Diabetes最新文献

{"title":"Whey Protein Ingestion Stimulates Glucagon Secretion and Raises Blood Glucose Levels in Adults With Type 1 Diabetes","authors":"Giang M. Dao, Sam Zhao, Cara Schofield, Sara Vogrin, Declan T. Hennessy, Carmel E. Smart, Dessi P. Zaharieva, David N. O’Neal, Clinton R. Bruce, Greg M. Kowalski, Dale J. Morrison","doi":"10.2337/db26-0059","DOIUrl":"https://doi.org/10.2337/db26-0059","url":null,"abstract":"This study characterized the dose effect of whey protein isolate (WPI) ingestion on glucagon secretion, glycemia, and the underlying mechanisms in adults with type 1 diabetes. Twelve insulin pump–treated adults with type 1 diabetes (mean ± SD age 47.3 ± 16.4 years; BMI 26.1 ± 3.8 kg/m2) and six adults without diabetes (age 36.2 ± 20.9 years; BMI 27.3 ± 5.8 kg/m2) received 1) control (water), 2) low-dose WPI (0.25 g/kg), or and 3) high-dose WPI (0.5 g/kg). Those with diabetes replaced subcutaneous insulin with fixed-rate i.v. insulin. [6,6-2H]glucose infusion was used to measure glucose flux. In participants with type 1 diabetes, low- and high-dose WPI raised plasma glucagon by approximately five- and approximately ninefold, respectively. Endogenous glucose production increased by ∼50% (peak) for both WPI doses, with the high dose producing more sustained stimulation. Plasma glucose decreased by a median (interquartile range) of ∼1.7 (2.0, 1.0) mmol/L for control but increased by 1.3 (1, 1.7) and 3.1 (2.5, 3.3) mmol/L for the low and high doses, respectively. Participants with and without diabetes had similar increases in amino acids, glucagon, glucagon-like peptide 1, and glucose-dependent insulinotropic polypeptide. This study highlights the substantial glucagon-stimulating and glycemic effects of WPI, which could be clinically useful for hypoglycemia management in type 1 diabetes. Article Highlights The effect of protein ingestion on glucagon and glycemic responses in individuals with type 1 diabetes is not well characterized. This study examined how ingestion of varying amounts of fast-absorbing whey protein (in the absence of other macronutrients) affected glucagon secretion, glucose levels, and associated metabolic hormone levels in adults with type 1 diabetes. Whey protein ingestion stimulated glucagon secretion and endogenous glucose production and increased blood glucose in adults with type 1 diabetes. Our findings highlight the potential of whey protein as a tool to support glycemic management and mitigate hypoglycemia in type 1 diabetes.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"54 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147739388","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":"Activating Transcription Factor 6α Governs Stress-Adaptive Pancreatic β-Cell Mass Expansion by Coordinating Proliferation and Survival","authors":"Daisuke Otani, Takaaki Murakami, Muhammad Fauzi, Ainur Botagarova, Sho Sekito, Hisato Tatsuoka, Shinsuke Tokumoto, Ryota Usui, Masahito Ogura, Taro Toyoda, Yasuhiro Murakawa, Daisuke Yabe, Nobuya Inagaki","doi":"10.2337/db26-0048","DOIUrl":"https://doi.org/10.2337/db26-0048","url":null,"abstract":"Progressive loss of pancreatic β-cell mass (BCM) is a hallmark of type 2 diabetes, yet strategies to preserve or restore BCM remain elusive due to incomplete understanding of the molecular mechanisms governing β-cell proliferation in adults. The unfolded protein response (UPR) maintains endoplasmic reticulum (ER) proteostasis, but the in vivo role of activating transcription factor 6α (ATF6α), the most recently evolved UPR branch, in β-cell proliferation and survival is unclear. Here, we investigated the role of ATF6α in β-cell adaptation under chronic metabolic and physiological stress. We demonstrated that β-cell–specific ATF6α knockout mice exhibited impaired BCM expansion accompanied by reduced β-cell proliferation and increased apoptosis during high-fat diet feeding and pregnancy, but not under basal conditions. In vitro, ATF6α knockdown suppressed proliferation and enhanced apoptosis in chronically stressed MIN6Akita cells, but not in MIN6 cells, whereas ATF6α overexpression promoted β-cell proliferation. Single-cell transcriptomic analysis further revealed that ATF6α directs proliferative transcriptional states in β-cells under metabolic stress, while its absence diverts cells toward nonproliferative states. Together, these findings establish ATF6α as a coordinating regulator of adaptive β-cell proliferation and survival that supports BCM expansion under sustained stress. Article Highlights The role of activating transcription factor 6α (ATF6α) in the stress-adaptive regulation of pancreatic β-cell mass (BCM) in vivo remains incompletely defined. We investigated the role of ATF6α in the regulation of BCM, β-cell proliferation, and survival under sustained stress using in vivo and in vitro models. Loss of ATF6α consistently impaired BCM expansion through reduced β-cell proliferation and increased apoptosis across models. Our findings establish ATF6α as an important regulator of stress-adaptive BCM expansion through coordinating β-cell survival and proliferation under sustained stress.