Diabetes最新文献

{"title":"Type 2 Diabetes Reduces IFN-α2 and Compromises Antiviral Defense: Evidence From Mendelian Randomization and H1N1-Infected Diabetic Mice.","authors":"Siye Lyu, Jiali Wu, Weihui Ma, Liping Sun, Sihui Xing, Haiyang Zhang, Fengyan Shao, Mingquan Li, Yilong Zhu, Xiaomiao Xiong, Jicheng Han","doi":"10.2337/db25-0974","DOIUrl":"10.2337/db25-0974","url":null,"abstract":"<p><p>Type 2 diabetes (T2D) impairs antiviral immunity; however, the causal link between T2D and interferon-α2 (IFN-α2) deficiency remains unclear. This study used genome-wide association study-based Mendelian randomization (MR) to investigate this relationship and validated the findings in an H1N1-infected diabetic mouse model. MR analysis of 26 single nucleotide polymorphisms showed a significant negative association between T2D and IFN-α2 levels (inverse variance weighted odds ratio 0.667; P = 0.000116) without heterogeneity or pleiotropy. In vivo experiments confirmed that db/db mice exhibited more severe H1N1-induced lung injury, higher viral loads, and lower survival rates compared with nondiabetic controls. However, exogenous IFN-α2 treatment significantly reversed these pathologic outcomes. Inflammatory cytokine profiling showed that IFN-α2 downregulated 21 elevated cytokines and restored Fas ligand levels in lung tissue. Mechanistically, Western blotting demonstrated that IFN-α2 inhibited the phosphorylation of JAK1/2 and STAT3, thereby suppressing excessive inflammation. In conclusion, our findings indicate that T2D leads to IFN-α2 deficiency, contributing to susceptibility to viral infection. Supplementation with IFN-α2 effectively attenuated virus-induced lung injury by inhibiting JAK/STAT3 signaling and cytokine storms, positioning IFN-α2 supplementation as a promising therapeutic strategy for managing influenza complications in patients with diabetes.</p><p><strong>Article highlights: </strong>Type 2 diabetes (T2D) is linked to impaired antiviral immunity, but whether it drives interferon-α2 (IFN-α2) deficiency remains unknown. We asked whether T2D causally suppresses IFN-α2 levels and whether exogenous supplementation could rescue host defense mechanisms against influenza infection. By integrating genetic analysis with an H1N1-infected diabetic mouse model, we show that T2D genetically lowers IFN-α2 and that treatment reverses lung injury by inhibiting JAK/STAT3-mediated hyperinflammation. Our study positions IFN-α2 supplementation as a promising therapeutic strategy to prevent severe viral pneumonia in patients with T2D.</p>","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":" ","pages":"1450-1459"},"PeriodicalIF":0.0,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13381667/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148229752","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":"MASLD as Complication of Diabetes.","authors":"Norbert Stefan","doi":"10.2337/dbi26-0001","DOIUrl":"10.2337/dbi26-0001","url":null,"abstract":"<p><p>Worldwide metabolic dysfunction-associated steatotic liver disease (MASLD) is the leading cause of chronic liver disease. Despite high global prevalence, MASLD is not yet recognized as a noncommunicable disease, although all of the criteria are fulfilled for such a classification. MASLD is strongly associated with type 2 diabetes, cardiovascular disease, chronic kidney disease, and certain extrahepatic cancers. At 65% and 37% the prevalence of MASLD is extremely high in adults and children with type 2 diabetes, respectively. The pathogenesis of MASLD is closely related to that of type 2 diabetes, and diabetes-associated hyperglycemia, hyperinsulinemia, and hyperlipidemia promote progression from simple steatosis to hepatic inflammation and fibrosis. Thus, MASLD is now considered a complication of diabetes. However, there is still a great deal of work to be done to implement screening for and treatment of MASLD in everyday clinical diabetes management. In this article, the major mechanisms involved in the pathogenesis of MASLD and type 2 diabetes are discussed. Furthermore, the heterogeneity in the pathophysiology of MASLD and clusters in MASLD that may be relevant for future stratification of MASLD-associated risk of diseases are addressed. Finally, because of their strong hepato-, cardio-, and nephroprotective effects this article provides support as to why sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide 1 receptor (co)agonists should be used as first-line pharmacotherapies in people with MASLD and type 2 diabetes.