Role of Hyperinsulinemia in NAFLD: Pancreatic Clamp Pilot & Feasibility Study

PROJECT SUMMARY/ABSTRACT Non-alcoholic fatty liver disease (NAFLD) is an under-appreciated complication of lipid dysmetabolism in type 2 diabetes (T2DM). Although it appears that insulin resistance (IR) is a mechanism common to both, the pathophysiology linking it to unhealthy fat accumulation in liver remains unclear. We propose that the hyperinsulinemia that accompanies IR drives the excessive hepatic de novo lipogenesis (DNL) that characterizes IR-associated NAFLD (IR- NAFLD). Our objective, therefore, is to observe the impact of lowering insulin levels on hepatic lipid metabolism in patients with insulin resistance (prediabetic state plus hyperinsulinemia) who are diagnosed with, or are at high risk for, NAFLD; we will accomplish this by using the somatostatin analogue- (octreotide-) assisted "pancreatic clamp" technique. In order to optimize pancreatic clamp conditions, we must first perform a pilot & feasibility study in which we test the effect of identifying and (1) maintaining the basal insulin infusion rate (IIR) ("maintenance hyperinsulinemia", MH protocol) versus (2) a stepwise decline in IIR to 90%, 75%, and 60% ("reduction toward euinsulinemia", RE protocol) of basal. All participants will be tested with both MH and RE protocols, in random order, separated by 2-4 weeks. We will evaluate changes in levels of glucose, insulin, and various lipid-metabolic parameters in order to gauge the insulin dose-glycemic response of insulin lowering and select the appropriate IIR to apply to the RE protocol in the main study.