Diabetes[JOURNAL]
Sun
200 papers
Mesenchymal Stem Cell and Secretome Treatments Inhibit the mTOR-NOX4 Pathway in Diabetic Kidney Disease.
Njeim R, Alkhansa S, Almoussawi S … +12 more , Slika A, Hamade S, Al Danaf G, Dia B, Lawandos L, Eid AH, Kassouf HK, Harb F, Fayad AA, Ziyadeh FN, Khuri FR, Eid AA
Diabetes · 2026 May · PMID 41811297 · Publisher ↗
UNLABELLED: Diabetic kidney disease (DKD) is a major complication of diabetes characterized by progressive renal dysfunction driven by oxidative stress and inflammation involving mammalian target of rapamycin (mTOR) and...
UNLABELLED: Diabetic kidney disease (DKD) is a major complication of diabetes characterized by progressive renal dysfunction driven by oxidative stress and inflammation involving mammalian target of rapamycin (mTOR) and NADPH oxidase (NOX) pathways. Mesenchymal stem cells (MSCs) have gained attention for their regenerative and immunomodulatory properties in attenuating DKD, but the mechanisms behind their protective effects are still being explored. Moreover, concerns regarding tumorigenic risks hinder their direct clinical use. In this study, we compared MSCs and their conditioned media (MSCs-CM; secretome) in a type 1 diabetic rodent model, demonstrating that both treatments attenuated glomerular injury, preserved podocyte integrity, reduced NOX4 expression and activity, and tempered inflammation, by inhibiting mTORC1 and mTORC2 signaling. Importantly, MSCs-CM replicated the renoprotective effects of MSCs, indicating that soluble factors mediate these benefits. To our knowledge, this is the first study to directly compare MSCs and their conditioned media (MSCs-CM) in DKD, revealing that MSCs-CM delivers equivalent therapeutic efficacy while circumventing the safety concerns inherent to cell-based therapies. These findings identify the mTOR/NOX axis as a therapeutic target and support MSCs-CM as a promising, safer, cell-free alternative for DKD treatment, potentially advancing regenerative strategies to mitigate diabetic renal injury. ARTICLE HIGHLIGHTS: Despite advances in diabetes management, diabetic kidney disease (DKD) remains a leading cause of end-stage renal disease. We investigated whether mesenchymal stem cells (MSCs) and their conditioned medium, containing the MSC-derived secretome, protect against DKD by modulating the mammalian target of rapamycin (mTOR)/NADPH oxidase (NOX) pathway. MSCs and MSCs-conditioned medium both reduced kidney injury, podocyte structural integrity, oxidative stress, and inflammation by inhibiting mTORC1/mTORC2 and NOX4. MSCs-conditioned medium offers a safe, secretome-based, cell-free approach for DKD therapy.
Normalization of Insulin Resistance Rather Than Hyperglycemia Before Stroke Improves Functional Outcomes in a Mouse Model of Type 2 Diabetes.
Vercalsteren E, Karampatsi D, Neicu M … +5 more , Romanitan MO, Nyström T, Klein T, Patrone C, Darsalia V
Diabetes · 2026 May · PMID 41805868 · Full text
UNLABELLED: 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 bo...
UNLABELLED: 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.
ANGPTL4 Induces Aberrant Lymphatic-Like Remodeling in Proliferative Diabetic Retinopathy.
Li Z, Guan L, Mu T … +11 more , Zhou H, Zong T, Tan C, Yang C, Xie T, Zhuang M, Yang J, Yang Q, Wu M, Yao Y, Wang X
Diabetes · 2026 May · PMID 41805865 · Publisher ↗
UNLABELLED: 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 gr...
UNLABELLED: 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.
Effects of Pancreatic Resection on Liver Fat Content and Amino Acid, Lipid, and Glucose Metabolism: A Prospective 1-Year Follow-up Study.
Grøndahl MFG, Rix I, Garvey LF … +12 more , Nielsen CK, Suppli MP, Willemoe GL, Kønig MJ, Chabanova E, Trammell SAJ, Grevengoed TJ, Hartmann B, Holst JJ, Hansen CP, Lund AB, Knop FK
Diabetes · 2026 May · PMID 41790961 · Publisher ↗
UNLABELLED: Individuals who undergo pancreatic resection are at increased risk of developing hepatic steatosis. Glucagon is a key regulator of hepatic glucose, amino acids, and lipid metabolism, and the change in circula...
