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It is well known that glucagon acts to stimulate glycogenolysis and gluconeogenesis. In addition to this, glucagon also regulates amino acid metabolism and ureagenesis and has an effect on hepatic fat metabolism.

The different roles of glucagon in the metabolism makes the hepatic glucagon resistance, found in NAFLD and NASH patients, a highly interesting and important player to study. Hepatic glucagon resistance has been associated with an increase in liver lipid infiltration, and moreover NAFLD/NASH patients have elevated glucagon levels independently of diabetes1,2. In preclinical studies it has been shown that by reducing the glucagon receptor signaling, the lipid content of the liver is increased3. Moreover, the disturbed hepatic glucagon signaling in the liver leads to an increase in plasma amino acids, which subsequently give rise to hypersecretion of glucagon and hyperplasia of alpha-cells in an liver – pancreas feedback loop4,5.

No pharmacological therapies are so far approved for NAFLD treatment, however GLP-1R/glucagon receptor dual agonists are currently under investigation6,7.

As stated by Wewer Albrechtsen and colleagues in 2018- “Observations of elevated fasting concentrations of plasma glucagon levels in humans should therefore direct attention to the​ functional status of the liver”8.


1.             Charbonneau, A., Couturier, K., Gauthier, M.-S. & Lavoie, J.-M. Evidence of Hepatic Glucagon Resistance Associated with Hepatic Steatosis: Reversal Effect of Training. Int. J. Sports Med. 26, 432–441 (2005).

2.             Junker, A. E., Gluud, L., Holst, J. J., Knop, F. K. & Vilsbøll, T. Diabetic and nondiabetic patients with nonalcoholic fatty liver disease have an impaired incretin effect and fasting hyperglucagonaemia. J. Intern. Med. 279, 485–93 (2016).

3.             Ali, S. & Drucker, D. J. Benefits and limitations of reducing glucagon action for the treatment of type 2 diabetes. Am. J. Physiol. Metab. 296, E415–E421 (2009).

4.             Solloway, M. J. et al. Glucagon Couples Hepatic Amino Acid Catabolism to mTOR-Dependent Regulation of α-Cell Mass. Cell Rep. 12, 495–510 (2015).

5.            Holst, J. J., Wewer Albrechtsen, N. J., Pedersen, J. & Knop, F. K. Glucagon and Amino Acids Are Linked in a Mutual Feedback Cycle: The Liver-α-Cell Axis. Diabetes 66, 235–240 (2017).

6.            Wewer Albrechtsen, N. J. Glucagon receptor signaling in metabolic diseases. Peptides 100, 42–47 (2018).

7.             Seghieri, M. et al. Future Perspectives on GLP-1 Receptor Agonists and GLP-1/glucagon Receptor Co-agonists in the Treatment of NAFLD. Front. Endocrinol. (Lausanne). 9, 649 (2018).

8.            Wewer Albrechtsen, N. J. et al. Evidence of a liver–alpha cell axis in humans: hepatic insulin resistance attenuates relationship between fasting plasma glucagon and glucagonotropic amino acids. Diabetologia 61, 671–680 (2018).