Impact of plasma lipids on glucose homeostasis

Hypertriglyceridemia is associated with reduced glucose tolerance and increased risk of type 2 diabetes, independent of obesity. Proposed mechanisms include lipid-induced insulin resistance and chronic hyperinsulinemia, both of which are early precursors of diabetes. In this thesis, we surveyed and critically discussed the latest evidence on the extent to which plasma triglycerides and their circulating substrates (free fatty acids, or FFA) can impair glucose tolerance in humans and animal models. Then, we designed and conducted an international research project implementing three experimental approaches. First, in a retrospective cross-sectional and longitudinal study, we demonstrated that circulating triglycerides and triglyceride-rich very-low density lipoproteins (VLDL) are independently associated with insulin resistance and model-derived insulin secretion in a large multiethnic cohort of adolescents. Second, direct evidence on the influence of triglyceride availability on the beta cell was collected from in vitro experiments, confirming an acute potentiation of beta cell secretory function in murine and human pancreatic islets exposed to high physiological VLDL concentrations. Finally, the hypothesis that mild hypertriglyceridemia is an important stimulus for beta cell insulin release, even in the context of consensual changes in glucose levels and insulin sensitivity, was thoroughly tested in a cross-over, randomized clinical study in healthy lean individuals. In this study, the acute rise in triglyceride levels induced by an i.v. lipid infusion markedly impaired glucose tolerance during a dual-labeled oral glucose tolerance test (OGTT) by reducing insulin sensitivity and – rather unexpectedly – by increasing oral glucose absorption, compared with a saline infusion. Lipid-induced insulin resistance was partly compensated by higher insulin levels, resulting from lower insulin clearance and enhanced insulin secretion in response to hyperglycemia. In spite of hyperinsulinemia, whole-body glucose disposal was reduced, while endogenous glucose production was more suppressed. Leveraging an integrated translational approach, the clinical and experimental studies reported in this thesis have yielded an improved understanding of the pathogenetic role of excess triglyceride availability in the etiology of type 2 diabetes. Novel insights on the negative metabolic effects of hypertriglyceridemia provide a clear framework for future lipid-related mechanistic studies and may reveal novel tools for risk assessment of diabetes. Furthermore, new treatment opportunities may emerge, as triglycerides are very sensitive to lifestyle and drug interventions and may thus represent an effective target for diabetes prevention and therapy.