UNLABELLED: Individuals who undergo pancreatic resection are at increased risk of developing hepatic steatosis. Glucagon is a key regulator of hepatic glucose, amino acids, and lipid metabolism, and the change in circulating glucagon is suggested to contribute to the pathogenesis of postoperative steatotic liver disease. Here, we aimed to elucidate hepatic and metabolic changes induced by pancreatic resection. Fifty individuals scheduled to undergo pancreatic surgery were recruited and evaluated by blood samples and a liver biopsy obtained during surgery. One year after surgery, 21 eligible participants (15 following pancreaticoduodenectomy, 6 following total pancreatectomy) met for a follow-up visit, with the remaining being excluded because of recurrent disease, comorbidities, or death. Follow-up MRS indicated increased liver fat in 12 of 19 participants despite a mean numerical decrease in body weight. Five eligible participants underwent a liver biopsy at follow-up, demonstrating increased liver fat content (largest individual increase: 80 percentage points). Circulating glucagon and C-peptide were significantly reduced at follow-up, with no detection of either following total pancreatectomy. No significant changes in fasting plasma glucose or HbA1c were observed, attributed to relevant exogenous insulin supplementation. Amino acids were markedly increased after both pancreaticoduodenectomy and total pancreatectomy, correlating negatively with remnant endocrine pancreatic function. In conclusion, our data suggest that reduced circulating glucagon levels may contribute to the increased liver fat content and hyperaminoacidemia observed after pancreatic resection. ARTICLE HIGHLIGHTS: Previous studies have demonstrated increased risk of hepatic steatosis in patients following pancreatic resection, which might be linked to decreased pancreatic function. Here, we evaluated liver fat content, circulating pancreatic hormones, amino acids, and more, before and 1 year after either total pancreatectomy or pancreaticoduodenectomy. At 1-year follow-up, we found increased liver fat content in more than half (63%) of the participants, evaluated both by liver histology and magnetic resonance imaging. The participants were characterized by hyperaminoacidemia, which correlated negatively with remnant endocrine pancreatic function. These findings further elucidate the relationship between glucagon, circulating amino acids, and hepatic metabolism.
Unraveling Diabetic Cardiomyopathy (DCM): The Critical Role of the Yap-miR-22-3p-Sirt1 Axis in the Pathogenesis of DCM.
Li Y, Zeng Y, Lian Y … +12 more , Zhang C, Chen X, Zhang S, Huang Y, Yuan W, Qin Y, Liu D, Liu Y, Chen Y, Shi Y, Yuan X, Hou N
Diabetes · 2026 Jun · PMID 41770102 · Publisher ↗
UNLABELLED: 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 remodeli...
UNLABELLED: 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. ARTICLE HIGHLIGHTS: 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.
Biallelic Pathogenic Variants in IL2RA Cause Neonatal-Onset Monogenic Autoimmune Diabetes.
Bonfield G, Russ-Silsby J, Ramchand S … +13 more , Luckett AM, Wakeling MN, Kulkarni A, Nagesh VS, Deeb A, Ravikumar KG, Nguyen PTK, Hattersley AT, Oram RA, Flanagan SE, De Franco E, Johnson MB, EXE-T1D Consortium*
Diabetes · 2026 May · PMID 41758964 · Full text
UNLABELLED: Autoimmune diabetes presenting in infancy or with additional autoimmune disorders can be the result of highly penetrant variants in key immune homeostasis genes. An example of this is observed with biallelic...
UNLABELLED: Autoimmune diabetes presenting in infancy or with additional autoimmune disorders can be the result of highly penetrant variants in key immune homeostasis genes. An example of this is observed with biallelic pathogenic variants in IL2RA (CD25), which causes immunodeficiency 41 (IMD41). IL2RA encodes the α-chain of the interleukin-2 receptor, which helps regulate the growth and activity of T cells. The diabetes phenotype in IMD41 has not been systematically described. We sequenced IL2RA in 290 individuals with diabetes diagnosed <6 months and in 64 individuals diagnosed <10 years who had additional autoimmunity. We also reviewed all previously reported IMD41 cases. We identified five new unrelated individuals with biallelic pathogenic IL2RA variants. Four presented with diabetes in the first month of life with very low/absent C-peptide, and all were GAD antibody-positive. Of 17 previously reported cases, 9 had diabetes, yielding a total of 14 of 22 (64%) with early-onset diabetes. No relationship between variant location/type and diabetes development was observed. Autoimmune diabetes is therefore a common and early feature of IMD41. IL2RA should be included in genetic testing panels for neonatal and monogenic autoimmune diabetes. These findings highlight the important role of IL2RA in immune tolerance and β-cell protection. ARTICLE HIGHLIGHTS: We report five new cases of neonatal or early childhood-onset diabetes caused by biallelic pathogenic variants in IL2RA. Autoimmune diabetes was the presenting feature in most individuals and occurs in 64% of all reported cases of immunodeficiency 41. Patients typically presented in infancy with diabetic ketoacidosis, low C-peptide, and GAD antibody positivity, highlighting an autoimmune etiology. The diabetes phenotype was consistent across cases but not linked to variant type or location. IL2RA should be included in genetic testing for neonatal diabetes and considered in children with diabetes plus immune dysregulation.
