Use of an in Vivo Model System to Investigate Niddm

Egan, J.

Abstract

Age is an independent risk factor for NIDDM. Age is also associated with a decline in insulin secretion. Using 6-cells from Wistar rats from the colony of aged rats at the GRC, we showed that insulin release in response to glucose decreases with age of the donor. This is a result of fewer beta cells releasing insulin as well as less insulin released per cell. We found that mRNA for insulin is preferentially diminished in islets, with glucokinase and glucagon messages unaffected. Therefore, it appears that throughout the lifespan of the rat, insulin message is decreasing. Islets compensate for this by increasing size. But, eventually this compensation becomes inadequate. Therefore, one can envision when a stress is put on the system so more insulin is required, diabetes could result. We are exploring what factors lead to this diminution of insulin message and the possibility that we can prevent or reverse it.

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: National Institute on Aging (NIA)
• Type: Intramural Research (Z01)
• Project #: 1Z01AG000214-03
• Application #: 3767774
• Support Year: 3
• Fiscal Year: 1993

Institution

• Name: National Institute on Aging
• Country: United States

Publications

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