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"9 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147708677","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":"Co-occurrence of Loss-of-Function GCK and ABCC8 Variants in a Pedigree With a Spectrum of Dysglycemia","authors":"Cécile Saint-Martin, Assmaa ElSheikh, Sophie Jacqueminet, Jean-Baptiste Arnoux, Cécile Ciangura, Christine Bellanné-Chantelot, Show-Ling Shyng","doi":"10.2337/db25-1098","DOIUrl":"https://doi.org/10.2337/db25-1098","url":null,"abstract":"Glucokinase and ATP-sensitive potassium (KATP) channels in pancreatic β-cells control insulin secretion in response to glucose stimulation to maintain glucose homeostasis. It is well established that loss-of-function (LOF) variants in GCK, which encodes glucokinase, are diabetogenic, whereas LOF variants in KATP channel genes lead to congenital hyperinsulinism (HI) and hypoglycemia. However, how the co-occurrence of GCK and KATP channel variants manifests in glycemic phenotypes is unknown. This study presents a multiplex pedigree with a heterozygous GCK deletion along with a heterozygous ABCC8 variant that results in the E1209K missense variant in the regulatory subunit of the KATP channel sulfonylurea receptor 1 (SUR1). The three-generation pedigree exhibits a complex spectrum of dysglycemia depending on genotype and age at referral. Individuals harboring the heterozygous GCK deletion alone present with maturity-onset diabetes; those harboring the heterozygous ABCC8 E1209K variant alone exhibit HI resulting from the LOF of KATP channels, with some developing diabetes later in life; and those harboring both GCK and ABCC8 variants escape HI but not diabetes. This unique pedigree offers insights into the complex interplay between LOF genetic variants of glucokinase and KATP channels in age-dependent dysglycemia. Article Highlights Genetic variants causing loss of function (LOF) of glucokinase or ATP-sensitive potassium (KATP) channels underlie diabetes or congenital hyperinsulinism, respectively, but how the co-occurrence of such variants affects glucose control is unknown. This study presents genotypes and clinical phenotypes in a pedigree with LOF variants in both GCK and the pancreatic KATP channel. Heterozygous glucokinase deletion masked infantile hyperinsulinemia and hypoglycemia caused by a heterozygous LOF KATP channel variant. Carriers of the LOF KATP variant exhibited a shift from hypoglycemia to diabetes, as has been reported previously in some carriers of KATP LOF variants.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"47 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147708675","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":"Cooperative Action of Cathepsin K Inhibitor and hUMSC-EVs in Attenuating Ferroptosis Sensitivity for Superior Diabetic Wound Healing","authors":"Qin Qin, Lei Liu, Yue Fang, Mengyu Zhang, Xiaoyu Liu, Ruocheng Zhang, Xiuzhu Chen, Li Zhong, Rui Guo","doi":"10.2337/db25-0817","DOIUrl":"https://doi.org/10.2337/db25-0817","url":null,"abstract":"Refractory chronic diabetic wounds severely threaten patient survival; however, current treatments do not adequately promote healing. Cathepsin K (CTSK), a collagen-degrading protease upregulated in early diabetic wounds, presents a potential therapeutic target, and human umbilical cord mesenchymal stem cell–derived extracellular vesicles (hUMSC-EVs) show promise in regeneration but are associated with challenges related to production yield and stability. This study hypothesized that combining a stable CTSK inhibitor with hUMSC-EVs could enhance therapeutic efficacy and overcome these challenges. The hypothesis was tested using diabetic wound models in db/db mice with high glucose-exposed human dermal fibroblasts and human umbilical vein endothelial cells. The combination of a CTSK