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  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  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.
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