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Endocrinology Vol. 141, No. 12 4600-4605
Copyright © 2000 by The Endocrine Society

ARTICLES

Glucagon-Like Peptide-1 Induces Cell Proliferation and Pancreatic-Duodenum Homeobox-1 Expression and Increases Endocrine Cell Mass in the Pancreas of Old, Glucose-Intolerant Rats

Riccardo Perfetti, Jie Zhou, Máire E. Doyle and Josephine M. Egan

Cedars-Sinai Medical Center (R.P.), Division of Endocrinology, Los Angeles, California 90048; and Diabetes Section (J.Z., M.E.D., J.M.E.), Gerontology Research Center, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224

Address all correspondence and requests for reprints to: J. M. Egan, M.D., Gerontology Research Center, National Institute on Aging, National Institutes of Health, Box 23, 5600 Nathan Shock Drive, Baltimore, Maryland 21224. E-mail: eganj{at}vax.grc.nia.nih.gov

Glucose homeostasis in mammals is maintained by insulin secretion from the ß-cells of the islets of Langerhans. Type 2 diabetes results either from primary ß-cell failure alone and/or a failure to secrete enough insulin to overcome insulin resistance. Here, we show that continuous infusion of glucagon-like peptide-1 (7–36) (GLP-1; an insulinotropic agent), to young and old animals, had effects on the ß-cell of the pancreas other than simply on the insulin secretory apparatus. Our previous studies on a rodent model of glucose intolerance, the aging Wistar rat, show that a plateau in islet size, insulin content, and ß-cell mass is reached at 13 months, despite a continuing increase in body weight. Continuous sc infusion of GLP-1 (1.5 pM/kg·min), over 5 days, resulted in normal glucose tolerance. Our current results in both young and old rats demonstrate that treatment caused an up-regulation of pancreatic-duodenum homeobox-1 (PDX-1) expression in islets and total pancreas, induced pancreatic cell proliferation, and ß-cell neogenesis. The effects on levels of PDX-1 messenger RNA were abrogated by simultaneous infusion of Exendin (9–39), a specific antagonist of GLP-1. PDX-1 protein levels increased 4-fold in whole pancreata and 6-fold in islets in response to treatment. ß-cell mass increased to 7.2 ± 0.58 from 4.88 ± 0.38 mg, treated vs. control, respectively, P < 0.02. Total pancreatic insulin content also increased from 0.55 ± 0.02 to 1.32 ± 0.11 µg/mg total pancreatic protein. Therefore, GLP-1 would seem to be a unique therapy that can stimulate pancreatic cell proliferation and ß-cell differentiation in the pancreas of rodents.




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