GLP-1-derived nonapeptide GLP-1(28-36)amide inhibits weight gain and attenuates diabetes and hepatic steatosis in diet-induced obese mice

Regul Pept. 2011 Aug 8;169(1-3):43-8. doi: 10.1016/j.regpep.2011.04.006. Epub 2011 May 4.


Background: The metabolic syndrome is an obesity-associated disease manifested as severe insulin resistance, hyperlipidemia, hepatic steatosis, and diabetes. Previously we proposed that a nonapeptide, FIAWLVKGRamide, GLP-1(28-36)amide, derived from the gluco-incretin hormone, glucagon-like peptide-1 (GLP-1), might have insulin-like actions. Recently, we reported that the nonapeptide appears to enter hepatocytes, target to mitochondria, and suppress glucose production and reactive oxygen species. Therefore, the effects of GLP-1(28-36)amide were examined in diet-induced obese, insulin-resistant mice as a model for the development of human metabolic syndrome.

Methods and results: Three- to 11-week infusions of GLP-1(28-36)amide were administered via osmopumps to mice fed a very high fat diet (VHFD) and to control mice on a normal low fat diet (LFD). Body weight, DXA, energy intake, plasma insulin and glucose, and liver triglyceride levels were assessed. GLP-1(28-36)amide inhibited weight gain, accumulation of liver triglycerides, and improved insulin sensitivity by attenuating the development of fasting hyperglycemia and hyperinsulinemia in mice fed VHFD. GLP-1(28-36)amide had no observable effects in control LFD mice. Surprisingly, the energy intake of peptide-infused obese mice is 25-70% greater than in obese mice receiving vehicle alone, yet did not gain excess weight.

Conclusions: GLP-1(28-36)amide exerts insulin-like actions selectively in conditions of obesity and insulin resistance. The peptide curtails weight gain in diet-induced obese mice in the face of an increase in energy intake suggesting increased energy expenditure. These findings suggest utility of GLP-1(28-36)amide, or a peptide mimetic derived there from, for the treatment of insulin resistance and the metabolic syndrome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Diabetes Mellitus, Type 2 / etiology
  • Diabetes Mellitus, Type 2 / physiopathology
  • Diabetes Mellitus, Type 2 / prevention & control*
  • Dietary Fats
  • Eating / drug effects
  • Fatty Liver / etiology
  • Fatty Liver / physiopathology
  • Fatty Liver / prevention & control*
  • Glucagon-Like Peptide 1 / administration & dosage*
  • Hyperglycemia / prevention & control
  • Hyperinsulinism / prevention & control
  • Insulin Resistance
  • Liver / drug effects
  • Liver / metabolism
  • Liver / pathology
  • Male
  • Metabolic Syndrome / drug therapy
  • Metabolic Syndrome / etiology
  • Metabolic Syndrome / physiopathology
  • Mice
  • Mice, Inbred C57BL
  • Obesity / drug therapy*
  • Obesity / etiology
  • Obesity / physiopathology
  • Peptide Fragments / administration & dosage*
  • Triglycerides / metabolism
  • Weight Gain / drug effects*


  • Dietary Fats
  • Peptide Fragments
  • Triglycerides
  • glucagon-like peptide-1(28-36)amide
  • Glucagon-Like Peptide 1