Diabetes最新文献

{"title":"Letter to the American Diabetes Association Board of Directors From Members of the Mentor Advisory Committee, ADA Pathway to Stop Diabetes Program","authors":"Barbara Anderson,Mark Anderson,David D’Alessio,Mary de Groot,Robert Eckel,David Harlan,Kevan Herold,Elbert Huang,Rohit Kulkarni,Lori Laffel,Christopher Newgard,Kathleen Page,Stephen Parker,Sumita Pennathur,Louis Phillipson,Lauretta Quinn,Alan Saltiel,Jean Schaffer,Viral Shah,Andrew Stewart,Karen Talmadge,Jill Weissberg-Benchell,Phillip White","doi":"10.2337/dbi26-0053","DOIUrl":"https://doi.org/10.2337/dbi26-0053","url":null,"abstract":"","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"76 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149089114","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial YME1L Restrains GRP75-Dependent ISR Activation to Prevent Podocyte Senescence in Diabetic Kidney Disease","authors":"Qianqian Yang,Yiyuan Zhang,Yaowu Zhang,Hui Zhang,Liqin Zhang,Xiaobo Zhang,Yong Xu,Qijing Wu","doi":"10.2337/db26-0413","DOIUrl":"https://doi.org/10.2337/db26-0413","url":null,"abstract":"Diabetic kidney disease (DKD) is characterized by progressive podocyte loss and cellular senescence, but the upstream stress pathways that determine podocyte fate are not fully understood. YME1L expression was markedly reduced in experimental models of DKD and was inversely associated with senescence markers. Genetic deletion of YME1L caused sustained eIF2α phosphorylation, enhanced ATF4 signaling, and promoted podocyte hypertrophy and senescence in vitro and in vivo. In contrast, restoration of YME1L suppressed integrated stress response (ISR) activation and alleviated diabetic podocyte senescence. Mechanistically, coimmunoprecipitation and mass spectrometry showed that YME1L interacts with the mitochondrial chaperone GRP75. Loss of YME1L led to abnormal accumulation of GRP75 in mitochondria and was accompanied by persistent ISR activation. Notably, GRP75 knockdown or pharmacological inhibition of ISR with ISR inhibitor reduced stress signaling and improved senescence-related phenotypes. Together, these findings identify a YME1L-GRP75 pathway that links mitochondrial stress to ISR activation and podocyte senescence in DKD. Article Highlights Loss of YME1L promotes podocyte senescence in diabetic kidney disease. YME1L deficiency induces sustained maladaptive integrated stress response activation. YME1L interacts with and regulates mitochondrial GRP75 homeostasis. GRP75 accumulation drives persistent integrated stress response activation and mitochondrial dysfunction.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"32 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149089111","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multiple ABCC8 Loss-of-Function Mutations Associated with Paradoxical Maturity-Onset Diabetes of the Young","authors":"Rosa Scala, Hao Zhang, Jian Gao, Colin G. Nichols","doi":"10.2337/db26-0406","DOIUrl":"https://doi.org/10.2337/db26-0406","url":null,"abstract":"ATP-sensitive potassium (KATP) channels, composed of SUR1 and Kir6.2 subunits, encoded by the ABCC8 and KCNJ11 genes, are critical regulators of membrane excitability and insulin secretion in pancreatic β-cells. A large number of ABCC8 and KCNJ11 missense variants have been identified in patients diagnosed with maturity-onset diabetes of the young (MODY), but the mechanistic link between these KATP variants and MODY remains quite unclear. As novel genetic variants do not often undergo functional characterization, there is confusion in the clinical literature as to whether the diabetes could be a late diagnosis of neonatal diabetes mellitus (NDM) caused by gain-of-function (GOF) mutations, or caused by loss-of-function (LOF) mutations that may initially manifest as hyperinsulinism and then cross over to diabetes. Here, we functionally characterized 16 ABCC8 variants previously reported as carried by patients diagnosed with MODY, most without an earlier diagnosis of hyperinsulinism, and traceable genetic inheritance. We demonstrate that 13 of 16 mutations cause an LOF of expressed SUR1/Kir6.2 KATP channels, 3 of 16 have no effect on channel activity (and are therefore presumably benign missense variants), and none causes KATP channel GOF. Together with other isolated cases reported by us and other groups, this solidifies the conclusion that KATP LOF can be associated with later-onset diabetes, and that it is inaccurate to assume that MODY-associated ABCC8 variants must induce KATP (GOF) or, therefore, that KATP inhibitors are appropriate treatment for this condition. Article Highlights The effects of 16 ABCC8 variants, previously reported in heterozygous association with maturity-onset diabetes of the young (MODY), some with prior diagnosis of hypersinulinism, were assessed in recombinant Kir6.2/SUR1 KATP channels. Thirteen of 16 variants cause loss-of-function, 3 of 16 have no effect on channel activity, and none causes channel gain of function. In conclusion, KATP loss of function is associated with later-onset diabetes. Any presumption that MODY-associated ABCC8 variants must induce KATP (gain of function) and that KATP inhibitors are appropriate treatment is therefore inaccurate.