• Eva Tomas, Jenna A Wood, Violeta Stanojevic, and Joel F Habener.
• Laboratory of Molecular Endocrinology, Massachusetts General Hospital , Boston, MA 02114, USA.
• Regul. Pept. 2011 Aug 8; 169 (1-3): 43-8.

BackgroundThe 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 ResultsThree- 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.ConclusionsGLP-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.Copyright © 2011 Elsevier B.V. All rights reserved.

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