(P06-021-23) Glucose and Lipid Metabolism in People With ANGPTL3 Loss-of-Function Gene Mutation: Multi-Tracer Kinetic Studies

Objectives: Increased plasma lipids are a major risk factor for atherosclerosis and associated with insulin resistance and type 2 diabetes. Angiopoietin-related protein 3 (ANGPTL3) is a circulating protein that inhibits lipoprotein lipase and can therefore regulate plasma lipid concentrations. The goal of the study is to evaluate the effect of ANGPTL3 deficiency on insulin sensitivity, β-cell function, and basal and postprandial lipid and glucose metabolism in in people.

Methods: Three participants with complete ANGPTL3 deficiency (S17X/E129X mutations) and five control participants who were matched on sex, adiposity, and health status with the ANGPTL3-deficient participants completed a two-stage hyperinsulinemic-euglycemic clamp procedure and a 24h metabolic profiling study in conjunction with stable-isotope labeled tracer infusions and ingestion to evaluate multi-organ (liver, muscle, adipose tissue) insulin sensitivity, β-cell function (defined as insulin secretion rate in relationship to plasma glucose during basal conditions and postprandially), triglyceride-rich lipoprotein (TRL) particle and triglyceride (TG) turnover, and 24-h plasma glucose and lipid homeostasis

Results: Multi-organ insulin sensitivity, β-cell function and 24-hour plasma glucose, insulin, and free-fatty acid concentrations were not different between the ANGPTL3 deficient and control participants. The ANGPTL3 deficient, compared with the control group, had much lower basal and postprandial total plasma and TRL-TG concentrations and much faster (more than three-fold) TRL-TG and apolipoprotein B turnover (all P < 0.0001).

Conclusions: Loss of function of the ANGPTL3 protein reduces plasma lipid concentrations due to markedly faster lipid clearance from the circulation. Insulin sensitivity and β-cell function are not affected by ANGPTL3 deficiency, despite marked alterations in plasma lipid turnover and concentration.

Funding Sources: Regeneron; NIH (Program Project Grants)