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"23 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149086012","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Blood-Derived DNA Methylation Biomarkers Predict Diabetic Kidney Disease and Map to Epigenomic Remodeling in Renal Cells","authors":"Ishant Khurana, Tine Willum Hansen, Frederik Persson, Sørine Birkelund, Tarunveer Singh Ahluwalia, Scott Maxwell, Ram Abou Zaki, Harikrishnan Kaipananickal, Sargunpreet Singh Gill, John Nazli, Simone Theilade, Vina Margaretha Miguna, Nete Tofte, Evy Connie Ottesen, Peter Rossing, Assam El-Osta","doi":"10.2337/db26-0015","DOIUrl":"https://doi.org/10.2337/db26-0015","url":null,"abstract":"Diabetic kidney disease (DKD) is a leading cause of end-stage kidney disease in type 1 diabetes (T1D); however, albuminuria and estimated glomerular filtration rate (eGFR) lack the precision necessary for early prognostication. We sought blood-derived DNA methylation biomarkers that predict DKD progression and reflect renal epigenomic remodeling. In the PROFIL cohort, we performed high-depth genome-wide methylation sequencing of leukocyte DNA from 101 adults with T1D and 20 control participants without diabetes, stratified by Kidney Disease: Improving Global Outcomes (KDIGO) risk and observed for a median of 5.6 years. Differentially methylated regions were identified across baseline KDIGO strata and prioritized based on hypomethylation, four or more CpGs per region, and discrimination between KDIGO categories; their associations with eGFR decline and rising albumin excretion were then evaluated. From these candidates, we derived a four-locus methylation risk score (MRS; SLC4A4, FSTL4, ICA1, and PTK2), validated by targeted assays in an independent subset of 330 participants with T1D with low or moderate KDIGO risk at baseline. Those with T1D showed global loss of 5-methylcytosine, with hypomethylated regions enriched at regulatory sites. In the discovery cohort, the combined MRS plus clinical model discriminated baseline KDIGO moderate- and high/very-high-risk strata (areas under the curve 0.91 and 0.86, respectively). In the independent validation cohort, the four-locus MRS predicted DKD progression within baseline low- and moderate-risk categories and improved risk stratification beyond clinical covariates, including eGFR and albumin excretion. In human podocytes, high glucose induced locus-specific hypomethylation, altered chromatin binding, and increased expression of MRS genes. These findings support a four-locus MRS for earlier, mechanistically grounded DKD risk stratification in T1D. Article Highlights We undertook this study because albuminuria and estimated glomerular filtration rate often identify diabetic kidney disease risk only after substantial kidney injury in type 1 diabetes. We asked whether blood DNA methylation patterns could predict future DKD progression and improve clinical risk stratification. Genome-wide leukocyte methylation sequencing identified hypomethylated regions and a four-locus methylation risk score (SLC4A4, FSTL4, ICA1, and PTK2) that improved prediction beyond clinical risk models and was validated in 330 participants. Podocyte multiomics showed concordant hyperglycemia-induced hypomethylation and gene activation, supporting the biological plausibility of the blood-derived risk score.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"35 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149086014","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dynorphin A Inhibits Insulin Secretion Through Opioid Receptor–Dependent Modulation of β-Cell Ca2+ Dynamics","authors":"Miranda Movahed, Mariam Gomareli, Ruy A. Louzada, Manuel Blandino-Rosano","doi":"10.2337/db26-0224","DOIUrl":"https://doi.org/10.2337/db26-0224","url":null,"abstract":"Opioids are classically associated with pain and reward; however, endogenous opioid peptides and their receptors are also expressed in pancreatic islets, where their physiologic role remains unclear. Building on evidence indicating that β-cells corelease dynorphin A with insulin, we show that applied dynorphin A inhibits insulin secretion during glucose stimulation. Dynorphin A dose-dependently suppresses glucose-stimulated insulin secretion in mouse and human islets