comprehensive targeted lipidomic profiling were associated with improved 12-h PPGRs. These lipidomic signatures explain individual variability in PPGRs and provide targets for future intervention studies.</p>","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":" ","pages":"1113-1124"},"PeriodicalIF":0.0,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13291855/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147978062","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":"Response to Comment on Sakaki et al. Quantitative β-Cell Mass Imaging Redefines Disease Staging and Glycemic Control in Type 1 Diabetes.","authors":"Kentaro Sakaki, Takaaki Murakami, Daisuke Yabe, Nobuya Inagaki","doi":"10.2337/dbi26-0017","DOIUrl":"10.2337/dbi26-0017","url":null,"abstract":"","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":"75 7","pages":"e23-e24"},"PeriodicalIF":0.0,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13291854/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148304418","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":"Unraveling Diabetic Cardiomyopathy (DCM): The Critical Role of the Yap-miR-22-3p-Sirt1 Axis in the Pathogenesis of DCM.","authors":"Yilang Li, Yue Zeng, Yuling Lian, Chi Zhang, Xiaoqing Chen, Siyu Zhang, Yipu Huang, Wenchang Yuan, Yuan Qin, Ducai Liu, Yun Liu, Yilin Chen, Yongying Shi, Xun Yuan, Ning Hou","doi":"10.2337/db25-0435","DOIUrl":"10.2337/db25-0435","url":null,"abstract":"<p><p>Diabetic cardiomyopathy (DCM), characterized by myocardial hypertrophy and fibrosis, is a severe complication of diabetes. Activation of Yes-associated protein (Yap) has been implicated in myocardial remodeling and cardiac dysfunction. This study aimed to elucidate the role and underlying molecular mechanisms of Yap in DCM. Yap expression was evaluated in mice with type 2 diabetes mellitus (T2DM) and in neonatal rat cardiomyocytes (NRCMs) treated with high glucose (HG) or HG + palmitic acid (PA). Adeno-associated virus transfection, adenovirus infection, and a transgenic mouse model were used to modulate Yap expression both in vivo and in vitro. RNA sequencing and miRNA sequencing were used to identify Yap's downstream targets and related mechanisms. Functional assays, including assessment of molecular markers, cell morphology, and echocardiography, were conducted to evaluate cardiomyocyte hypertrophy and fibrosis. Results showed that Yap expression was elevated in HG or HG+PA-treated NRCMs and hearts of T2DM mice, promoting myocardial hypertrophy and fibrosis. Inhibition of Yap reduced cardiomyocyte cross-sectional area, collagen deposition, and levels of hypertrophy markers atrial natriuretic peptide and β-myosin heavy chain. RNA sequencing identified Sirt1 as a downstream target of Yap. Bioinformatics analysis indicated that Yap positively regulated miR-22-3p, which in turn inhibited Sirt1. Yap inhibition increased Sirt1 expression, alleviating myocardial remodeling. Conversely, Sirt1 knockdown reversed the protective effects of Yap inhibition, exacerbating hypertrophy and fibrosis. In conclusion, Yap promotes the progression of DCM by upregulating miR-22-3p expression and suppressing Sirt1 expression. Therapeutically targeting the newly identified Yap-miR-22-3p-Sirt1 axis could mitigate multiple aspects of diabetic cardiac remodeling.</p><p><strong>Article highlights: </strong>Diabetic cardiomyopathy (DCM) describes the abnormality of myocardial structure and function caused by diabetes, and Yes-associated protein (Yap) is linked to various cardiovascular diseases, modulating remodeling and cardiac function in hearts, but its role in DCM is unclear. How Yap affects myocardial structure and function in mice with type 2 diabetes mellitus and the underlying pathways were investigated. High glucose or high glucose plus palmitic acid levels enhance Yap activity, thereby promoting miR-22-3p expression and inhibiting sirtuin 1 (Sirt1) expression. The Yap-miR-22-3p-Sirt1 axis plays critical roles in the cause of DCM. The molecular pathways investigated offer promising targets for therapeutic intervention against DCM and provide new insights into the development of innovative treatment strategies to combat cardiac dysfunction in patients with diabetes.</p>","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":" ","pages":"974-990"},"PeriodicalIF":0.0,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147328791","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":"Ketogenic Diet and Exercise Improve Peripheral Neuropathy in a Mouse Model of Metabolic Syndrome.","authors":"Stéphanie A Eid, Pongrat Jaisil, Kai Guo, John M Hayes, Crystal Pacut, Diana M Rigan, Andrew Carter, Samuel J Teener, Bhumsoo Kim, Chloe Kiriluk, William Lentz, Cameron M Miller, Ian Webber-Davis, Haley McQuown, Dae-Gyu Jang, Adam Patterson, Emily J Koubek, Dave Bridges, Junguk Hur, Jacob D Meyer, Eva L Feldman","doi":"10.2337/db25-1015","DOIUrl":"10.2337/db25-1015","url":null,"abstract":"<p><p>Metabolic syndrome (MetS) is a growing health concern that increases risk for peripheral neuropathy (PN), defined by nerve degeneration and sensory dysfunction. Although lifestyle strategies, like ketogenic diet (KD) and exercise, are known to mitigate MetS, their efficacy in maintaining nerve health or reversing established PN is less clear. First, in a maintenance paradigm, we tested whether long-term KD could maintain nerve health in mice, as opposed to a Western-style high-fat diet (HFD) that induces MetS PN. Second, in an intervention paradigm of mice with established MetS PN, we compared the efficacy of low-fat standard diet, KD, exercise, and combined KD-exercise interventions in reversing MetS PN. Long-term KD maintained body composition, nerve function, and neuromuscular innervation. In mice with established MetS PN, all interventions improved metabolic parameters and nerve function, albeit to varying extents. Transcriptomic profiling revealed that HFD dysregulated genes related to cytoskeletal dynamics and inflammation in sciatic nerve, with interventions partially reversing these changes. In muscle, dietary interventions modulated fatty acid and amino acid metabolism. Notably, exercise generated a unique gene expression signature in nerve and muscle. These findings support KD and exercise as promising approaches for treating MetS PN and offer mechanistic insights into their therapeutic benefits.</p><p><strong>Article highlights: </strong>Metabolic syndrome (MetS) increases risk for peripheral neuropathy (PN), a progressive nerve disorder with limited treatment options. We examined whether long-term ketogenic diet (KD) could maintain nerve health, and whether KD, exercise, or both could reverse established MetS PN. Maintenance KD preserved body composition, liver health, and nerve function, while all interventions improved metabolic and nerve outcomes to varying degrees. Transcriptomic profiling of sciatic nerve and gastrocnemius muscle revealed partial reversal of MetS-induced inflammatory, cytoskeletal, and metabolic gene alterations. These findings highlight KD and exercise for treating MetS PN.</p>","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":" ","pages":"991-1006"},"PeriodicalIF":0.0,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13191425/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147492373","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}