Joel Habener, M.D.

Hormonal Regulation of Metabolism

Our studies are focused on the biology of the glucagon-like peptides (GLP’s), and sub-peptides derived therefrom. The GLP’s consist of a family of small peptides that function in the regulation of nutrient metabolism. Glucagon, GLP-1, and GLP-2 are all produced by enzymatic cleavages of a prohormone (proglucagon) expressed in the alpha cells of the pancreas, the intestinal L-cells, and the brain [1] GLP-1 mimetics effectively treat diabetes as they not only stimulate glucose-dependent insulin secretion but also exert cytoprotective and pro-proliferative actions on beta cells. Although in normal physiological conditions the alpha cells produce glucagon from proglucagon, we have discovered that injuries of beta cells, such as glucotoxicity (type 2 diabetes) and cytokines (type 1 diabetes) result in the production of GLP-1 by the alpha cells [2] Since GLP-1 promotes beta cell growth and survival, the local intra-islet production of GLP-1 in response to beta cell injuries provides a potential paracrine mechanism for the regeneration and restoration of beta cell functions. We are also exploring the role of the chemokine CXCL12, known as stromal-cell derived factor-1 (SDF-1), as a factor secreted locally within islets in response to beta cell injury that acts on adjacent alpha cells, and triggers the production of GLP-1.

The observations that the endopeptidase neprilysin, produced by adipose tissue and present in the circulation, cleaves GLP-1 within the C-terminal domain to produce two small amphiphilic peptides (five and nine amino acids), prompted us to test the peptides for bioactivities [3]. The administration of the peptides to obese mice inhibits weight gain, reduces body fat mass, and increases basal energy expenditure without change in energy (food) intake or physical activity [4, 5]. Further, the peptides reduce glycemia and increase insulin sensitivity. Notably, the actions of the peptides occur independently of the GLP-1 receptor. The administration of the pentapeptide into hyperglycemic dogs demonstrates a pronounced stimulation of whole body glucose disposal [6]. Further, the nonapeptide (and pentapeptide) protect pancreatic beta cells against oxidative stress-induced cell death [7]. We are examining the mechanism(s) of action of these peptides on hepatocytes [8] and skeletal muscle ex vivo and in vivo and find that they exert effects on mitochondrial energy production. The pentapeptide stimulates energy dissipation, lowers oxidative potential (oxidative stress), activates the energy sensors AMP kinase and sirtuin, increases fatty acid oxidation, and suppresses hepatic glucose production. We are currently investigating the peptides as potential therapies for obesity and diabetes based on their energy dissipation, fat burning, and insulin-sensitizing actions, properties that distinguish the peptides from those of GLP-1 receptor agonists.

References

1. Habener JF, Stanojevic V. Alpha-cell role in beta-cell generation and regeneration. Islets. 2012 May-Jun;4(3):188-98. PMID: 22847495.

2. Liu Z, Stanojevic V, Avadhani S, Yano T, Habener JF. Stromal cell-derived factor-1 (SDF-1)/chemokine (C-X-C motif) receptor 4 (CXCR4) axis activation induces intra-islet glucagon-like peptide-1 (GLP-1) production and enhances beta cell survival. Diabetologia. 2011 Aug;54(8):2067-76. PMID: 21567300.

3. Tomas E, Habener JF. Insulin-like actions of glucagon-like peptide-1: a dual receptor hypothesis. Trends Endocrinol Metab. 2010 Feb;21(2):59-67 PMID: 20018525.

4. Tomas E, Wood JA, Stanojevic V, Habener JF. 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. PMID: 21549160.

5. Tomas E, Stanojevic V, Laudone R, Everill P, Bachovchin W, Habener JF. GLP-1-derived pentapeptide GLP-1(32-36)amide attenuates the development of obesity, diabetes, hepatic steatosis, and increases energy expenditure in diet-induced obese mice Diabetes 2012;61 Suppl:1915-P.

7. Liu Z, Stanojevic V, Brindamour LJ, Habener JF. GLP1-derived nonapeptide GLP1(28-36)amide protects pancreatic β-cells from glucolipotoxicity. J Endocrinol. 2012 May;213(2):143-54. PMID: 22414687.

8. Tomas E, Stanojevic V, Habener JF. 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. PMID: 21256872

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