while preserving insulin content and β-cell viability. Under dynamic perifusion, dynorphin A attenuates both first- and second-phase insulin release. Mechanistically, dynorphin A slows glucose-stimulated β-cell Ca2+ oscillations in pancreatic slices, reducing oscillatory frequency while prolonging individual Ca2+ events. Notably, the receptor requirements for the inhibitory response to applied dynorphin A differ across species; μ-opioid receptor blockade or β-cell–specific deletion abolishes inhibition in mouse islets, whereas δ-opioid receptor antagonism prevents dynorphin A–mediated inhibition in human islets. These findings define the opioid receptor mechanisms underlying the inhibitory response to applied dynorphin A and reveal species-dependent receptor involvement in mouse and human islets. Article Highlights The role of endogenous opioid signaling within pancreatic islets remains poorly defined. We investigated whether dynorphin A regulates insulin secretion and characterized the receptor requirements for the acute response to applied dynorphin A in mouse and human islets. Applied dynorphin A suppressed glucose-stimulated insulin secretion by remodeling β-cell Ca2+ oscillations through an opioid receptor–dependent, Na+/K+-ATPase–associated pathway. This response required μ-opioid receptors in mouse β-cells and was pharmacologically consistent with δ-opioid receptor involvement in human islets, defining species-dependent receptor mechanisms for the acute response to dynorphin A.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"56 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149086013","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Insulin Resistance in the 21st Century: New Takes on an Old Problem—2025 Diabetes, Diabetes Care , and Diabetologia Expert Forum","authors":"Amalia Gastaldelli, Eunhee Choi, Karin Conde-Knape, Olga Göransson, Anna Krook, Sanna Lehtonen, Michael Roden, Patrick Schrauwen, Lauren M. Sparks, Martin Heni","doi":"10.2337/dbi26-0044","DOIUrl":"https://doi.org/10.2337/dbi26-0044","url":null,"abstract":"Insulin resistance is a hallmark of type 2 diabetes and several other metabolic diseases. However, efforts to improve insulin resistance are hindered by the biological complexity inherent to insulin action, as well as conceptual and methodological limitations to date. In September 2025, the editors of Diabetes, Diabetes Care, and Diabetologia convened an Expert Forum in advance of the 61st Annual Meeting of the European Association for the Study of Diabetes (EASD). Participants reviewed the latest research, clarified key concepts, and recommended future research priorities. Their insights were presented at a symposium during the EASD meeting and are offered in more detail here. The authors challenge the historical view of insulin resistance as a single, uniform pathophysiological condition, describing it instead as a diverse and highly plastic set of adaptive, maladaptive, acute, and chronic responses that manifest differently throughout the body, in numerous biological processes, within and among individuals, and under various physiological and environmental conditions. They describe existing methods of measuring whole-body and tissue-specific insulin resistance and offer a primer on the two main insulin signaling networks. Next, they review current therapeutic options, which offer mostly indirect effects on insulin resistance, and highlight promising strategies to inform the eventual development of true insulin-sensitizing agents. The authors call for continued investigation of the complex factors accounting for variability in insulin resistance, as well as pathway-specific defects, with the ultimate goal of developing targeted and more effective therapies for type 2 diabetes and the broader spectrum of cardiometabolic complications and related comorbidities.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"33 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149067338","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nutrient-Sensitive Senescence Checkpoints in Diabetic Kidney Disease","authors":"Rui Ji, Qian Yang, Hongtu Hu","doi":"10.2337/db26-0464","DOIUrl":"https://doi.org/10.2337/db26-0464","url":null,"abstract":"Diabetic kidney disease (DKD) remains a leading cause of chronic kidney disease and kidney failure despite advances in glucose-lowering, hemodynamic, anti-inflammatory, and cardiorenal protective therapies. Cellular senescence has emerged as a key cell fate pathway linking persistent diabetic stress to renal inflammation, fibrosis, impaired repair, and progressive nephron loss. However, senescence in DKD should not be viewed simply as a terminal response to hyperglycemia, oxidative stress, or DNA damage. In this article, we