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.

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.

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.

Phosphoglucomutase 1 (PGM1) is a type 1 diabetes susceptibility gene that potentially plays a key role in regulating central carbon metabolism in β-cells. Previous work suggested that β-cell PGM1 transcription is lowered after coxsackievirus B4 infection. Thus, we hypothesized that decreased PGM1 levels disrupt β-cell metabolic homeostasis and result in β-cell fragility and type 1 diabetes. First, we showed that the synthetic double-stranded RNA polyinosinic:polycytidylic acid, or Poly(I:C) attenuated PGM1 transcription both in human islets and EndoC-βH1 cell line. At 5.5 mmol/L glucose, PGM1 deficiency enhanced the rate of glycolysis, tricarboxylic acid cycle, hexosamine, and pentose phosphate pathway. However, at 20 mmol/L glucose, PGM1-deficient cells showed impaired mitochondrial respiration. Moreover, truncated N-glycans were enriched in PGM1-deficient cells, suggesting aberrant protein glycosylation. Autophagic flux, which was dependent on the lysosomal glycosylated protein function, was impaired in PGM1-deficient cells. Increased endoplasmic reticulum stress was evident in PGM1-deficient cells. Our results suggest that PGM1 is a metabolic regulator of pancreatic β-cells. Its deficiency leads to metabolic imbalance and cellular stress, potentially augmenting type 1 diabetes development.

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.

Metabolic syndrome (MetS) increases risk for peripheral neuropathy (PN), a progressive nerve disorder with limited treatment options. We examined whether long-term ketogenic diet (KD) could maintain nerve health, and whether KD, exercise, or both could reverse established MetS PN. Maintenance KD preserved body composition, liver health, and nerve function, while all interventions improved metabolic and nerve outcomes to varying degrees. Transcriptomic profiling of sciatic nerve and gastrocnemius muscle revealed partial reversal of MetS-induced inflammatory, cytoskeletal, and metabolic gene alterations. These findings highlight KD and exercise for treating MetS PN.

We undertook this study to improve early identification of the metabolic inflection point (IP) preceding clinical type 1 diabetes in autoantibody-positive individuals. We aimed to develop and validate machine learning models using oral glucose tolerance test-derived dynamic features to detect proximity to the IP. A support vector machine trained on TrialNet Pathway to Prevention and tested on Diabetes Prevention Trial-Type 1 achieved an area under the curve of 0.77 at 1.4 years prior to diagnosis, with strong calibration and interpretability. Additionally, a Cox proportional hazards model provided numeric estimates of time to IP, offering complementary predictions. These results can support earlier intervention and timely monitoring through personalized oral glucose tolerance test-based risk stratification.

The role of the pentose phosphate pathway (PPP) in the pathogenesis of intrahepatic lipid (IHL) accumulation has not been studied before in humans. Is the PPP, proxied by 24-h urinary erythritol, associated with IHL content at the population level? In the fully adjusted model, 24-h urinary erythritol levels were associated with higher IHL content. Furthermore, genetically predicted erythritol levels were not associated with liver fat, suggesting that erythritol per se is not responsible for the former observation. Findings of the current study suggest that 1) the PPP is associated with IHL content at the population level, and 2) erythritol could potentially serve as a urinary biomarker for IHL content.

We investigated the consequence of reducing GRP78 abundance in pancreatic β-cells of adult mice in normal physiological conditions. Genetic Grp78 reduction caused β-cell failure and diabetes in male mice, with weight loss, hyperglycemia, glucose intolerance, β-cell mass reduction, and β-cell dedifferentiation. Male and female mice showed similar increases in β-cell death, but proliferation was more profoundly increased in females. Ex vivo Grp78 deletion led to hyperactivation of ATF6 target genes in male islet cells compared with female. Preserving β-cell GRP78 abundance may reduce the likelihood of diabetes, especially in males.

We undertook this study to address the persistent need for noninvasive assessment of β-cell mass in type 1 diabetes. We aimed to determine whether 18F-exendin positron emission tomography/computed tomography can reliably visualize residual β-cell mass and distinguish stages of disease. We found that pancreatic tracer uptake was consistently reduced in type 1 diabetes, differentiated insulin-dependent patients from control participants, and aligned with markers of β-cell function and glycemic status. Our findings suggest that 18F-exendin imaging may offer fundamental platform for disease staging, therapeutic monitoring, and individualized care.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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."