GLP-1-derived nonapeptide GLP-1(28-36)amide targets to mitochondria and suppresses glucose production and oxidative stress in isolated mouse hepatocytes

Regul Pept. 2011 Apr 11;167(2-3):177-84. doi: 10.1016/j.regpep.2011.01.003. Epub 2011 Jan 21.

Abstract

Background: Uncontrolled hepatic glucose production (gluconeogenesis), and glycogenolysis, is a major contributor to the fasting hyperglycemia associated with type 2 diabetes. Here we report the discovery of a C-terminal nonapeptide (FIAWLVKGRamide) derived from GLP-1 that suppresses glucose production and oxidative stress in isolated mouse hepatocytes. The nonapeptide, GLP-1(28-36)amide, was reported earlier to be a major product derived from the cleavage of GLP-1 by the endopeptidase NEP 24.11.

Methods and results: Hepatocytes were isolated from the livers of normal and diet-induced obese mice. We find that the GLP-1(28-36)amide nonapeptide rapidly enters isolated mouse hepatocytes by GLP-1 receptor-independent mechanisms, and targets to mitochondria where it inhibits gluconeogenesis and oxidative stress.

Conclusions: These findings suggest that GLP-1 not only acts on a cell surface G-protein coupled receptor activating kinase-regulated signaling pathways, but a small C-terminal peptide derived from GLP-1 also enters cells, targets mitochondria, and exerts insulin-like actions by modulating oxidative phosphorylation. GLP-1(28-36)amide, or a peptide mimetic derived there from, might prove to be a useful treatment for fasting hyperglycemia and metabolic syndrome in type 2 diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Female
  • Glucagon-Like Peptide 1 / metabolism
  • Glucagon-Like Peptide 1 / pharmacology*
  • Glucagon-Like Peptide-1 Receptor
  • Glucose / biosynthesis*
  • Hepatocytes / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Obese
  • Mitochondria / drug effects*
  • Mitochondria / metabolism
  • Oxidative Stress / drug effects*
  • Oxidative Stress / physiology
  • Peptide Fragments / metabolism
  • Peptide Fragments / pharmacology*
  • Receptors, Glucagon / metabolism

Substances

  • Glp1r protein, mouse
  • Glucagon-Like Peptide-1 Receptor
  • Peptide Fragments
  • Receptors, Glucagon
  • glucagon-like peptide-1(28-36)amide
  • Glucagon-Like Peptide 1
  • Glucose