</p><p><p></p>","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":" ","pages":"1359-1370"},"PeriodicalIF":0.0,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13381670/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148195276","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":"Myeloid Cell Protein Tyrosine Phosphatase 1B Drives Retinal Neurodegeneration in Diabetic Mice.","authors":"Ayaz Ali, Morgan Boyne, Abrar Othman, Sarah Kamli-Salino, Lucia Kuffova, John V Forrester, Mirela Delibegovic","doi":"10.2337/db25-0904","DOIUrl":"10.2337/db25-0904","url":null,"abstract":"<p><p>Diabetic retinopathy (DR) is the leading cause of vision loss in the working-age population, with public health economic implications worldwide. Systemic inflammation and leukocyte activation are early events in diabetes, whereas microglial activation, neuroinflammation, and retinal neurodegeneration are early events in DR. Protein tyrosine phosphatase 1B (PTP1B) plays a complex role in monocyte and macrophage activation, which may affect DR. We investigated the role of myeloid cell-specific PTP1B using LysMcre-PTP1B fl/fl (LysM-PTP1B) transgenic mice, as well as pharmacological inhibition with a PTP1B inhibitor, MSI-1436, in the early stages of DR. Mice were rendered diabetic for 6 weeks using anomer-equilibrated streptozotocin (STZ). Retinal changes were evaluated by histology and immunohistochemistry, and systemic leukocyte activation by flow cytometry. Mitochondrial function in high-glucose-concentration-challenged, cultured bone marrow-derived macrophages (BMDMs) from LysM-PTP1B- and MSI-I436-treated mice was determined in vitro. Both myeloid cell-specific depletion and pharmacological inhibition of PTP1B prevented STZ-induced retinal neurodegeneration, development of acellular retinal capillaries, as well as microglial and systemic leukocyte activation without altering the development of diabetes. In vitro, inhibition of PTP1B prevented high-glucose-level-induced mitochondrial dysfunction in BMDMs. We conclude that inhibition of PTP1B prevents DR by decreasing myeloid cell-driven inflammation, and PTP1B represents a therapeutic target for prevention DR.</p><p><strong>Article highlights: </strong>Myeloid cell PTP1B is required to induce retinal neurodegeneration in diabetes. Both local (microglia) and systemic (bone marrow-derived) myeloid cells are implicated. Inhibition of myeloid cell PTP1B prevents development of acellular retinal capillaries in diabetic mice. PTP1B mediates superoxide production, decreases mitochondrial membrane potential, and, in female mice, increases macrophage cell death in chronic conditions associated with abnormally high glucose levels. Protective effects of PTP1B deletion on diabetic retinopathy were also observed in mice treated with the small molecular PTP1B inhibitor MSI-1436; both retinal neurodegeneration and local glial cell activation were decreased.</p>","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":" ","pages":"1272-1284"},"PeriodicalIF":0.0,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147990516","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":"HMGA1 Lactylation-Mediated Regulation of the SP1/VEGFA Axis in Pathological Angiogenesis Under Diabetic Retinopathy.","authors":"Jingjing Hou, Sha Liu, Yishuang Zhou, Jiawei Fan, Duncheng Xiao, Chuanxi Wang, Siyu Lin, Liming Tao, Zhengxuan Jiang","doi":"10.2337/db25-1103","DOIUrl":"10.2337/db25-1103","url":null,"abstract":"<p><p>Diabetic retinopathy (DR), a major complication of diabetes that causes blindness, is characterized by hyperglycemia-induced vascular dysfunction of incompletely defined mechanisms. Our study demonstrated glycolytic pathway activation in a DR rat model, which led to lactate accumulation and elevated pan lysine lactylation. Reduced lactate levels ameliorate vascular dysfunction. Global lactylome analysis of rat retinal tissues revealed 49 proteins with upregulated lactylation at 55 sites. The findings revealed that HMGA1 at lysine 74 (K74) directly promotes the transcriptional upregulation of specificity protein 1, enhancing vascular endothelial growth factor A expression and aggravating vascular dysfunction. Crucially, a K74 mutation in HMGA1 mitigated these pathological changes. This study is the first to identify HMGA1 lactylation as a critical molecular mechanism driving vascular dysfunction in DR, revealing a promising interventional target for the development of novel diagnostic markers and therapeutic strategies aimed at this specific posttranslational modification.</p><p><strong>Article highlights: </strong>Diabetic retinopathy (DR) is a major complication of diabetes that results in blindness. The underlying mechanisms of the hyperglycemia-induced vascular dysfunction that characterizes DR are not fully elucidated. Glycolytic pathway activation in DR rats causes lactate accumulation; reduced lactate levels ameliorate vascular dysfunction in DR; HMGA1 at lysine 74 (K74) lactylation promotes specificity protein 1 upregulation, enhancing vascular endothelial growth factor A expression; and K74 mutation in HMGA1 mitigates pathological changes in DR. HMGA1 lactylation is a critical molecular mechanism driving DR vascular dysfunction.