Memory Regulatory T Cells as a Biomarker of Early Type 1 Diabetes.
Raineri D, Savastio S, Bellone S … +7 more , Scotti L, Barbero-Mazzucca C, Cappellano G, Prodam F, Pozzi E, Rabbone I, Chiocchetti A
Diabetes · 2026 Apr · PMID 41729832 · Full text
UNLABELLED: Type 1 diabetes (T1D) is the most common chronic autoimmune disease in children, driven by a breakdown in self-tolerance and T cell-mediated immune attack of pancreatic β-cells. There are no biomarkers to eff...
UNLABELLED: Type 1 diabetes (T1D) is the most common chronic autoimmune disease in children, driven by a breakdown in self-tolerance and T cell-mediated immune attack of pancreatic β-cells. There are no biomarkers to effectively diagnose autoimmunity before disease onset and clinical symptom development. Here, we applied deep multiparametric immunophenotyping to compare immune landscapes in 38 patients with new-onset T1D, 24 siblings, and 18 healthy control participants (HCs). Patients with T1D underwent clinical and metabolic evaluations. Immune populations in fresh whole-blood samples were analyzed using a panel of 26 antibodies, detecting 39 different cell populations. Memory regulatory T cells (memory Tregs) were significantly increased in patients with T1D (P < 0.05) and their siblings (P < 0.01) compared with HCs but not between patients with T1D and siblings. Memory Tregs were associated with disease status and age in multivariable analysis. There was a positive correlation between age and memory Tregs in the HC and sibling groups but not in patients with T1D. Baseline memory Treg levels in siblings resembled those of patients with T1D. These findings highlight the existence of an age-independent, disease-specific immune fingerprint that could serve as a minimally invasive biomarker for early diagnosis and personalized immunotherapy. Further studies using functional and single-cells analysis are needed to confirm memory Tregs as a pathogenic trait. ARTICLE HIGHLIGHTS: There are more memory regulatory T cells (Tregs) in individuals with type 1 diabetes (T1D) and siblings than in healthy control (HC) individuals. Individuals with T1D and their siblings share an immunological profile, with siblings displaying an intermediate phenotype that overlaps with both T1D and HC individuals. Memory Tregs increased with age in HC individuals and siblings but not in individuals with T1D. Diabetic ketoacidosis status had no impact on immune cell populations in patients with T1D.
Diabetes Spotlight: Martin Myers, MD, PhD-Understanding Metabolism and Glucose Through Neural Networks.
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Diabetes · 2026 Mar · PMID 41719447 · Publisher ↗
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Metabolic Signature of Gestational Diabetes Mellitus and Risk of Adverse Birth Outcomes: A Prospective Birth Cohort Study.
Wang J, Jiang Y, Lv H … +16 more , Pi D, Han X, Xu B, Liu X, Zhou K, Jiang Y, Yang X, Xu X, Dou Y, Jiang T, Du J, Jin G, Ma H, Hu Z, Shen H, Lin Y
Diabetes · 2026 Apr · PMID 41718722 · Publisher ↗
UNLABELLED: Gestational diabetes mellitus (GDM) is a heterogeneous condition diagnosed solely through glucose. It is characterized by profound perturbations in the metabolome, with specific metabolic profiles linked to a...
UNLABELLED: Gestational diabetes mellitus (GDM) is a heterogeneous condition diagnosed solely through glucose. It is characterized by profound perturbations in the metabolome, with specific metabolic profiles linked to adverse birth outcomes. Metabolomics can reveal population heterogeneity in health and disease. Here, we used nontargeted metabolomics to systematically profile the circulating metabolome in 2,050 pregnant women during midpregnancy, identifying 30 metabolites that define the GDM metabolic signature (mGDM). Participants were stratified into four groups by distinct glycemic and metabolic profiles, namely normoglycemic non-mGDM, hyperglycemic non-mGDM, normoglycemic mGDM, and hyperglycemic mGDM, and associations with subsequent adverse birth outcomes were assessed. Compared with normoglycemic non-mGDM, normoglycemic mGDM demonstrated nearly a twofold increased risk of preterm birth (odds ratio [OR] 1.93, 95% CI 1.02-3.65) and large for gestational age (OR 2.11, 95% CI 1.53-2.92). Conversely, the hyperglycemic non-mGDM group did not show elevated risks in adverse birth outcomes versus the normoglycemic group. The hyperglycemic mGDM profile was associated with higher risks of preterm birth (OR 2.37, 95% CI 1.04-5.39), large for gestational age (OR 2.28, 95% CI 1.50-3.47), congenital malformations (OR 1.87, 95% CI 1.03-3.39), and neonatal intensive care unit (NICU) admissions (OR 1.69, 95% CI 1.09-2.61). We observed a stepwise increase in adverse outcome risk across the four-level metabolic-glycemic categories (P for trend < 0.001 for large for gestational age, 0.013 for preterm birth, and 0.018 for NICU admission). Taken together, our study outlines the metabolic profile of GDM and reveals clinically relevant heterogeneity in adverse pregnancy outcomes by metabolic signature. Integrating blood glucose and metabolomics may improve risk stratification and advance precision maternal care. ARTICLE HIGHLIGHTS: Women diagnosed with gestational diabetes mellitus (GDM) exhibit variability in symptom presentation and pregnancy outcomes. The heterogeneity in metabolic features beyond a GDM diagnosis and their influences on health outcomes is less studied. We aimed to identify the metabolic signatures of GDM, stratify pregnant women by glycemic and metabolic profiles, and further investigate the intergroup heterogeneity and their respective associations with adverse birth outcomes. Maternal metabolic dysregulation, rather than blood glucose alone, exerts more profound associations with adverse outcomes in pregnant women and their offspring. Targeted risk stratification using metabolomics offers a novel opportunity for precision medicine in GDM, potentially improving health management of pregnant women.