inhibitor and hUMSC-EVs at half doses outperformed full-dose monotherapies, accelerating wound healing through superior effects on collagen synthesis, cell proliferation, migration, and angiogenesis. Mechanistically, the combined treatment promoted wound healing by inhibiting ferroptosis. This strategy demonstrates accelerated wound healing with a lower hUMSC-EV dosage, suggesting promising clinical application potential. Article Highlights A half-dose combination of a cathepsin K and human umbilical cord mesenchymal stem cell–derived extracellular vesicles (hUMSC-EVs) achieved superior diabetic wound healing compared with full-dose monotherapies. The combined therapy more potently suppressed ferroptosis in diabetic wound tissue as well as in high glucose–exposed fibroblasts and endothelial cells. Ferroptosis inhibition enhanced cell survival, migration, angiogenesis, and mitochondrial function in high glucose–exposed fibroblasts and endothelial cells. This dual-target strategy has the potential to reduce the hUMSC-EV dosage while improving wound healing outcomes, thus enhancing clinical potential.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"6 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147684646","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":"Gut-Derived FGF15 Modulates Lean Mass, Bone, and Bile Acid Responses to Weight Loss","authors":"Nadejda Bozadjieva-Kramer, Garrett McMahon, Ziru Li, Jordan Wean, Jae Hoon Shin, Andriy Myronovych, Robert W. O’Rourke, Ormond A. MacDougald, Randy J. Seeley","doi":"10.2337/db25-0466","DOIUrl":"https://doi.org/10.2337/db25-0466","url":null,"abstract":"Dietary, surgical, and pharmacological methods can effectively reduce body weight; however, rapid weight loss can also be accompanied by a loss of lean mass. Previously, we found that intestinal fibroblast growth factor 15 (FGF15; mouse ortholog of human FGF19) protects against lean mass loss after sleeve gastrectomy in mice and that circulating FGF19 predicts lean mass retention after very-low-energy diets in humans. We investigated the regulatory functions of intestine-derived FGF15 in lean and bone mass, glucose tolerance, and changes in bile acid and lipid parameters after weight loss in mice. Rapid weight loss was induced either by transitioning high-fat diet–fed intestine-specific FGF15–knockout and control mice to standard chow for 25 days or by administering daily semaglutide. Semaglutide decreased body weight, fat mass, and lean mass, all of which returned to baseline levels after treatment cessation. Lean mass was not preserved during dietary intervention in mice lacking FGF15, whereas semaglutide decreased lean mass irrespective of FGF15. Dietary intervention reduced hepatic triglyceride levels more efficiently, whereas greater improvement in glucose tolerance was observed with semaglutide. Semaglutide modulated shifts in bile acid composition, with particularly pronounced changes seen in the absence of FGF15. These data indicate that multiple factors, including intervention strategy and dietary context, modulate gut–liver and muscle communication and preservation of lean mass. Article Highlights We evaluated the role of intestinal fibroblast growth factor 15 (FGF15) in regulating lean mass, glucose tolerance, bile acid, and lipid profiles after diet- compared with semaglutide-induced weight loss in mice. Mice lacking FGF15 lost more lean mass during dietary intervention, whereas semaglutide decreased lean mass irrespective of FGF15; dietary intervention reduced hepatic triglyceride levels more efficiently, whereas greater improvement in glucose tolerance and elevated cecal bile acid levels were observed with semaglutide; and loss of FGF15 altered bile acid levels, whereas semaglutide treatment further regulated these levels in both genotypes, with particularly pronounced changes observed in the absence of FGF15. Weight-loss intervention strategy and dietary context modulate gut–liver and muscle communication and preservation of lean mass.