define nutrient-sensitive senescence checkpoints as metabolic decision nodes that integrate amino acid flux, mitochondrial quality control, lipid routing, redox balance, oxygen stress, endoplasmic reticulum (ER) proteostasis, and inflammatory danger signaling to determine renal cell fate. We distinguish classical senescence in proliferative renal cells from senescence-like dysfunction in postmitotic podocytes, and we emphasize that interpretation requires a composite phenotype rather than any single marker. We discuss how serine, branched chain amino acids, arginine-citrulline metabolism, tryptophan-derived metabolites, and carnitine-linked lipid handling shape cell fate pathways in podocytes, tubular epithelial cells, endothelial cells, and immune-stromal compartments. We further examine how mitophagy, ferroptotic lipid peroxidation, ER stress, mitochondrial DNA leakage, cGAS-STING activation, AMPK-mTOR signaling, NAD+-sirtuin pathways, and nuclear receptor networks convert nutrient stress into maladaptive renal aging. Finally, we outline therapeutic opportunities to reprogram nutrient-sensitive senescence, including established DKD therapies, mitochondrial quality control enhancement, lipid-routing correction, senolytics, senomorphics, hypoxia-inducible factor pathway modulation, and biomarker-guided precision medicine. Article Highlights Diabetic kidney disease remains progressive in many patients despite modern cardiorenal therapies, suggesting that additional persistent cell fate pathways sustain kidney injury. An unresolved question is how nutrient-derived signals determine whether renal cells undergo adaptive repair or maladaptive senescence-like dysfunction. Amino acid flux, mitophagy, lipid routing, redox balance, endoplasmic reticulum proteostasis, and inflammatory danger signaling may form nutrient-sensitive senescence checkpoints in diabetic kidney disease. Distinguishing cell cycle arrest in proliferative cells from composite senescence-like injury in postmitotic cells may improve biomarker-based patient stratification and guide metabolism-informed senescence-targeted therapies.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"168 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149067335","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Insulin Resistance Mosaic: Defect, Defense, or Both? A Perspective on What Insulin Resistance Means and Whether It Should be Treated","authors":"David E. James","doi":"10.2337/dbi26-0047","DOIUrl":"https://doi.org/10.2337/dbi26-0047","url":null,"abstract":"Insulin resistance is conventionally framed as a pathological defect in insulin action that contributes to type 2 diabetes and related metabolic disease and should therefore be identified and reversed. The comprehensive review by Gastaldelli and colleagues highlights a more complicated reality: insulin resistance is heterogeneous between individuals, tissues, pathways, and physiological states. I argue that this heterogeneity exposes a fundamental issue—insulin resistance is a phenotype, not a mechanism. It can arise through many molecular routes, occur in both disease and normal physiology, originate in different tissues, and long precede overt disease. I propose an “insulin resistance mosaic” in which its clinical significance depends on why and where insulin resistance develops, physiological compensation, environmental exposure, and end-organ vulnerability. Similar degrees of insulin resistance could therefore lead to very different clinical outcomes, remain compensated for decades, or even, in some contexts, be protective. This framework challenges the assumption that insulin resistance represents a single disease process that should invariably be overcome. Instead, we should determine why it has developed, where it resides, what it predicts, and whether modifying it improves clinical outcomes.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"1 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149067336","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Associations of Ultraprocessed Food Intake, Wearable-Measured Lifestyle Factors, and Genetic Susceptibility With Incident Type 2 Diabetes","authors":"Wenxin Xu, Tong Chen, Wei Zhang, Collin Sakal, Xinyue Li","doi":"10.2337/db26-0395","DOIUrl":"https://doi.org/10.2337/db26-0395","url":null,"abstract":"Growing evidence links ultraprocessed food (UPF) intake to type 2 diabetes (T2D) risk; however, whether reducing UPF consumption is associated with lower risk across genetic susceptibility strata and whether protective lifestyle factors are associated with lower risk among high UPF consumers remain uncertain. We studied 56,964 UK Biobank participants without diabetes at baseline. Diet was assessed using 24-h dietary records, and