Kasper W Ter Horst1, Daniel F Vatner2, Dongyan Zhang2, Gary W Cline2, Mariette T Ackermans3, Aart J Nederveen4, Joanne Verheij5, Ahmet Demirkiran6, Bart A van Wagensveld7, Geesje M Dallinga-Thie8, Max Nieuwdorp8,9,10, Johannes A Romijn9, Gerald I Shulman2,11, Mireille J Serlie12. 1. Department of Endocrinology and Metabolism, Amsterdam University Medical Center, Amsterdam, the Netherlands. 2. Department of Internal Medicine, Yale School of Medicine, New Haven, CT. 3. Department of Clinical Chemistry, Laboratory of Endocrinology, Amsterdam University Medical Center, Amsterdam, the Netherlands. 4. Department of Radiology, Amsterdam University Medical Center, Amsterdam, the Netherlands. 5. Department of Pathology, Amsterdam University Medical Center, Amsterdam, the Netherlands. 6. Department of Surgery, Red Cross Hospital, Beverwijk, the Netherlands. 7. Department of Surgery, OLVG West, Amsterdam, the Netherlands. 8. Department of Vascular Medicine, Amsterdam University Medical Center, Amsterdam, the Netherlands. 9. Internal Medicine, Amsterdam University Medical Center, Amsterdam, the Netherlands. 10. Institute for Cardiovascular Research, Amsterdam University Medical Center, Amsterdam, the Netherlands. 11. Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, CT. 12. Department of Endocrinology and Metabolism, Amsterdam University Medical Center, Amsterdam, the Netherlands m.j.serlie@amsterdamumc.nl.
Abstract
OBJECTIVE: Both glucose and triglyceride production are increased in type 2 diabetes and nonalcoholic fatty liver disease (NAFLD). For decades, the leading hypothesis to explain these paradoxical observations has been selective hepatic insulin resistance wherein insulin drives de novo lipogenesis (DNL) while failing to suppress glucose production. Here, we aimed to test this hypothesis in humans. RESEARCH DESIGN AND METHODS: We recruited obese subjects who met criteria for bariatric surgery with (n = 16) or without (n = 15) NAFLD and assessed 1) insulin-mediated regulation of hepatic and peripheral glucose metabolism using hyperinsulinemic-euglycemic clamps with [6,6-2H2]glucose, 2) fasting and carbohydrate-driven hepatic DNL using deuterated water (2H2O), and 3) hepatocellular insulin signaling in liver biopsy samples collected during bariatric surgery. RESULTS: Compared with subjects without NAFLD, those 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.
OBJECTIVE: Both glucose and triglyceride production are increased in type 2 diabetes and nonalcoholic fatty liver disease (NAFLD). For decades, the leading hypothesis to explain these paradoxical observations has been selective hepatic insulin resistance wherein insulin drives de novo lipogenesis (DNL) while failing to suppress glucose production. Here, we aimed to test this hypothesis in humans. RESEARCH DESIGN AND METHODS: We recruited obese subjects who met criteria for bariatric surgery with (n = 16) or without (n = 15) NAFLD and assessed 1) insulin-mediated regulation of hepatic and peripheral glucose metabolism using hyperinsulinemic-euglycemic clamps with [6,6-2H2]glucose, 2) fasting and carbohydrate-driven hepatic DNL using deuterated water (2H2O), and 3) hepatocellular insulin signaling in liver biopsy samples collected during bariatric surgery. RESULTS: Compared with subjects without NAFLD, those 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.
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