Month: October 2025

The recent identification of liver-expressed antimicrobial peptide 2 (LEAP2) as an endogenous antagonist and inverse agonist of the growth hormone secretagogue receptor (GHSR) has revived interest in targeting the ghrelin-GHSR pathway for obesity treatment. Here, we assessed the preclinical efficacy of treatment with a long-acting LEAP2 (LA-LEAP2) analog for weight loss and explored its potential […]

An acute increase of lipids in the upper small intestine (USI) of rodents and humans triggers lipid-sensing pathways to reduce food intake. However, USI lipid sensing does not reduce feeding in high-fat (HF) fed conditions, and the underlying mechanism remains elusive. Here, we report that HF feeding in male rats impaired USI lipid infusion to […]

In type 1 diabetes (T1D), insulin (INS) deficiency results from immune-mediated destruction of β-cells. The majority of functional β-cell mass is typically lost within months to years of disease diagnosis, but the timing and nature of this loss, particularly in early disease stages, remain unclear. We developed a whole-slide scanned image analysis pipeline for semiautomated […]

An accurate genetic diagnosis of maturity-onset diabetes of the young (MODY) is critical for personalized treatment. To avoid misdiagnosis, only genes with strong evidence of causality must be tested. Heterozygous variants in NEUROD1, PDX1, APPL1, and WFS1 have been implicated in MODY, but strong genetic evidence supporting causality is lacking. We therefore assessed their existing […]

Diabetes has a large medical and public health impact in American Indians. Studies have used genetic data to distinguish type 1 diabetes (T1D) and type 2 diabetes (T2D) and uncover biologic mechanisms underlying T2D clinical heterogeneity. We applied a T1D polygenic score (PS) to 3,084 American Indians (mean age 56 years, 58% women, 39% diabetes). […]

Diabetic retinopathy (DR) is characterized by microvascular damage and increased vascular permeability in the retina. The investigation of visual outcomes in late-stage DR is limited by challenges of maintaining chronically hyperglycemic mice, and most reports are restricted to early-stage DR. In this study, we used carefully managed diabetic mice to longitudinally investigate associations between vascular […]

Pancreatic β-cells undergo senescence and loss during aging; however, the underlying mechanisms remain incompletely understood. This study aimed to investigate what sirtuin 6 (SIRT6) does during β-cell aging. Pancreatic β-cell–specific Sirt6 transgenic (TgSIRT6) mice were generated for this study. DNA damage, cell death, and cell proliferation were analyzed in cell and mouse models. SIRT6 protein […]

Despite the increasing prevalence of type 2 diabetes in youth, its causal associations with circulating biomarkers remain elusive. We first aimed to identify circulating metabolites causally linked to youth-onset type 2 diabetes using Mendelian randomization (MR). By analyzing 675 metabolites from large metabolomic European genome-wide association studies (GWAS) and data on youth type 2 diabetes […]

Growth differentiation factor 15 (GDF15) is an anorectic and weight loss–inducing hormone that responds to stimuli such as endoplasmic reticulum stress, exercise, metformin, and, more recently, dietary lipids. Given its potential as an antiobesogenic agent, we examined how endogenous GDF15 responds to an Intralipid infusion in different organs to regulate food intake in vivo. We found […]