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

Metabolic dysfunction-associated fatty liver disease (MAFLD) is an under-appreciated complication of lipid dysmetabolism in the insulin resistance (IR) that underlies type 2 diabetes (T2DM). We propose that the hyperinsulinemia that accompanies IR drives the excessive hepatic de novo lipogenesis (DNL) that characterizes MAFLD. Our objective is therefore to observe the impact of lowering insulin levels on DNL in patients with IR (prediabetic state plus hyperinsulinemia) by using the somatostatin analogue- (octreotide-) assisted "pancreatic clamp" technique. To optimize clamp conditions, we must first perform a pilot & feasibility study in which we assess maintaining hyperinsulinemia (MH protocol) at roughly endogenous levels versus a stepwise decrease in insulin levels by 10%, 25%, and 40% ("reduction toward euinsulinemia", RE protocol). 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 insulin infusion rate to apply to the RE protocol in the main study.