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"421 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147586789","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":"A Self-Reinforcing LGR5–Wnt/β-Catenin–Nedd4L Circuit Drives Fibrotic Progression in Diabetic Kidney Disease","authors":"Shanshan Yu, Fangfang Wang, Xingcheng Zhou, Luqun Liang, Yuanyuan Ruan, Xun Mo, Shuang Li, Wanlin Tan, Xiaoxiao Xu, Jing Jia, Jin Peng, Chuanmin Long, Mengqin Li, Yadi Zhu, Yao Mu, Yao Ran, Xuelang Ma, Lirong Liu, Bing Guo, Yuanyuan Wang","doi":"10.2337/db25-0870","DOIUrl":"https://doi.org/10.2337/db25-0870","url":null,"abstract":"Diabetic kidney disease (DKD) is a major cause of end-stage renal failure, driven by tubulointerstitial fibrosis. While persistent Wnt/β-catenin signaling promotes fibrosis, its sustained activation mechanism was unclear. This study, using DKD patient samples, db/db mice, and Nedd4L knockout models combined with molecular techniques, identified a key pathogenic circuit. LGR5, upregulated in diabetic kidneys, amplifies Wnt signaling by stabilizing Wnt receptors. The E3 ligase Nedd4L counteracts this by targeting LGR5 for degradation. Crucially, in DKD, the activated β-catenin/TCF4 complex transcriptionally represses Nedd4L, creating a self-reinforcing feedback loop that maintains high LGR5 levels and perpetual Wnt/β-catenin activation. This loop promotes nuclear translocation of β-catenin and expression of fibrotic mediators like Snail and fibronectin. Disrupting this circuit by restoring Nedd4L or knocking down LGR5 attenuated renal fibrosis in experimental models. Thus, the LGR5-Wnt-Nedd4L feed-forward circuit is a key driver of fibrosis in DKD, suggesting Nedd4L restoration or LGR5 inhibition as potential therapeutic strategies. Article Highlights This study was undertaken to explain why Wnt/β-catenin signaling stays persistently active in diabetic kidney disease tubules. This study aimed to determine whether LGR5 amplifies Wnt signaling and whether Nedd4L controls LGR5 stability via ubiquitination. This study found a feed-forward loop: Wnt induces LGR5, LGR5 limits RNF43-receptor interactions to stabilize Wnt receptors, and β-catenin/TCF4 represses Nedd4L to reduce LGR5 ubiquitination. This LGR5-Wnt-Nedd4L circuit represents a targetable mechanism to dampen Wnt signaling and renal fibrosis in diabetic kidney disease.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"7 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147587119","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":"Inhibition of miR-181c-5p Rescues Diabetes-Impaired Angiogenesis in Ischemia and Wound Healing","authors":"Emma L. Solly, Yingjun Luo, Khalia R. Primer, Jocelyne Mulangala, Belinda A. Di Bartolo, Stephen J. Nicholls, Peter J. Psaltis, Zhen Bouman Chen, Christina A. Bursill, Joanne T.M. Tan","doi":"10.2337/db24-0867","DOIUrl":"https://doi.org/10.2337/db24-0867","url":null,"abstract":"Diabetes-related vascular complications are characterized by impaired ischemia-driven angiogenesis and delayed wound healing. MicroRNAs (miRNAs) are emerging as powerful targets for multifaceted diseases. We previously identified that miRNA-181c-5p has anti-angiogenic properties, but its role in diabetes is unknown. In a hindlimb ischemia model, streptozotocin-rendered diabetic mice treated with an miRNA-181c-5p inhibitor (anti–miR-181c-5p) exhibited improved blood flow reperfusion and increased arteriolar density, compared with diabetic anti–miR-negative (anti–miR-Neg) control mice. Diabetic anti–miR-Neg mice had reduced perfusion relative to nondiabetic control mice. In a murine wound-healing model, inhibition of miRNA-181c-5p rescued diabetes-impaired wound closure rate and increased capillary density, whereas diabetic anti–miR-Neg wounds healed more slowly than nondiabetic anti–miR-Neg wounds. In vitro, inhibition of miRNA-181c-5p increased endothelial tubule formation and cell migration under high-glucose conditions. Mechanistically, anti–miR-181c-5p elevated VEGFA and VEGFR2 protein expression, ERK2 phosphorylation, and Bcl2 mRNA levels. Whole-transcriptome sequencing identified two genes (Elmo3 and Trib1) that were upregulated in anti–miR-181c-5p–treated hindlimbs and wounds. Luciferase assays confirmed VEGFA as a likely direct target of miR-181c-5p, whereas ERK2, ELMO3, and TRIB1 are indirectly regulated. These findings demonstrate that miRNA-181c-5p inhibition promotes angiogenesis and improves vascular repair in diabetes, identifying miRNA-181c-5p as a potential therapeutic target for preventing diabetic vascular complications. Article Highlights We found that patients with diabetic vascular complications have elevated circulating levels of miR-181c-5p, an antiangiogenic microRNA. We tested whether inhibition of miR-181c-5p increases angiogenesis in diabetic hindlimb ischemia and wound-healing models and elucidated its mechanisms of action. miR-181c-5p inhibition rescues diabetes-impaired ischemia-driven angiogenesis and wound healing and increases endothelial angiogenic capacity. This was concomitant with increases in VEGFA, VEGFR2, ERK2 phosphorylation, Bcl2, Elmo3, and Trib1. VEGFA is a likely direct target of miR-181c-5p, whereas ERK2, ELMO3, and TRIB1, although upregulated after miR-181c-5p inhibition, are indirectly regulated downstream. miR-181c-5p inhibition represents a promising therapeutic strategy for diabetic vascular complications.