Hepatic Insulin Resistance Is Not Pathway Selective in Humans With Nonalcoholic Fatty Liver Disease
Research Design and Methods: We recruited obese subjects who met criteria for bariatric surgery with (n=16) or without (n=15) NAFLD and assessed: i) insulin-mediated regulation of hepatic and peripheral glucose metabolism using hyperinsulinemic-euglycemic clamps with [6,6-2H2]glucose, ii) fasting and carbohydrate-driven hepatic DNL using deuterated water (2H2O), and iii) hepatocellular insulin signaling in liver biopsies collected during bariatric surgery.
Results: As compared with subjects without NAFLD, subjects with NAFLD demonstrated impaired insulin-mediated suppression of glucose production and attenuated -not increased- glucose-stimulated/high-insulin lipogenesis. Fructose-stimulated/low-insulin lipogenesis was intact. Hepatocellular insulin signaling, assessed for the first time in humans, exhibited a proximal block in insulin-resistant subjects: signaling was attenuated from the level of the insulin receptor through both glucose and lipogenesis pathways. The carbohydrate-regulated lipogenic transcription factor ChREBP was increased in subjects with NAFLD.Conclusions: Acute increases in lipogenesis in humans with NAFLD are not explained by altered molecular regulation of lipogenesis through a paradoxical increase in lipogenic insulin action; rather, increases in lipogenic substrate availability may be the key.