REVIEWThe feedback cycles between glucose, amino acids and lipids and alpha cell secretion and their role in metabolic fatty liver diseaseWinther-Sørensen, Mariea,b; Holst, Jens J.a; Wewer Albrechtsen, Nicolai J.a,b,c Author Information aDepartment of Biomedical Sciences bNNF Center for Protein Research, Faculty of Health and Medical Sciences cDepartment for Clinical Biochemistry, Bispebjerg and Frederiksberg Hospital, University of Copenhagen, Copenhagen, Denmark Correspondence to Marie Winther-Sørensen, Department of Biomedical Sciences and Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 9, 2200 Copenhagen N, Denmark. Tel: +45 22994907; e-mail: [email protected] Current Opinion in Lipidology: November 14, 2022 - Volume - Issue - 10.1097/MOL.0000000000000857 doi: 10.1097/MOL.0000000000000857 Buy PAP Metrics Abstract Purpose of review Glucagon increases hepatic glucose production and in patients with metabolic diseases, glucagon secretion is increased contributing to diabetic hyperglycemia. This review explores the role of amino acids and lipids in the regulation of glucagon secretion and how it may be disturbed in metabolic diseases such as obesity and metabolic associated fatty liver disease (MAFLD). Recent findings Human and animal studies have shown that MAFLD is associated with glucagon resistance towards amino acid catabolism, resulting in elevated plasma levels of amino acids. A recent clinical study showed that MAFLD is also associated with glucagon resistance towards lipid metabolism. In contrast, MAFLD may not decrease hepatic sensitivity to the stimulatory effects of glucagon on glucose production. Summary Elevated plasma levels of amino acids and lipids associated with MAFLD may cause diabetogenic hyperglucagonemia. MAFLD and glucagon resistance may therefore be causally linked to hyperglycemia and the development of type 2 diabetes. Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.