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"275 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147586636","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":"LEAP2 Reduces Ad Libitum Food Intake and Attenuates Postprandial Glucose Excursions in Men With Obesity","authors":"Anders Englund, Andreas H. Lange, Christoffer A. Hagemann, Hüsün S. Kizilkaya, Mette M. Rosenkilde, Bolette Hartmann, Jens J. Holst, Flemming Dela, Asger B. Lund, Lærke S. Gasbjerg, Filip K. Knop","doi":"10.2337/db25-1132","DOIUrl":"https://doi.org/10.2337/db25-1132","url":null,"abstract":"The naturally occurring peptide, liver-expressed antimicrobial peptide 2 (LEAP2), has gained interest as a ghrelin receptor antagonist. We previously reported reduced food intake and plasma glucose–lowering effects of LEAP2 infusion in lean healthy men; however, the effects of this competitive antagonist and inverse agonist of the ghrelin receptor in men with obesity have not been investigated. In the current study, 20 men with obesity were enrolled in a randomized, double-blind, placebo-controlled, crossover study comprising two experimental visits, each involving a ∼5-h intravenous infusion of LEAP2 (infusion rate 40 pmol/kg/min) or placebo during which a liquid mixed meal test and a subsequent ad libitum meal test were performed. The LEAP2 infusion resulted in a fivefold increase in plasma concentrations of LEAP2 compared with placebo. The infusion lowered postprandial plasma glucose levels and reduced ad libitum food intake by ∼12%. We conclude that a continuous intravenous LEAP2 infusion reduces glycemia and food intake in men with obesity, supporting further exploration of LEAP2’s therapeutic potential in obesity and related metabolic conditions. Article Highlights Liver-expressed antimicrobial peptide 2 (LEAP2), a ghrelin receptor antagonist and inverse agonist, reduces food intake and improves markers of dysmetabolism in preclinical studies and in lean men; however, the effects of LEAP2 in obesity is unknown. We investigated the effects of exogenous LEAP2 on ad libitum food intake and metabolic parameters in men with obesity. We found that LEAP2 reduces ad libitum food intake and reduces postprandial plasma glucose concentration, revitalizing the ghrelin receptor as a potential target in the treatment of obesity and its related conditions.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"21 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147577932","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":"Normalization of Insulin Resistance, Rather Than Hyperglycemia, Before Stroke Improves Functional Outcomes in a Mouse Model of Type 2 Diabetes","authors":"Ellen Vercalsteren, Dimitra Karampatsi, Maria Neicu, Mihaela Oana Romanitan, Thomas Nyström, Thomas Klein, Cesare Patrone, Vladimer Darsalia","doi":"10.2337/db25-0532","DOIUrl":"https://doi.org/10.2337/db25-0532","url":null,"abstract":"Prestroke hyperglycemia and insulin resistance (IR) independently correlate with poor stroke outcomes in type 2 diabetes (T2D), although their causative effect is undetermined. Interestingly, an increasing body of evidence points toward the importance of IR in determining stroke outcomes. Filling this gap is fundamental to identifying effective anti-T2D strategies to improve stroke prognosis in people with T2D. The aim of this study was to determine experimentally whether normalizing IR rather than hyperglycemia before stroke improves stroke outcomes in T2D. To address this research question, hyperglycemia or IR was normalized with intermediate-acting insulin or long-acting selective glucagon receptor agonist (La-GCGRa), respectively, in obese/T2D mice before inducing stroke. Functional recovery (primary outcome) was assessed by neurological testing. Systemic inflammation, infarct size, and neuroinflammation (secondary outcomes) were assessed by ELISA and immunohistochemistry, respectively. The results showed that insulin treatment normalized hyperglycemia without affecting IR and did not improve