The Liver-α-Cell Axis in Health and in Disease.
Diabetes. 2022 Sep 01; 71(9):1852-1861.D

Abstract

Glucagon and insulin are the main regulators of blood glucose. While the actions of insulin are extensively mapped, less is known about glucagon. Besides glucagon's role in glucose homeostasis, there are additional links between the pancreatic α-cells and the hepatocytes, often collectively referred to as the liver-α-cell axis, that may be of importance for health and disease. Thus, glucagon receptor antagonism (pharmacological or genetic), which disrupts the liver-α-cell axis, results not only in lower fasting glucose but also in reduced amino acid turnover and dyslipidemia. Here, we review the actions of glucagon on glucose homeostasis, amino acid catabolism, and lipid metabolism in the context of the liver-α-cell axis. The concept of glucagon resistance is also discussed, and we argue that the various elements of the liver-α-cell axis may be differentially affected in metabolic diseases such as diabetes, obesity, and nonalcoholic fatty liver disease (NAFLD). This conceptual rethinking of glucagon biology may explain why patients with type 2 diabetes have hyperglucagonemia and how NAFLD disrupts the liver-α-cell axis, compromising the normal glucagon-mediated enhancement of substrate-induced amino acid turnover and possibly fatty acid β-oxidation. In contrast to amino acid catabolism, glucagon-induced glucose production may not be affected by NAFLD, explaining the diabetogenic effect of NAFLD-associated hyperglucagonemia. Consideration of the liver-α-cell axis is essential to understanding the complex pathophysiology underlying diabetes and other metabolic diseases.

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Authors+Show Affiliations

Richter MM

Galsgaard KD

Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

Elmelund E

Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

Knop FK

Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark. Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Steno Diabetes Center Copenhagen, Herlev, Denmark.

Suppli MP

Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark.

Holst JJ

Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

Winther-Sørensen M

Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

Kjeldsen SAS

Wewer Albrechtsen NJ

Department of Clinical Biochemistry, Diagnostic Center, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark. Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Department of Clinical Biochemistry, Copenhagen University Hospital-Bispebjerg and Frederiksberg Hospital, Bispebjerg, Denmark.

MeSH

Amino AcidsBlood GlucoseDiabetes Mellitus, Type 2GlucagonGlucoseHepatocytesHumansInsulinNon-alcoholic Fatty Liver Disease

Pub Type(s)

Journal Article

Review

Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

35657688

Citation

Richter, Michael M., et al. "The Liver-α-Cell Axis in Health and in Disease." Diabetes, vol. 71, no. 9, 2022, pp. 1852-1861.

Richter MM, Galsgaard KD, Elmelund E, et al. The Liver-α-Cell Axis in Health and in Disease. Diabetes. 2022;71(9):1852-1861.

Richter, M. M., Galsgaard, K. D., Elmelund, E., Knop, F. K., Suppli, M. P., Holst, J. J., Winther-Sørensen, M., Kjeldsen, S. A. S., & Wewer Albrechtsen, N. J. (2022). The Liver-α-Cell Axis in Health and in Disease. Diabetes, 71(9), 1852-1861. https://doi.org/10.2337/dbi22-0004

Richter MM, et al. The Liver-α-Cell Axis in Health and in Disease. Diabetes. 2022 Sep 1;71(9):1852-1861. PubMed PMID: 35657688.

* Article titles in AMA citation format should be in sentence-case

TY - JOUR T1 - The Liver-α-Cell Axis in Health and in Disease. AU - Richter,Michael M, AU - Galsgaard,Katrine D, AU - Elmelund,Emilie, AU - Knop,Filip K, AU - Suppli,Malte P, AU - Holst,Jens J, AU - Winther-Sørensen,Marie, AU - Kjeldsen,Sasha A S, AU - Wewer Albrechtsen,Nicolai J, PY - 2022/2/25/received PY - 2022/5/19/accepted PY - 2022/6/4/pubmed PY - 2022/8/24/medline PY - 2022/6/3/entrez SP - 1852 EP - 1861 JF - Diabetes JO - Diabetes VL - 71 IS - 9 N2 - Glucagon and insulin are the main regulators of blood glucose. While the actions of insulin are extensively mapped, less is known about glucagon. Besides glucagon's role in glucose homeostasis, there are additional links between the pancreatic α-cells and the hepatocytes, often collectively referred to as the liver-α-cell axis, that may be of importance for health and disease. Thus, glucagon receptor antagonism (pharmacological or genetic), which disrupts the liver-α-cell axis, results not only in lower fasting glucose but also in reduced amino acid turnover and dyslipidemia. Here, we review the actions of glucagon on glucose homeostasis, amino acid catabolism, and lipid metabolism in the context of the liver-α-cell axis. The concept of glucagon resistance is also discussed, and we argue that the various elements of the liver-α-cell axis may be differentially affected in metabolic diseases such as diabetes, obesity, and nonalcoholic fatty liver disease (NAFLD). This conceptual rethinking of glucagon biology may explain why patients with type 2 diabetes have hyperglucagonemia and how NAFLD disrupts the liver-α-cell axis, compromising the normal glucagon-mediated enhancement of substrate-induced amino acid turnover and possibly fatty acid β-oxidation. In contrast to amino acid catabolism, glucagon-induced glucose production may not be affected by NAFLD, explaining the diabetogenic effect of NAFLD-associated hyperglucagonemia. Consideration of the liver-α-cell axis is essential to understanding the complex pathophysiology underlying diabetes and other metabolic diseases. SN - 1939-327X UR - https://www.unboundmedicine.com/medline/citation/35657688/The_Liver_ DB - PRIME DP - Unbound Medicine ER -

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The Liver-α-Cell Axis in Health and in Disease.Diabetes. 2022 Sep 01; 71(9):1852-1861.D