Epigenetic Regulation of VCAM-1 by Lipoxin A4 Is Renoprotective Against Diabetic Kidney Disease.
Bose M, Mohan M, Okabe J … +17 more , Kaipananickal H, Priori V, Chhor C, Sourris KC, Radman R, Tikellis C, Zhang Y, El-Osta A, Brennan E, Guiry PJ, Gahan K, Tighe C, Thomas M, Jandeleit-Dahm K, Godson C, Kantharidis P, Cooper ME
Diabetes · 2026 Apr · PMID 41706038 · Full text
UNLABELLED: Chronic low-grade inflammation underlies many microvascular complications of diabetes, including diabetic kidney disease (DKD). Lipoxins (LXs), an endogenously produced family of lipid mediators, resolve infl...
UNLABELLED: Chronic low-grade inflammation underlies many microvascular complications of diabetes, including diabetic kidney disease (DKD). Lipoxins (LXs), an endogenously produced family of lipid mediators, resolve inflammation and protect against renal scarring as occurs in DKD. This study examined the mechanism by which LXs protect against DKD, focusing on the regulation of VCAM-1 and the recruitment of macrophages to the diabetic glomerulus. LXA4 and two fourth-generation mimetics were assessed in diabetic ApoE knockout mice, followed by in vitro studies in the main renal cell populations, including podocytes, proximal tubular, mesangial, and glomerular endothelial cells. LXs attenuated albuminuria, mesangial expansion, and collagen and fibronectin deposition as both a preventive and delayed intervention in experimental DKD. LXs also consistently attenuated the TNF-α-induced expression of VCAM-1 in all the human and mouse renal cell populations examined. Further analysis identified that the renoprotection was in part mediated by an epigenetic modification of the VCAM-1 gene through H3K4 monomethylation, which did not appear to be dependent on NF-κB activation in human glomerular endothelial cells. LXs protect against DKD by modulating glomerular endothelial cell inflammation and via a novel LX-mediated epigenetic mechanism regulating the VCAM-1 promoter in these cells. ARTICLE HIGHLIGHTS: Lipoxins (LXs) protect against diabetic kidney disease (DKD) by resolving chronic low-grade inflammation, but the exact mechanism by which this occurs is not known. We investigated the effect of LXs on inflammatory markers and the recruitment of macrophages to the diabetic glomerulus by using LXs as both a preventive and delayed interventional treatment in streptozotocin-induced diabetic ApoE knockout mice. Protection against DKD was associated with reduced glomerular macrophage accumulation. LXs also attenuated the expression of VCAM1 in glomerular endothelial cells. LXs protect against DKD in part by a mechanism that reduces VCAM1 gene expression via H3K4 monomethylation on the VCAM1 gene.
Adipose Tissue Resistance to the Antilipolytic Effect of Insulin and Niacin in Humans With Obesity.
Lin S, Lytle KA, Fink N … +1 more , Jensen MD
Diabetes · 2026 Apr · PMID 41701570 · Full text
UNLABELLED: Adipose tissue (AT) lipolysis insulin resistance results in excess free fatty acid (FFA) release. We tested the hypothesis that the ability of insulin to suppress AT lipolysis is unrelated to the ability of n...