</p>","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":" ","pages":"1256-1271"},"PeriodicalIF":0.0,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13291883/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147857953","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":"Growth Differentiation Factor-15 in Diabetic Kidney and Cardiovascular Disease: Pathogenic Driver or Protective Modulator.","authors":"Amani Slika, Maya Noureddine, Dalal Jomaa, Elie Emmanuel Abboud, Sarah Zaidan, Sami Azar, Fuad Ziyadeh, Rachel Njeim, Assaad A Eid","doi":"10.2337/db26-0133","DOIUrl":"10.2337/db26-0133","url":null,"abstract":"<p><p>Diabetic kidney disease (DKD) and diabetic cardiomyopathy continue to drive excess morbidity and mortality in diabetes, underscoring a critical gap between mechanistic insight and clinical translation. Growth differentiation factor-15 (GDF-15), a stress-inducible cytokine of the transforming growth factor-β superfamily, has emerged as a critical biomarker and putative modulator of metabolic inflammation. Yet the field remains divided on a fundamental question: is GDF-15 simply reporting tissue distress, or does it shape disease trajectories? In this article, we explore how GDF-15 may both signal and shape DKD and cardiovascular disease. Drawing on evidence from experimental models, longitudinal clinical studies, and multi-omics analyses, we highlight the context-dependent biology of GDF-15, protective during acute metabolic or inflammatory stress but potentially pathogenic when chronically elevated in diabetes. We examine its regulation via the GFRAL-RET signaling axis, its segment-specific expression across renal tubular compartments, and its emerging role in cardiac remodeling and metabolic inflammation. Recent clinical data position circulating GDF-15 as an early and sensitive indicator of DKD progression and cardiovascular events. At the same time, mechanistic studies increasingly implicate sustained GDF-15 signaling in mitochondrial dysfunction, inflammatory amplification, and maladaptive tissue remodeling. Together, these observations place GDF-15 at a critical inflection point between risk stratification and disease mechanism. A key unresolved challenge is defining when, where, and how GDF-15 signaling exerts adaptive versus maladaptive effects-knowledge that will be essential for determining whether GDF-15 should be targeted, harnessed, or restrained in diabetes.</p><p><strong>Article highlights: </strong>GDF-15 is a stress-responsive cytokine of the TGF-β superfamily regulated by p53, mitochondrial dysfunction, and inflammatory signaling. Circulating GDF-15 levels are low under physiological conditions but rise markedly in response to cellular and metabolic stress. Elevated GDF-15 predicts incident diabetes and reflects hyperglycemia-induced oxidative and cellular stress. GDF-15 correlates with albuminuria, estimated glomerular filtration rate decline, and progression risk in diabetic kidney disease. Increased levels predict heart failure, myocardial infarction, and cardiovascular mortality in diabetes. Targeting the GDF-15-GFRAL axis and leveraging GDF-15 as a biomarker offer emerging translational potential.</p>","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":" ","pages":"1071-1082"},"PeriodicalIF":0.0,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13291867/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147965891","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":"CHD4 and NKX2.2 Cooperate to Regulate β-Cell Function by Repressing Non-β-Cell Gene Programs.","authors":"Dylan Sarbaugh, Thais Gaia Oliveira, Michelle A Guney, McKenna R Casey, Victoria M Hoelscher, Christopher J Hill, Cole R Michel, Kristen L Wells, Richard K P Benninger, Lori Sussel","doi":"10.2337/db25-0945","DOIUrl":"10.2337/db25-0945","url":null,"abstract":"<p><p>NKX2.2 is a transcription factor that regulates pancreatic islet β-cell identity and function; however, cofactor proteins that modulate the functional activity of NKX2.2 in β-cells are relatively unexplored. An unbiased proteomics screen identified chromodomain helicase DNA-binding protein 4 (CHD4) as an NKX2.2 interacting partner. CHD4 is a nucleosome remodeler that directs the appropriate differentiation, maturation and function of many cell types. To characterize the roles of CHD4 in β-cells, we generated Chd4 β-knockout (βKO) mice. Deletion of Chd4 substantially impaired the function of β-cells. The Chd4 βKO mice became diabetic due to the disruption of islet integrity, calcium signaling, and downregulation of essential β-cell regulatory genes. We also discovered CHD4 is required to bind at and repress non-β-cell genes, including Kcnj5, the gene that encodes the G protein-activated inward rectifier potassium channel 4 (GIRK4) in β-cells. Aberrant upregulation of GIRK4 causes impaired glucose-stimulated insulin secretion. These studies demonstrate that CHD4 is an essential transcriptional cofactor of NKX2.2 that is required for the proper maturation and function of pancreatic β-cells.