GLP-1 (9-36) amide metabolite suppression of glucose production in isolated mouse hepatocytes

Horm Metab Res. 2010 Aug;42(9):657-62. doi: 10.1055/s-0030-1253421. Epub 2010 May 28.


The glucoincretin hormone glucagon-like peptide-1 (GLP-1) augments glucose-stimulated insulin secretion and is in use as an effective treatment for diabetes. However, after its secretion from the intestine, the insulinotropic GLP-1 (7-36) amide hormone is rapidly inactivated by enzymatic cleavage by the diaminopeptidyl peptidase-4 giving rise to GLP-1 (9-36) amide. Inasmuch as most of the circulating GLP-1 is in the form of the metabolite GLP-1 (9-36) amide it has been suggested that it has insulin-like actions on peripheral insulin-sensitive tissues. In earlier studies, infusions of GLP-1 (9-36) amide in obese insulin-resistant subjects showed a marked suppression of hepatic glucose production. However, it remained uncertain whether the effects on glucose production were due to direct effects on hepatocytes, involved central or portal vein-mediated actions, or were mediated by insulin secretion. Here we show that GLP-1 (9-36) amide directly suppresses glucose production in isolated mouse hepatocytes ex vivo independent of the GLP-1 receptor. These findings support direct insulinomimetic actions of the GLP-1 metabolite on gluconeogenesis in hepatocytes that are independent of insulin action and the GLP-1 receptor, and suggest that GLP-1 (9-36) amide-based peptides might present a novel therapy for the treatment of excessive hepatic glucose production in individuals with insulin-resistant diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amides / metabolism*
  • Animals
  • Cell Separation
  • Gene Expression Regulation / drug effects
  • Glucagon / pharmacology
  • Glucagon-Like Peptide 1 / metabolism*
  • Glucagon-Like Peptide 1 / pharmacology
  • Glucagon-Like Peptide-1 Receptor
  • Gluconeogenesis / drug effects
  • Gluconeogenesis / genetics
  • Glucose / biosynthesis*
  • Glucose-6-Phosphatase / metabolism
  • Hepatocytes / drug effects
  • Hepatocytes / enzymology
  • Hepatocytes / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Phosphoenolpyruvate Carboxykinase (GTP) / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, Glucagon / genetics
  • Receptors, Glucagon / metabolism


  • Amides
  • Glp1r protein, mouse
  • Glucagon-Like Peptide-1 Receptor
  • RNA, Messenger
  • Receptors, Glucagon
  • Glucagon-Like Peptide 1
  • Glucagon
  • Glucose-6-Phosphatase
  • Phosphoenolpyruvate Carboxykinase (GTP)
  • Glucose