UNLABELLED: Adipose tissue (AT) lipolysis insulin resistance results in excess free fatty acid (FFA) release. We tested the hypothesis that the ability of insulin to suppress AT lipolysis is unrelated to the ability of niacin to suppress lipolysis, because niacin acts through a different proximal signaling pathway. Ten volunteers (5 women and 5 men) with upper-body obesity and/or type 2 diabetes mellitus (T2DM) underwent two study visits with overnight intravenous infusions of niacin (1.4 mg/min) or saline, followed by a hyperinsulinemic-euglycemic clamp. FFA-palmitate Ra was measured using [U-13C] and [2H9]palmitate infusions; abdominal AT biopsies were performed before and during the insulin clamp. The suppression of FFA-palmitate Ra by insulin on the saline control day and by niacin after an overnight infusion were highly correlated (r = -0.93, P < 0.001). Fasting AT Akt (pAktS473/474-to-panAkt ratio, P = 0.01) and perilipin 1 (PLN1) (pPLN1S552-to-panPLN1 ratio, P = 0.02) phosphorylation were less during niacin treatment than in the saline control study. Because the suppression of lipolysis by insulin and niacin are highly correlated within individuals and because niacin and insulin act through different proximal signaling pathways, we propose dysregulated AT lipolysis in obesity/T2DM is due to dysfunction(s) in distal lipolysis proteins rather than isolated "insulin resistance." ARTICLE HIGHLIGHTS: We undertook this study to compare adipose tissue lipolysis responses to insulin and niacin in humans. We tested the hypothesis that adipose tissue insulin resistance would be unrelated to adipose tissue niacin resistance. The suppression of lipolysis by insulin and niacin were highly correlated. Dysregulated adipose tissue lipolysis in obesity/type 2 diabetes is due to dysfunction(s) in distal lipolysis proteins rather than isolated "insulin resistance."
Activation of the Pancreatic "Metabolic Synapse" Aggravates Type 2 Diabetes Mellitus by Inducing PANoptosis in β-Cells.
Xiang Z, Zitian L, Guangwei Y … +2 more , Shuohui D, Kexin W
Diabetes · 2026 Apr · PMID 41701561 · Full text
UNLABELLED: Pancreatic β-cells play a central role in type 2 diabetes mellitus (T2DM), yet the interactions between β-cells and stromal components within the islet microenvironment remain poorly defined. We investigated...
UNLABELLED: Pancreatic β-cells play a central role in type 2 diabetes mellitus (T2DM), yet the interactions between β-cells and stromal components within the islet microenvironment remain poorly defined. We investigated the contribution of pancreatic fibroblasts to β-cell dysfunction and T2DM progression. We used single-cell sequencing technology and in vitro experiments to investigate the mechanisms by which bariatric surgery ameliorates T2DM. We introduce the novel concept of a "metabolic synapse" to describe the interaction between pancreatic fibroblasts and β-cells. Our findings reveal that pancreatic fibroblasts secrete excessive glutamate in the early stages of T2DM. Elevated glutamate concentrations within the islet microenvironment subsequently activate N-methyl-d-aspartic acid receptors (NMDARs), triggering PANoptosis in pancreatic β-cells and accelerating T2DM progression. Consistent with this, significant changes in NMDAR expression were observed in human pancreatic samples from patients with T2DM. These findings uncover a previously unrecognized fibroblast-β-cell communication pathway in the islet niche, provide mechanistic insights into T2DM pathogenesis, and highlight the glutamate-NMDAR axis as a potential therapeutic target for nonsurgical intervention. ARTICLE HIGHLIGHTS: We identify a fibroblast-β-cell "metabolic synapse" in type 2 diabetes that couples stromal glutamate overflow to-β-cell N-methyl-d-aspartic acid receptor (NMDAR) activation. Single-cell maps and coculture assays show diabetogenic stress drives fibroblasts to hypersecrete glutamate, whereas β-cells upregulate NMDARs, triggering PANoptosis. In rodents, pharmacologic NMDAR blockade attenuates β-cell PANoptosis, preserves islet function, and improves glycemic control. Human pancreatic samples cohorts reveal fibrosis regression and stage-wise NMDAR upregulation, highlighting the glutamate-NMDAR axis as a therapeutic target.
GDF5 Exacerbates Tubulointerstitial Injury by Inducing Partial Epithelial-Mesenchymal Transition of Tubular Epithelial Cells in Diabetic Kidney Disease.
Tong S, Peng C, Xiong Y … +14 more , Lei J, Gao R, Luo T, Qi S, Du M, Liu Y, Ma L, Wang Z, Huang W, Xu Y, Yang S, Hu J, Li Q, Chen X
Diabetes · 2026 Apr · PMID 41701540 · Publisher ↗
UNLABELLED: Adipokines serve crucial functions in diabetic kidney disease (DKD) pathogenesis. Growth differentiation factor 5 (GDF5) is highly expressed in adipose tissue, but its specific role in DKD is unknown. In this...
