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Endocrinology Vol. 143, No. 4 1378-1385
Copyright © 2002 by The Endocrine Society

INSULIN-GLUCAGON-GI PEPTIDES-DIABETES MELLITUS

Targeted Deletion of the PRL Receptor: Effects on Islet Development, Insulin Production, and Glucose Tolerance

Michael Freemark, Isabelle Avril, Don Fleenor, Phyllis Driscoll, Ann Petro, Emmanuel Opara, Will Kendall, Jon Oden, Spencer Bridges, Nadine Binart, Bernadette Breant and Paul A. Kelly

Departments of Pediatrics (M.F., D.F., P.D., J.O.), Cell Biology (M.F., A.P.), and Surgery (E.O., W.K., S.B.), Duke University Medical Center, Durham, North Carolina 27710; Institut National de la Santé et de la Recherche Médicale 344 (N.B., P.A.K.), Necker Faculty of Medicine, Paris 15F-75730, France; and Institut National de la Santé et de la Recherche Médicale 457 (I.A., B.B.), Hopital Robert Debre, Paris F-75019, France

Address all correspondence and requests for reprints to: Dr. Michael Freemark, Department of Pediatrics, Box 3080, Duke University Medical Center, Durham, North Carolina 27710. E-mail: . freem001{at}mc.duke.edu

PRL and placental lactogen (PL) stimulate ß-cell proliferation and insulin gene transcription in isolated islets and rat insulinoma cells, but the roles of the lactogenic hormones in islet development and insulin production in vivo remain unclear. To clarify the roles of the lactogens in pancreatic development and function, we measured islet density (number of islets/cm2) and mean islet size, ß-cell mass, pancreatic insulin mRNA levels, islet insulin content, and the insulin secretory response to glucose in an experimental model of lactogen resistance: the PRL receptor (PRLR)-deficient mouse. We then measured plasma glucose concentrations after ip injections of glucose or insulin. Compared with wild-type littermates, PRLR-deficient mice had 26–42% reductions (P < 0.01) in islet density and ß-cell mass. The reductions in islet density and ß-cell mass were noted as early as 3 wk of age and persisted through 8 months of age and were observed in both male and female mice. Pancreatic islets of PRLR-deficient mice were smaller than those of wild-type mice at weaning but not in adulthood. Pancreatic insulin mRNA levels were 20–30% lower (P < 0.05) in adult PRLR-deficient mice than in wild-type mice, and the insulin content of isolated islets was reduced by 16–25%. The insulin secretory response to ip glucose was blunted in PRLR-deficient males in vivo (P < 0.05) and in isolated islets of PRLR-deficient females and males in vitro (P < 0.01). Fasting blood glucose concentrations in PRLR-deficient mice were normal, but glucose levels after an ip glucose load were 10–20% higher (P < 0.02) than those in wild-type mice. On the other hand, the glucose response to ip insulin was normal. Our observations establish a physiologic role for lactogens in islet development and function.




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