</p><p><strong>Article highlights: </strong>NKX2.2 interacts with the nucleosome remodeling and deacetylase complex through its interaction with chromodomain helicase DNA-binding protein 4 (CHD4). Deletion of CHD4 from developing pancreatic β-cells in mice causes diabetes due to a loss of islet integrity, disrupted calcium signaling, and impaired insulin secretion. β-Cells lacking CHD4 inappropriately upregulate the G protein-activated inward rectifier potassium channel 4 (GIRK4) potassium channel; inhibition of GIRK4 rescues the insulin secretion defect.</p>","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":" ","pages":"1189-1200"},"PeriodicalIF":0.0,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13291869/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147824842","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":"Global and Partitioned Polygenic Risk Scores: Associations With Pathophysiology and Incidence of Type 2 Diabetes in People With Prediabetes.","authors":"Elsa Vazquez Arreola, William C Knowler, Robert L Hanson","doi":"10.2337/db25-0640","DOIUrl":"10.2337/db25-0640","url":null,"abstract":"<p><p>Type 2 diabetes partitioned polygenic risk scores (pPRS) are related to their physiological impact on insulin secretion and sensitivity. We investigated associations of two pPRS sets obtained from multiancestry cohorts with the relationship between insulin secretion and sensitivity and diabetes incidence in the Diabetes Prevention Program (DPP). We generated 12 and 8 pPRS from soft- and hard-clustering approaches, respectively, in 2,052 DPP participants randomized to intensive lifestyle intervention, metformin, or placebo. Baseline insulin secretion demand and compensation were estimated through the relationship between secretion and sensitivity. Most expected associations of pPRS with insulin secretion and sensitivity were replicated. Some pPRS associated with lower secretion compensation. Global PRS associations with diabetes incidence were stronger than those of any pPRS in both sets. When insulin secretion compensation and demand modified pPRS associations with diabetes incidence, modification occurred only for demand: higher compensation associated with decreased diabetes incidence regardless of pPRS level. A β-cell dysfunction pPRS interacted with DPP treatments in a way that suggested that these treatments may be less effective in those genetically predisposed to diabetes due to insulin deficiency. Regardless of genetic risk as measured by pPRS, inadequate compensatory insulin secretion contributes to progression to diabetes in people with prediabetes.</p><p><strong>Article highlights: </strong>The extent to which partitioned polygenic risk scores (pPRS) for type 2 diabetes influence the relationship between insulin secretion and sensitivity has not been examined in people with prediabetes. We investigated whether insulin secretion compensation and demand, estimated through the relationship between insulin secretion and sensitivity, mediated or modified the associations of two sets of pPRS with diabetes incidence in Diabetes Prevention Program participants. Several pPRS modified the effects of insulin demand on diabetes incidence, but none modified the effect of compensation. In people with prediabetes, inadequate compensatory insulin secretion contributes to progression to diabetes regardless of genetic risk as measured by pPRS.</p>","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":"75 7","pages":"1329-1337"},"PeriodicalIF":0.0,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13468951/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148304437","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 Differences in ER Stress Pathways Are a Key Determinant of β-Cell Proliferation and Resilience.","authors":"Sing-Young Chen, Elizabeth J Rideout, James D Johnson","doi":"10.2337/dbi26-0012","DOIUrl":"10.2337/dbi26-0012","url":null,"abstract":"","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":"75 7","pages":"1083-1085"},"PeriodicalIF":0.0,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13291862/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148304483","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":"Lysosomal Ion Channel TRPML1 Contributes to Neuropathic Pain Associated With Diabetic Peripheral Neuropathy in Mice.","authors":"Yuanhong Yang, Silin Teng, Yihong Zhang, Yong-Hua Ji, Hongjie Wang, Zhi-Yong Tan","doi":"10.2337/db25-0901","DOIUrl":"10.2337/db25-0901","url":null,"abstract":"<p><p>Neuropathic pain associated with diabetic peripheral neuropathy (DPN) is a common