UNLABELLED: Adipokines serve crucial functions in diabetic kidney disease (DKD) pathogenesis. Growth differentiation factor 5 (GDF5) is highly expressed in adipose tissue, but its specific role in DKD is unknown. In this study, we observed elevated GDF5 expression in both patients with DKD and db/db mice, suggesting a potential association between GDF5 and DKD progression. Elevated plasma GDF5 levels are associated with an increased risk of incident chronic kidney disease in patients with type 2 diabetes. In animal studies, adipose-specific overexpression of GDF5 increased circulating GDF5 and exacerbated renal injury in db/db mice, characterized by increased tubulointerstitial injury and inflammation infiltration. Conversely, adipose-specific knockdown reduced circulating GDF5 and alleviated renal injury. In vitro studies demonstrated that GDF5 induces partial epithelial-mesenchymal transition in renal tubular epithelial cells via activation of the SMAD1/5/8 signaling pathway, as evidenced by reduced E-cadherin expression and increased Snail1 levels. Notably, the supernatant from GDF5-treated injured HK-2 cells was found to enhance the secretion of proinflammatory cytokines by macrophages. These findings suggest that adipose-derived GDF5 acts as a novel mediator contributing to tubulointerstitial injury in DKD. ARTICLE HIGHLIGHTS: Elevated growth differentiation factor 5 (GDF5) expression is correlated with disease progression in both patients with diabetic kidney disease and db/db mice. Adipose-specific GDF5 overexpression exacerbates, whereas its knockdown alleviates, renal tubulointerstitial injury in vivo. GDF5 directly induces partial epithelial-mesenchymal transition in tubular cells by activating the SMAD1/5/8 signaling pathway. Tubular cells exposed to GDF5 release factors that promote proinflammatory cytokine secretion in macrophages.
Interrupting T-Cell Memory Ameliorates Exaggerated Metabolic Response to Weight Cycling.
Garcia JN, Cottam MA, Rodriguez AS … +4 more , Agha AFH, Caslin HL, Winn NC, Hasty AH
Diabetes · 2026 Jun · PMID 41701539 · Full text
UNLABELLED: Weight cycling has been demonstrated, in humans and animal models, to increase cardiometabolic disease and disrupt glucose homeostasis. Both obesity itself and weight cycling cause adipose tissue inflammation...
UNLABELLED: Weight cycling has been demonstrated, in humans and animal models, to increase cardiometabolic disease and disrupt glucose homeostasis. Both obesity itself and weight cycling cause adipose tissue inflammation and metabolic dysfunction. Studies show that even after weight loss, increased numbers of lipid-associated macrophages and memory T cells persist in adipose tissue and become more inflammatory on weight regain. This suggests that the immune system retains an obesogenic memory, which may contribute to the elevated inflammation and metabolic dysfunction associated with weight cycling. We show that blocking the CD70-CD27 axis, critical for the formation of immunologic memory, decreases the number of memory T cells and T-cell clonality within adipose tissue after weight loss and weight cycling. Furthermore, although CD70-/- mice have metabolic responses to stable obesity similar to those of wild-type mice, they are protected from the worsened glucose tolerance associated with weight cycling. Our data are the first to support mitigating the metabolic consequences of weight cycling through an immunomodulatory mechanism. We propose a new avenue of therapeutic intervention targeting memory T cells to minimize the adverse consequences of weight cycling. These findings are timely, given the increasing use of weight-loss drugs, which may lead to more instances of human weight cycling. ARTICLE HIGHLIGHTS: We aimed to address a critical gap in understanding how persistent immune changes with weight cycling contribute to worsened metabolic health. We wanted to determine whether disrupting immune memory formation could prevent the accumulation and reactivation of memory T cells in adipose tissue and thereby protect against the metabolic dysfunction associated with weight cycling. In targeting the CD70-CD27 axis, thereby inhibiting T-cell memory formation, we were able to mitigate the exacerbated glucose intolerance observed in wild-type weight-cycled mice. This study highlights the potential to address the negative metabolic effects of weight cycling through an immunomodulatory approach, offering a novel therapeutic target by disrupting obesogenic immune memory.
Staying Functional Through Connection and Adaptation: When Islets Inspire Islet Biologists.
Dhawan S, Hughes J, Matveyenko AV … +1 more , Poitout V
Diabetes · 2026 Apr · PMID 41700931 · Full text
In response to the lockdowns and travel bans during the coronavirus disease 2019 pandemic, Peter C. Butler at the University of California, Los Angeles (UCLA), started a virtual islet biology seminar series. After the au...