foods were classified according to the Nova system. Physical activity and sleep were measured by accelerometers for 7 consecutive days, and polygenic risk was derived from 424 T2D-associated single nucleotide polymorphisms. Multivariable Cox proportional hazards models and restricted cubic splines were used to estimate hazard ratios (HRs) and dose–response relationships. Each 10% higher UPF intake was associated with 7% higher T2D risk (HR 1.07 [95% CI 1.03, 1.12]). Dose–response analyses revealed a linear association with UPF intake and an L-shaped association with moderate to vigorous physical activity (MVPA; Pnonlinearity < 0.001). Among individuals with high genetic susceptibility, lower risk was observed with lower UPF intake (HR 0.65 [95% CI 0.49, 0.85]), higher total physical activity (0.79 [0.65, 0.97]), sufficient MVPA (0.67 [0.55, 0.81]), and adequate sleep (0.57 [0.39, 0.84]). In joint analyses, sufficient MVPA (HR 0.69 [95% CI 0.50, 0.96]) and adequate sleep (0.42 [0.24, 0.75]) were associated with lower risk among participants with high UPF intake and high genetic risk. Together, our findings show that healthier modifiable behaviors were associated with lower diabetes risk across genetic susceptibility strata, and wearable-derived evidence highlights MVPA and adequate sleep as behavioral targets among individuals with high UPF intake. Article Highlights Dietary intake, inactivity, poor sleep, and genetic risk may all contribute to diabetes risk, but their combined effects are unclear. Whether modifiable lifestyle factors are associated with diabetes risk across genetic risk strata and whether wearable-derived behaviors are associated with lower risk among individuals with high ultraprocessed food (UPF) intake remain uncertain. Lower UPF intake was associated with lower diabetes risk across all levels of genetic risk, and meeting moderate to vigorous physical activity targets and getting adequate sleep were associated with lower risk among individuals with high UPF intake. Wearable-derived behavioral targets may be practical solutions for reducing UPF-associated diabetes risk and supporting diabetes prevention.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"17 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148985114","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lysine Lactylation Modifies Cryab-Hspa1b Interactions and Prevents MAPK Signaling to Slow Diabetic Cardiomyopathy Progression","authors":"Di Ma, Xiao Liang, Haoran Jing, Xi Liu, Peng Liu, Wenjie Cai, Xin Zhong, Xiaoxue Li, Shiyun Dong, Ye Tian, Can Wei","doi":"10.2337/db26-0432","DOIUrl":"https://doi.org/10.2337/db26-0432","url":null,"abstract":"Protein posttranslational modifications, including lactylation, have been intimately associated with myocardial energy metabolism. In this study, we investigated the role of Cryab in diabetic cardiomyopathy (DbCM) and its lysine lactylation (Kla). A spontaneous DbCM mouse model in db/db mice and a high-fat diet combined with i.p. streptozotocin injection mouse model were used. Primary cardiomyocytes were subjected to liposome-mediated transfection, followed by exposure to high glucose and palmitate. Cryab exhibited reduced Kla modification in myocardial tissue from DbCM mouse models and in damaged cardiomyocytes, while protein expression remained unchanged. Kla modification site mutation at K90R worsened cardiac systolic and diastolic dysfunction, myocardial hypertrophy, fibrosis, and apoptosis in vivo and in vitro. Cryab modulated the Hspa1b protein in a Kla-dependent manner and enhanced the stability of the Hspa1b protein. In DbCM mouse models or cardiomyocytes, Hspa1b protein expression was reduced, and the MAPK pathway was activated, which was further exacerbated following mutation at K90R. These findings demonstrate that reduced Kla modification in Cryab accelerated degradation of Hspa1b and activation of the MAPK pathway, thereby contributing to cardiac dysfunction associated with DbCM. These findings suggest that novel therapeutic strategies targeting protein Kla modification could be significant in the clinical management of DbCM. Article Highlights Cryab lysine lactylation (Kla) modification in myocardial tissue is reduced in db/db mice with diabetic cardiomyopathy (DbCM). Mutations in the Cryab Kla site exacerbate DbCM damage in vivo and in vitro. Cryab Kla enhances the stability of the Hspa1b protein by interacting with Hspa1b. Cryab blocks DbCM-induced MAPK signaling in an Hspa1b-dependent manner. Cryab/Hspa1b/MAPK signaling influences DbCM-associated cardiac dysfunction.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"127 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148985113","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}