1820-P: Autonomic Tone Is Necessary for Bile Acid-Induced Hepatic Insulin Resistance

Diabetes and obesity cost the American healthcare system in excess of $322 billion dollars annually. Currently, one of the most effective treatments for obesity and metabolic disorders is bariatric surgery. Bariatric surgery leads to almost immediate metabolic benefits, independent of weight loss. Concurrent with the metabolic benefits, an elevation in systemic bile acids is also detected in these patients. Several investigations posit that the rise in systemic bile acids contributes to, or potentially drives, the beneficial outcomes described in these patients; however, the mechanism and direct effects of increased bile acids must be more thoroughly elucidated. Previous studies indicate that not only does the autonomic nervous system impact insulin action, but it also plays a role in bile acid synthesis and secretion. Specifically, studies in humans show that autonomic blockade in insulin resistant subjects leads to improved insulin sensitivity. Furthermore, in rats, a vagotomy results in increased serum bile acids concentrations. Prior data from our group demonstrates that during hyperinsulinemic-euglycemic clamps, increased circulating bile acids induce hepatic insulin resistance, resulting in a decrease in glucose infusion rates (GIR) (10±3 mg/kg/min) compared to control mice (21±4 mg/kg/min). Together these data led to the hypothesis that bile acids signal indirectly via the nervous system to impair hepatic insulin action. To test this hypothesis, autonomic tone was inhibited by infusion of a ganglionic blocker combined with an infusion of an alpha agonist to maintain blood pressure during clamps. In the presence of ganglionic blockade, bile acids do not induce hepatic insulin resistance. Instead, bile acid-treated mice have an increased GIR (66±3 mg/kg/min) compared to control mice (45±5 mg/kg/min). From these data we conclude that the autonomic nervous system is necessary for elevated systemic bile acids to impair insulin action in lean animals. Disclosure K. Syring: None. N.A. Mignemi: None. O.P. McGuinness: None. Funding National Institutes of Health