In response to the lockdowns and travel bans during the coronavirus disease 2019 pandemic, Peter C. Butler at the University of California, Los Angeles (UCLA), started a virtual islet biology seminar series. After the authors of this article joined him as co-organizers, this initiative became the Islet Research Seminar Series (IRSS). Like islets of Langerhans adapt to their changing environment, the islet biology community quickly embraced this new format. The IRSS evolved into a lasting scientific forum that convenes weekly and is attended by islet biologists from the U.S., Canada, Europe, and Israel. The series covers a range of topics in islet biology, with presentations from scientists representing all career stages. It has proven particularly valuable for trainees and early-stage investigators in exposing them to a variety of topics in islet biology without travel required and facilitating more spontaneous interactions with senior scientists than at in-person meetings. While the online format is not meant to replace live scientific conferences, we believe that the IRSS plays a unique role in keeping the islet biology community connected and abreast of the most recent scientific discoveries in our field. The success of this platform stands as a testament to the scientific community to adapt and thrive through challenges. This article is dedicated to Peter C. Butler, UCLA, who initiated the IRSS.
ISL1 Restricts Progenitor Programs and Promotes β-Cell Maturation, Revealing Sex Differences in Diabetes Progression.
Fabriciova V, Bohuslavova R, Lebron-Mora L … +6 more , Slaninova V, Abaffy P, Berkova Z, Saudek F, Kaestner KH, Pavlinkova G
Diabetes · 2026 Apr · PMID 41700921 · Publisher ↗
UNLABELLED: Pancreatic islet cells differentiate from a common progenitor pool through tightly regulated transcriptional and epigenetic programs. ISL1, a LIM homeodomain transcription factor, is essential for islet devel...
UNLABELLED: Pancreatic islet cells differentiate from a common progenitor pool through tightly regulated transcriptional and epigenetic programs. ISL1, a LIM homeodomain transcription factor, is essential for islet development, but its molecular functions remain poorly defined. Here, we demonstrate that ISL1 is critical for maintaining endocrine cell identity and enabling terminal differentiation, particularly of α- and β-cells. Using conditional Isl1 deletion in endocrine precursors, combined with single-cell RNA sequencing and chromatin profiling (H3K27ac and H3K27me3), we reveal disruption of the transcriptional and epigenetic landscape in Isl1-deficient islets. Loss of Isl1 results in the failure to establish α-cell identity, loss of δ- and γ-cell lineages, and the persistence of immature β-cells with impaired functional profiles in Isl1CKO mice. Longitudinal single-cell analysis shows that Isl1CKO endocrine cells exhibit sustained progenitor-like states and defective β-cell maturation. These defects are accompanied by activation of stress and diabetes-associated transcriptional programs, along with sex-specific responses that may influence disease onset and progression. Mechanistically, ISL1 represses intermediate progenitor programs and facilitates chromatin remodeling necessary for endocrine lineage commitment and terminal maturation. Our findings highlight a previously underappreciated role for ISL1 in preserving endocrine cell fate and function and offer insight into how its dysregulation may contribute to diabetes. ARTICLE HIGHLIGHTS: ISL1 is a known maturity-onset diabetes of the young candidate and type 2 diabetes susceptibility gene, yet its molecular role in pancreatic endocrine maturation has remained unresolved. Deletion of Isl1 in endocrine progenitors results in islets composed of dysfunctional α-cells lacking glucagon production and immature β-cells with impaired basal insulin secretion, ultimately accelerating diabetes progression. ISL1 functions as a transcriptional repressor guiding chromatin remodeling and transcriptional transitions toward hormone-producing endocrine cells. The metabolic phenotype resulting from Isl1 deletion is associated with sustained progenitor-like states and activation of diabetes- and stress-associated pathways, with distinct sex-specific responses observed between male and female mice.
Exofacial Epitope-Specific Antibodies Detect GLUT4 Translocation in Adult Human, Rat, and Mouse Skeletal Muscle.
Persson KW, Fjeldsøe C, Frandsen LW … +10 more , Knudsen JR, Kwak S, Wang H, Voldstedlund CT, Leandersson MR, Witczak CA, Wojtaszewski JFP, Richter EA, Cartee GD, Jensen TE
Diabetes · 2026 Apr · PMID 41686119 · Full text
UNLABELLED: Skeletal muscle glucose transporter 4 (GLUT4) translocation to the plasma membrane determines glucose uptake in response to insulin and exercise and is disrupted in insulin resistance, making its experimental...
