Journal Article

Regulation of hepatic glucose metabolism in health and disease

Vatner, Daniel F., Petersen, Max C., Shulman, Gerald I.

2017

Overview

Key Points Hepatic glucose metabolism encompasses several catabolic and anabolic fluxes that have distinct modes of hepatocyte-autonomous (direct) and hepatocyte- non-autonomous (indirect) regulatory mechanisms Acute regulation of hepatic glucose metabolism is achieved through changes in protein phosphorylation, substrate availability, allostery and redox state Chronic regulation of hepatic glucose metabolism occurs through transcriptional mechanisms and the development of insulin resistance Acute suppression of hepatic gluconeogenesis by insulin is largely an indirect effect that is mediated mostly through the suppression of adipose lipolysis, which reduces delivery of nonesterified fatty acids and glycerol to the liver The major direct effect of insulin on hepatic glucose metabolism is the acute regulation of hepatic glycogen metabolism; however, hyperglycaemia and hyperinsulinaemia are required to maximally stimulate net hepatic glycogenesis Lipid-induced hepatic insulin resistance, hyperglucagonaemia and excessive adipose lipolysis represent three pathophysiological processes that might be amenable to pharmacological intervention in humans who have impaired hepatic glucose metabolism The balance of catabolic and anabolic glucose fluxes in the liver is crucial for glucose homeostasis and is disturbed in diabetes mellitus. In this Review, the authors discuss progress in our understanding of the regulation of hepatic glucose metabolism and highlight potential therapeutic targets for decreasing hepatic glucose production in T2DM, including lipid-induced hepatic insulin resistance, hyperglucagonaemia and excessive adipose lipolysis. The liver is crucial for the maintenance of normal glucose homeostasis — it produces glucose during fasting and stores glucose postprandially. However, these hepatic processes are dysregulated in type 1 and type 2 diabetes mellitus, and this imbalance contributes to hyperglycaemia in the fasted and postprandial states. Net hepatic glucose production is the summation of glucose fluxes from gluconeogenesis, glycogenolysis, glycogen synthesis, glycolysis and other pathways. In this Review, we discuss the in vivo regulation of these hepatic glucose fluxes. In particular, we highlight the importance of indirect (extrahepatic) control of hepatic gluconeogenesis and direct (hepatic) control of hepatic glycogen metabolism. We also propose a mechanism for the progression of subclinical hepatic insulin resistance to overt fasting hyperglycaemia in type 2 diabetes mellitus. Insights into the control of hepatic gluconeogenesis by metformin and insulin and into the role of lipid-induced hepatic insulin resistance in modifying gluconeogenic and net hepatic glycogen synthetic flux are also discussed. Finally, we consider the therapeutic potential of strategies that target hepatosteatosis, hyperglucagonaemia and adipose lipolysis.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/443/319 / 631/443/319/1642 / 692/163/2743/137 / 692/163/2743/137/773 / 692/698/2741/288 / Care and treatment / Case-Control Studies / Development and progression / Diabetes / Diabetes mellitus / Diabetes mellitus (insulin dependent) / Diabetes mellitus (non-insulin dependent) / Diabetes Mellitus, Type 2 - metabolism / Diabetes Mellitus, Type 2 - physiopathology / Endocrinology / Fasting / Fatty Liver - metabolism / Fatty Liver - physiopathology / Female / Gluconeogenesis / Gluconeogenesis - physiology / Glucose / Glucose - metabolism / Glycogen / Glycolysis / Health aspects / Homeostasis / Humans / Hyperglycemia / Insulin / Insulin Resistance / Lipolysis / Liver - metabolism / Liver diseases / Liver Glycogen - metabolism / Male / Medicine & Public Health / Metabolic regulation / Metabolism / Metformin / Reference Values / review-article / Type 2 diabetes