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Hepatic Insulin Resistance Is Not Pathway Selective in Humans With Nonalcoholic Fatty Liver Disease.

Citation
Horst, K. W. T., et al. “Hepatic Insulin Resistance Is Not Pathway Selective In Humans With Nonalcoholic Fatty Liver Disease.”. Diabetes Care, pp. 489-498.
Center Yale University
Author Kasper W Ter Horst, Daniel F Vatner, Dongyan Zhang, Gary W Cline, Mariette T Ackermans, Aart J Nederveen, Joanne Verheij, Ahmet Demirkiran, Bart A van Wagensveld, Geesje M Dallinga-Thie, Max Nieuwdorp, Johannes A Romijn, Gerald I Shulman, Mireille J Serlie
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 ( = 16) or without ( = 15) NAFLD and assessed ) insulin-mediated regulation of hepatic and peripheral glucose metabolism using hyperinsulinemic-euglycemic clamps with [6,6-H]glucose, ) fasting and carbohydrate-driven hepatic DNL using deuterated water (HO), and ) 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 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.

Year of Publication
2021
Journal
Diabetes care
Volume
44
Issue
2
Number of Pages
489-498
Date Published
02/2021
ISSN Number
1935-5548
DOI
10.2337/dc20-1644
Alternate Journal
Diabetes Care
PMID
33293347
PMCID
PMC7818337
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