A major thrust of our research is understanding what controls beta cell mass of the pancreas. With age and type 2 diabetes, there is a failure of expansion of beta cell mass. This is possibly due to increased apoptosis of existing beta cells as well as decreased beta cell neogenesis. We have been investigating the properties of GLP-1, a gut hormone, as they relate to insulin release. We found that it upregulates insulin biosynthesis, increases translocation of pdx-1, a transcription factor necessary for maintenance of the beta cell phenotype, and it increases glucokinase protein levels (the essential glucose sensor in beta cells). We also found that it increases beta cell mass in islets of Langerhans. Other investigators demonstrated antiapototic effects of GLP-1 in beta cell lines and whole islets. GLP-1 is a serious candidate to treat type 2 diabetes in the elderly because its insulin-releasing mechanism of action is dependent on the presence of glucose being transported into beta cells. Therefore, hypoglycemia does not develop. A major component of our basic research is investigating how GLP-1 is both antiapoptotic and proneogenic to beta cells of the pancreas. We recently uncovered evidence for the Notch pathway in adult beta cells and its regulation by GLP-1. GLP-1 increases notch translocation to the nucleus of beta cells with a subsequent upregulation of IRS-2, and beta cell growth and differentiation. This does not occur in GLP-1 receptor knockout animals, demonstrating the specificity of the effects of GLP-1. Notch 1 activation, in turn, increases insulin promoter activity and IRS2 protein levels.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Intramural Research (Z01)
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Carlson, Olga D; David, Jehan D; Schrieder, Jessica M et al. (2007) Contribution of nonesterified fatty acids to insulin resistance in the elderly with normal fasting but diabetic 2-hour postchallenge plasma glucose levels: the Baltimore Longitudinal Study of Aging. Metabolism 56:1444-51
Doyle, Maire E; Egan, Josephine M (2007) Mechanisms of action of glucagon-like peptide 1 in the pancreas. Pharmacol Ther 113:546-93
Mager, Donald E; Abernethy, Darrell R; Egan, Josephine M et al. (2004) Exendin-4 pharmacodynamics: insights from the hyperglycemic clamp technique. J Pharmacol Exp Ther 311:830-5
Meneilly, Graydon S; Greig, Nigel; Tildesley, Hugh et al. (2003) Effects of 3 months of continuous subcutaneous administration of glucagon-like peptide 1 in elderly patients with type 2 diabetes. Diabetes Care 26:2835-41
Elahi, Dariush; Muller, Denis C; Egan, Josephine M et al. (2002) Glucose tolerance, glucose utilization and insulin secretion in ageing. Novartis Found Symp 242:222-42; discussion 242-6
Egan, Josephine M; Meneilly, Graydon S; Habener, Joel F et al. (2002) Glucagon-like peptide-1 augments insulin-mediated glucose uptake in the obese state. J Clin Endocrinol Metab 87:3768-73
Zhou, Jie; Pineyro, Marco A; Wang, Xiaolin et al. (2002) Exendin-4 differentiation of a human pancreatic duct cell line into endocrine cells: involvement of PDX-1 and HNF3beta transcription factors. J Cell Physiol 192:304-14
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Vila Petroff, M G; Egan, J M; Wang, X et al. (2001) Glucagon-like peptide-1 increases cAMP but fails to augment contraction in adult rat cardiac myocytes. Circ Res 89:445-52
Wang, X; Zhou, J; Doyle, M E et al. (2001) Glucagon-like peptide-1 causes pancreatic duodenal homeobox-1 protein translocation from the cytoplasm to the nucleus of pancreatic beta-cells by a cyclic adenosine monophosphate/protein kinase A-dependent mechanism. Endocrinology 142:1820-7

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