UNLABELLED: Skeletal muscle glucose transporter 4 (GLUT4) translocation to the plasma membrane determines glucose uptake in response to insulin and exercise and is disrupted in insulin resistance, making its experimental measurement critical. Confocal light microscopy is widely used for this purpose because of its ability to provide quantitative, high-resolution spatial information from small tissue amounts. However, conventional immunofluorescence colocalization microscopy lacks sensitivity and specificity in the detection of GLUT4 translocation. We validated the use of exofacial epitope-specific GLUT4 antibodies to quantify sarcolemmal GLUT4 translocation in fixed, nonpermeabilized adult human and rodent muscle fibers. Across human, mouse, and rat muscles, these antibodies sensitively detected stimulus-induced GLUT4 translocation, and labeling was abolished in muscle-specific GLUT4-knockout muscle, confirming specificity. Importantly, this study includes the first unambiguous visualization of endogenous GLUT4 translocation in intact human skeletal muscle fibers after insulin stimulation and exercise. In TBC1D4-knockout rats, insulin-stimulated GLUT4 translocation was absent despite wild-type-level GLUT4 expression, confirming an essential role for TBC1D4 in this process. Thus, exofacial GLUT4 antibodies provide a straightforward, sensitive, and specific approach to quantify endogenous GLUT4 translocation in fixed adult skeletal muscle. ARTICLE HIGHLIGHTS: Reliable quantification of glucose transporter 4 (GLUT4) translocation in intact skeletal muscle is essential for understanding insulin and exercise responses but remains technically challenging. We aimed to test whether exofacial GLUT4 antibodies can specifically detect sarcolemmal GLUT4 translocation in fixed, nonpermeabilized muscle fibers from humans and rodents. GLUT4 translocation in response to insulin, AMPK activation, and exercise was detectable in human and rodent muscles. Insulin-stimulated translocation correlated with 2-deoxyglucose uptake and was abolished in TBC1D4-knockout muscle. Exofacial GLUT4 antibodies enable straightforward, specific quantification of endogenous GLUT4 translocation in rodent and human muscles in healthy and insulin-resistant states.
Distinct Enterovirus Antigen Landscape in Children With Islet Autoimmunity.
Delgado-Corrales B, Fingerhut L, Leung P … +29 more , Yau CSA, Foster CSP, Ward EJ, Foskett DB, Annadurai A, Barry SC, Colman PG, Couper JJ, Davis EA, Hamilton-Williams EE, Harrison LC, Haynes A, Huynh T, McGorm KJ, Morahan G, Oakey H, Penno MAS, Soldatos G, Thomson RL, Tye-Din JA, Vuillermin PJ, Wentworth JM, Wilkins MR, Laiho JE, Hyöty H, Rawlinson WD, Craig ME, Kim KW, ENDIA Study Group
Diabetes · 2026 Apr · PMID 41662565 · Full text
UNLABELLED: Enteroviruses (EVs) have long been implicated in the development of islet autoimmunity (IA) and type 1 diabetes. However, given the ubiquity of EV infections in children, disease susceptibility is likely driv...
UNLABELLED: Enteroviruses (EVs) have long been implicated in the development of islet autoimmunity (IA) and type 1 diabetes. However, given the ubiquity of EV infections in children, disease susceptibility is likely driven by host-specific immune responses rather than viral exposure alone. To investigate the host antibody response to EVs, we used virome-wide serological profiling (VirScan) to compare the EV antigen landscapes in IA-positive case children versus IA-negative control children across two independent pediatric cohorts separated by 12 years, using samples collected at the time point of seroconversion. We identified a reproducible and distinct EV-specific antibody signature in IA-positive case samples, with an enriched immunogenic hotspot localized within a highly conserved region in the 3D RNA-dependent RNA polymerase. Additionally, IA-positive male children exhibited significantly heightened antibody responses against a motif in the VP1 capsid protein compared with IA-negative male children (risk ratio 1.24; 95% CI 1.02, 1.52; P = 0.03). Our findings provide paradigm-shifting evidence that differential antiviral humoral responses, rather than the specific types of EV infection, play a central role in IA development, highlighting the need for an updated framework to study host-virus interactions in autoimmune pathogenesis. ARTICLE HIGHLIGHTS: Children positive for islet autoimmunity (IA) in two different Australian cohorts showed a distinct enterovirus (EV) antibody signature against specific regions of the EV genome polyprotein. A specific motif in the 3D region of the EV polyprotein was consistently enriched across cohorts and sexes, making it a potential marker for IA onset. Anti-VP1 motif antibody levels varied by sex, with significantly elevated levels in male children linked to early IA onset, highlighting possible sex-specific antiviral immunity. Findings support that host immune responses against EVs drive IA development, calling for a new framework to study host-virus interactions in IA.
Erratum. δ-Cells Control a Subset of β-Cells in Mouse Pancreatic Islets. Diabetes 2025;74:2365-2374.
Miranda C, Santos C, Tolö J … +7 more , Gao R, Hill TG, Kothegala L, Tarasov AI, Zhang Q, Rorsman P, Dou H
Diabetes · 2026 Apr · PMID 41628391 · Full text
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Erratum. Cardioprotection During Myocardial Infarction in Diabetic Cardiomyopathy. Diabetes 2025;74:1021-1032.
Alcover S, López S, Ramos-Regalado L … +5 more , Muñoz-García N, Gallinat A, Suades R, Badimon L, Vilahur G
Diabetes · 2026 Apr · PMID 41628359 · Full text
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