and hard-to-treat complication of diabetes. Ion channels of plasma membrane are major mechanisms and targets for DPN pain. This study explores the role of a major lysosomal ion channel, TRPML1, in DPN pain. Mouse models of DPN pain and TRPML1 knockout were combined with pharmacological inhibition and detection of molecular expression and function. Major findings included 1) BKS db/db increased expression and function of TRPML1 in dorsal root ganglion (DRG); 2) lysosomes of DRG neurons expressed functional TRPML1 currents; 3) global knockout (gKO) or conditional knockout (cKO) in DRG neurons of TRPML1 prevented mechanical allodynia in male mice fed a high-fat diet; 4) a TRPML1 inhibitor significantly reversed mechanical allodynia in BKS db/db mice through intraperitoneal injection and in streptozotocin (STZ) mice through intrathecal injection; and 5) gKO or astrocyte cKO of TRPML1 prevented STZ-induced mechanical allodynia in male and female mice. The results suggest that TRPML1 in DRG neurons and astrocytes contributes to type 2 and type 1 DPN pain, respectively (type 1 and type 2 DPN pain refer to neuropathic pain associated with type 1 diabetes and type 2 diabetes or pre-diabetes). This study may serve as a proof of concept to explore the role of lysosomal ion channels in painful DPN, painless DPN, and chronic pain.</p><p><strong>Article highlights: </strong>A lysosomal ion channel, TRPML1, contributes to neuropathic pain associated with diabetic peripheral neuropathy (DPN). TRPML1 of dorsal root ganglion neurons contributes to type 2 DPN pain. Astrocyte TRPML1 contributes to type 1 DPN pain. Lysosomal ion channels may be novel mechanisms and targets for DPN pain.</p>","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":" ","pages":"1298-1306"},"PeriodicalIF":0.0,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13291871/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147792883","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Distinct Interplay Between β-Cell Function and Insulin Resistance in Latent Autoimmune Diabetes in Adults Versus Type 2 Diabetes.","authors":"Rocco Amendolara, Francesco De Vita, Vahideh Abedi, Daniela Luverà, Renata Risi, Luca D'Onofrio, Marta Zerunian, Damiano Caruso, Raffaella Buzzetti, Ernesto Maddaloni","doi":"10.2337/db25-0933","DOIUrl":"10.2337/db25-0933","url":null,"abstract":"<p><p>We conducted a cross-sectional study to explore the interplay between β-cell function and peripheral insulin resistance in latent autoimmune diabetes in adults (LADA) compared with type 2 diabetes. Thirty-one people with LADA were matched for sex, BMI, and disease duration with 31 people with type 2 diabetes. Insulin resistance was estimated using established surrogate indexes, and serum C-peptide levels were measured by ELISA. Despite the similar BMI, the LADA group exhibited lower mean values of estimated insulin resistance compared with the type 2 diabetes group. Among individuals with similar insulin resistance, the LADA group consistently showed lower C-peptide values compared with the type 2 diabetes group. C-peptide levels showed a direct relationship with the majority of insulin resistance indexes exclusively in type 2 diabetes, but not in LADA. Our findings show that people with LADA exhibit a blunted insulin secretory capacity compared with people with type 2 diabetes, even at similar levels of insulin resistance, being unable to mount a meaningful compensatory response to insulin resistance. This discrepancy may explain the worse glycemic control often observed in people with LADA, placing these people at higher risk of suboptimal glycemic control and highlighting the importance of early and accurate classification of adult-onset diabetes and tailored therapeutic strategies.</p><p><strong>Article highlights: </strong>The identification of differences in the relationship between insulin secretion and resistance among different diabetes types will help inform clinical decisions. The interplay between insulin secretion and resistance may distinguish latent autoimmune diabetes in adults (LADA) from type 2 diabetes. Individuals with LADA are less capable of mounting a sustained compensatory insulin secretion compared with those with type 2 diabetes, even at similar insulin resistance levels. Distinct pathophysiology characterizes LADA and type 2 diabetes. The defect in insulin secretion for similar levels of insulin resistance might contribute to the higher risk of poor glycemic control often observed in LADA, arguing for accurate diagnosis of adult-onset diabetes types.</p>","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":" ","pages":"1233-1242"},"PeriodicalIF":0.0,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13291872/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147876833","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}