OVEREXPRESSION OF PARATHYROID HORMONE-RELATED PROTEIN IN THE PANCREATIC-ISLETS OF TRANSGENIC MICE CAUSES ISLET HYPERPLASIA, HYPERINSULINEMIA, AND HYPOGLYCEMIA

Parathyroid hormone-related protein (PTHrP) is produced by the pancrea tic islet. It also has receptors on islet cells, suggesting that it ma y serve a paracrine or autocrine role within the islet. We have develo ped transgenic mice, which overexpress PTHrP in the islet through the use of the rat insulin II promoter (RIP). Glucose homeostasis in these mice is markedly abnormal; RIP-PTHrP mice are hypoglycemic in the pos tprandial and fasting states and display inappropriate hyperinsulinemi a. At the end of a 24-hour fast, blood glucose values are 49 mg/dl in RIP-PTHrP mice, as compared to 77 mg/dl in normal littermates; insulin concentrations at this time are 6.3 and 3.9 ng/ml, respectively, Isle t perifusion studies failed to demonstrate abnormalities in insulin se cretion. In contrast, quantitative islet histomorphometry demonstrates that the total islet number and total islet mass are 2-fold higher in RIP-PTHrP mice than in their normal littermates. PTHrP very likely pl ays a normal physiologic role within the pancreatic islet. This role i s most likely paracrine or autocrine. PTHrP appears to regulate insuli n secretion either directly or indirectly, through developmental or gr owth effects on islet mass. PTHrP may have a role as an agent that enh ances islet mass and/or enhances insulin secretion.