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Regulation of hepatic glucose metabolism in health and disease

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

Abstract

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.

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Figure 1: Control of hepatic gluconeogenesis.
Figure 2: Control of hepatic glycogen metabolism.
Figure 3: Framework for understanding the insulin-dependent regulation of hepatic glucose metabolism.
Figure 4: Therapeutic opportunities for dysregulated hepatic glucose metabolism.

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Acknowledgements

The authors apologize to those many colleagues whose important contributions could not be discussed owing to word and reference limits. The authors thank A.K. Madiraju for helpful comments. M.C.P. acknowledges grant support from the US National Institutes of Health (NIH; grants F30 DK-104596 and T32 GM-007205). D.F.V. acknowledges grant support from the NIH (grant K23 DK-102874). G.I.S. acknowledges grant support from the NIH (grants R01 DK40936, R01 DK113984 and P30 DK045735).

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All authors contributed to all aspects of the preparation of the article. The order of authorship and contribution is M.C.P., D.F.V. and G.I.S.

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Correspondence to Gerald I. Shulman.

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M.C.P. and D.F.V. declare no competing interests. G.I.S. serves on scientific advisory boards for Merck, Novo Nordisk, Celgene, Aegerion and AstraZeneca, receives investigator-initiated support from Gilead Sciences, Inc., and is an inventor on Yale patents for liver-targeted mitochondrial uncoupling agents for the treatment of NAFLD, NASH, type 2 diabetes and related metabolic disorders.

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Glossary

Hyperinsulinaemic–euglycaemic clamp technique

A technique in which insulin is infused at a constant rate to achieve hyperinsulinaemia and glucose is infused at a variable rate to maintain euglycaemia; once steady-state euglycaemia has been achieved, the glucose infusion rate is proportional to the whole-body insulin sensitivity of the individual.

Pyruvate tolerance test

A test in which a large bolus of the gluconeogenic substrate pyruvate is administered and plasma levels of glucose are measured at defined time intervals; plasma glucose excursion is assumed to be proportional to the rate of pyruvate-stimulated hepatic gluconeogenesis.

Pancreoprivic diabetes mellitus

Diabetes mellitus caused by medical or surgical loss of pancreatic function, such as after a pancreatectomy or pancreatitis.

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Petersen, M., Vatner, D. & Shulman, G. Regulation of hepatic glucose metabolism in health and disease. Nat Rev Endocrinol 13, 572–587 (2017). https://doi.org/10.1038/nrendo.2017.80

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