995-P: LRG1 Mediates Diet-Induced Hyperinsulinemia by Enhancing Glucose-Stimulated Insulin Secretion

Abstract

Childhood obesity and metabolic syndrome sequelae associated with early-onset insulin resistance and type 2 diabetes are at epidemic levels globally with increasing evidence for worrisome young adult health sequelae trajectories. Pediatric obesity is often associated with dramatic rise in hyperinsulinemia and acanthosis during puberty, a risk for progression to type 2 diabetes and/or hepatic steatosis. Recently, we reported leucine-rich alpha-2-glycoprotein 1 (LRG1) as an adipokine, which levels in sera are positively associated with BMI in humans. LRG1 binds with multiple metabolic organs in vivo, including the liver and pancreas. Deletion of the Lrg1 gene in mice alleviates high-fat diet (HFD) -induced hyperinsulinemia, hepatosteatosis, insulin resistance, and obesity at a young age. Our current study indicates that treating the MIN6 beta-cells with LRG1 was sufficient to trigger insulin secretion both in the absence and presence of glucose in a dose-dependent manner, specifically enhancing the first phase of insulin secretion. We also identified an LRG1 monoclonal antibody that neutralizes LRG1-related stimulation of insulin secretion in MIN6 beta-cells. Serum levels of LRG1 in young mice fed with HFD led to enhanced levels of LRG1 in sera in these mice, which preceded hyperinsulinemia and subsequent increased weight gain. Together, our results reveal that up-regulated LRG1 in circulation could be a causal factor for persistent hyperinsulinemia by directly targeting pancreatic beta-cells to enhance insulin secretion in childhood obesity and a likely biomarker for early childhood hyperinsulinemia and treatment assessments. Understanding the impact of LRG1 on childhood obesity provides critical information to prevent early-stage insulin resistance and type 2 diabetes. Disclosure D.Morales: None. J.Ryu: None. J.L.Lynch: Consultant; Novo Nordisk, Novo Nordisk, Novo Nordisk, Research Support; Beta Bionics, Inc., Beta Bionics, Inc., Beta Bionics, Inc., Jaeb Center for Health Research, Jaeb Center for Health Research, Jaeb Center for Health Research. R.Duggirala: None. L.Q.Dong: None.