functional recovery. On the contrary, La-GCGRa normalized IR without affecting hyperglycemia and improved functional recovery. This effect occurred in association with reduced systemic and stroke-induced neuroinflammation. Neither treatment affected infarct size. The data demonstrate that targeting IR in T2D is crucial for improving stroke outcomes and may have significant implications for human therapy. Article Highlights Hyperglycemia and insulin resistance independently correlate with poor stroke outcomes in type 2 diabetes, although their causative role is unclear. The aim of this study was to determine experimentally whether normalizing insulin resistance rather than hyperglycemia before stroke improves stroke outcomes in type 2 diabetes. To answer this question, we specifically normalized either hyperglycemia or insulin resistance in obese, type 2 diabetic mice before inducing stroke. We show that targeting insulin resistance, rather than hyperglycemia, before stroke in type 2 diabetes is crucial to improving stroke outcomes.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"7 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147383342","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":"ANGPTL4 Induces Aberrant Lymphatic-Like Remodeling in Proliferative Diabetic Retinopathy","authors":"Ziwen Li, Lipeng Guan, Tong Mu, Haoyuan Zhou, Tianyi Zong, Chengye Tan, Chenyu Yang, Tianhua Xie, Miao Zhuang, Jiahui Yang, Qian Yang, Meili Wu, Yong Yao, Xiaolu Wang","doi":"10.2337/db25-0445","DOIUrl":"https://doi.org/10.2337/db25-0445","url":null,"abstract":"Diabetic retinopathy (DR) is a leading cause of vision loss in working-age adults and often progresses to proliferative diabetic retinopathy (PDR) with irreversible complications. Anti–vascular endothelial growth factor (VEGF) therapy remains the first-line treatment; however, resistance poses a significant challenge, necessitating alternative therapeutic targets. This study explores the role of angiopoietin-like protein 4 (ANGPTL4) in PDR pathogenesis, emphasizing vascular-immune-lymphatic interactions. We found significantly elevated ANGPTL4 and VEGF-C levels in the vitreous humor of patients with PDR, which were not affected by anti-VEGF therapy. In vivo, full-length ANGPTL4 and its C-terminal fragment promoted pathological angiogenesis and lymphatic-like remodeling in diabetic murine retinas, characterized by increased lymphatic vessel endothelial hyaluronan receptor 1, prospero homeobox 1, and VEGF receptor 3 (VEGFR3) expression. Single-cell sequencing further revealed ANGPTL4-driven immune dysregulation, with abnormal infiltration of CD4+ T cells and dendritic cells. Knockdown of ANGPTL4 in mice with oxygen-induced retinopathy alleviated retinal hypoxia, neovascularization, and vascular leakage. Mechanistically, retinal hypoxia markedly increased ANGPTL4 expression levels in the retina, which activated the activator protein-1 (AP-1) transcription factor complex and promoted Cd83 transcription in mouse heart microvascular endothelial cells. Additionally, ANGPTL4 bound to neuropilin-1 (NRP1)/VEGFR3, driving human lymphatic endothelial cell proliferation and lymphatic vessel ingrowth from the optic nerve sheath into the retina, a finding that suggests a novel pathway independent of angiopoietin-Tie signaling. These findings establish ANGPTL4 as a key mediator of immune–vascular interactions in PDR and a potential therapeutic target to address both pathological angiogenesis and lymphatic dysfunction. Article Highlights Some patients with proliferative diabetic retinopathy (PDR) have poor responses to anti–vascular endothelial growth factor (anti-VEGF) therapy. This situation highlights the need for additional therapeutic approaches. In proliferative diabetic retinopathy, what is the role of ANGPTL4 that differs from VEGF? We found that ANGPTL4 is elevated in the vitreous humor of patients with PDR who are poorly responsive to anti-VEGF therapy. ANGPTL4, particularly its C-terminal fragment, causes retinal lymphatic-like remodeling in diabetic mice. This study provides novel insights into the complex interplay between immune activation, neovascularization, and lymphatic-like remodeling in PDR. Our findings deepen our understanding of PDR pathophysiology and propose a promising therapeutic target.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"44 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147383343","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}