Glucagon Resistance at the Level of Amino Acid Turnover in Obese Subjects With Hepatic Steatosis.

Abstract

Glucagon secretion is regulated by circulating glucose, but it has turned out that amino acids also play an important role and that hepatic amino acid metabolism and glucagon are linked in a mutual feedback cycle, the liver-α-cell axis. On the basis of this knowledge, we hypothesized that hepatic steatosis might impair glucagon's action on hepatic amino acid metabolism and lead to hyperaminoacidemia and hyperglucagonemia. We subjected 15 healthy lean and 15 obese steatotic male participants to a pancreatic clamp with somatostatin and evaluated hepatic glucose and amino acid metabolism when glucagon was at basal levels and at high physiological levels. The degree of steatosis was evaluated from liver biopsy specimens. Total RNA sequencing of liver biopsy specimens from the obese steatotic individuals revealed perturbations in the expression of genes predominantly involved in amino acid metabolism. This group was characterized by fasting hyperglucagonemia, hyperaminoacidemia, and no lowering of amino acid levels in response to high levels of glucagon. Endogenous glucose production was similar between lean and obese individuals. Our results suggest that hepatic steatosis causes resistance to the effect of glucagon on amino acid metabolism. This results in increased amino acid concentrations and increased glucagon secretion, providing a likely explanation for fatty liver-associated hyperglucagonemia.

• Authors: Malte P Suppli, Jonatan I Bagger, Asger Lund, Mia Demant, Gerrit van Hall, Charlotte Strandberg, Merete J Kønig, Kristoffer Rigbolt, Jill L Langhoff, Nicolai J Wewer Albrechtsen, Jens J Holst, Tina Vilsbøll, Filip K Knop
• Journal: Diabetes (Diabetes) Vol. 69 Issue 6 Pg. 1090-1099 (06 2020) ISSN: 1939-327X [Electronic] United States
• PMID: 31974144 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 by the American Diabetes Association.

Chemical References

• Amino Acids
• Blood Glucose
• Hormones
• Insulin
• Somatostatin
• Glucagon

Topics

• Adult
• Aged
• Aged, 80 and over
• Amino Acids (blood, metabolism)
• Blood Glucose
• Fatty Liver (metabolism)
• Glucagon (metabolism)
• Hormones (pharmacology)
• Humans
• Hyperammonemia (blood)
• Insulin (blood)
• Male
• Middle Aged
• Obesity (metabolism)
• Pancreas (drug effects)
• Somatostatin (pharmacology)