Aging is associated with an increased incidence of type 2 diabetes mellitus. It appears that the abnormality in insulin secretion that occurs in the diabetic state is an exaggeration of normal aging processes, coupled with increasing demand for insulin release in the setting of insulin resistance. There is a decrease with age in insulin synthesis and storage of insulin, a decrease in the ability of the beta cells to replicate and a decline in the function of the proteins which sense the prevailing levels of glucose. We showed that these changes could be reversed with continuous administration of GLP-1, an endogenous insulinotropic gut peptide. Insulin mRNA was increased 3-fold in the GLP-1 infused animals. Old rats, which have a lower amount of mRNA (50% lower) for insulin than young rats, had a 3-fold increase in insulin mRNA. The abnormality in insulin secretion with aging was also normalized by this treatment (J. Clin. Invest. 99:2883-2889,1997). Of great interest is the fact that there was an increase in beta cell mass and islet mass after chronic treatment with GLP-1, a naturally occurring peptide produced and released from the gut in response to food (Diabetes 49:741-748, 2000;Endocrinology 141:2000). GLP-1 also caused endocrine cell proliferation. It will require further study to determine the mechanism by which GLP-1 activates islet specific genes and it has implications for treating pancreatitis and type 1 diabetes, also. One specific gene which GLP-1 largely influences is IPF-1 (Islet-pancreatic factor). It is necessary for pancreatic development and in adult beta-cells, it regulates the insulin, glucose transporter 2 and glucokinase genes. We recently reported the GLP-1 plays a major role in regulating levels and translocation to the nucleus of IPF-1 (Endocrinology 140:4904-4907, 1999 and Endocrinology 142:1820-1827, 2001). Using an acinar cell line, AR42J cells, we have shown that the cells can become insulin-producing when treated with GLP-1, and they become responsive to glucose (Diabetes 48: 2358-2366, 1999). We have investigated the intracellular signals involved in the GLP-1-induced differentiation of AR42J cells and found that it is dependent on the continuous activation of the MAP kinase pathway. We also completed studies in duct cells lines to see if the same pathways are involved as well as completed in vivo studies in rodents (Diabetes 49:741-748, 2000). We are continuing our studies on the mechanisms whereby GLP-1 regulates IPF-1. A major thrust of our research is to isolate the epithelial stem cells of the pancreas(which have the capacity to become islets cells, duct cells and acinar cells) and study the factors involved. We are also continuing to study extra pancreatic effects of GLP-1 which lead to a recent publication in Circulation Research (89;445-452, 2001).

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Intramural Research (Z01)
Project #
1Z01AG000214-11
Application #
6663515
Study Section
(LCI)
Project Start
Project End
Budget Start
Budget End
Support Year
11
Fiscal Year
2002
Total Cost
Indirect Cost
Name
Aging
Department
Type
DUNS #
City
State
Country
United States
Zip Code
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
Korosi, J; McIntosh, C H; Pederson, R A et al. (2001) Effect of aging and diabetes on the enteroinsular axis. J Gerontol A Biol Sci Med Sci 56:M575-9
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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