1186-P: Mechanisms of Glucose Intolerance Induced by Excess Triglycerides and Free Fatty Acids

Chronic hypertriglyceridemia is associated with reduced glucose tolerance. Whether this association is mediated by triglycerides or free fatty acids (FFA) and which mechanisms are involved is unclear. To examine the effect of excess triglycerides alone or combined with FFA, two matched groups of healthy volunteers underwent 5h IV infusions of either saline or Intralipid without (n=12) or with heparin (I+H; n=10), during which 3h oral glucose tolerance tests (OGTT) were performed. Plasma triglycerides reached similar high-physiological levels during both lipid infusions (~2.5 mmol/L) while FFAs were markedly higher during I+H (AUC 249 [130] vs. 77 [20] mmol/L, p=0.0001). At baseline, Intralipid reduced insulin clearance while I+H increased insulin secretion and reduced insulin sensitivity and clearance. Both lipid infusions impaired glucose tolerance. Intralipid inhibited glucose-stimulated insulin secretion (i.e., β-cell glucose sensitivity), stimulated potentiation, and reduced insulin sensitivity and clearance, while I+H induced a greater impairment in insulin sensitivity but enhanced the dynamic component of insulin secretion (i.e., β-cell rate sensitivity). Acute hypertriglyceridemia impairs glucose tolerance in healthy subjects by reducing insulin sensitivity and β-cell glucose sensitivity. A concomitant increase in FFA further reduces insulin sensitivity while enhancing β-cell function. Disclosure D. Trico: None. B. D. Astiarraga: None. M. Seghieri: None. A. Mengozzi: None. S. Baldi: None. A. Mari: Research Support; Self; Eli Lilly and Company. A. Natali: None. Funding European Foundation for the Study of Diabetes