Impaired glucose tolerance in mice lacking cellular prion protein.

Objectives: We previously demonstrated that the expression of cellular prion protein (PrPC) in islet β-cells is suppressed in hyperglycemic rats suggesting a major role for PrPC in blood glucose regulation. To further characterize the function of PrPC in glucose homeostasis, we studied glucoregulation in PrPC knockout (PrPC KO) mice. Methods: Glucose tolerance, insulin secretion, and insulin sensitivity were analyzed to assess glucoregulation in Zrch I PrPC KO and the C57BL/6 (control) mice. Immunohistochemistry and morphometry were used to measure β-cell mass. Results: Male PrPC KO mice had significantly increased blood glucose concentration 60, 120, and 180 minutes after intraperitoneal injection of glucose compared with C57BL/6 mice. Female PrPC KO mice showed a less pronounced phenotype of glucose intolerance. Evaluation of β-cell mass, insulin and proinsulin deficiency, and insulin resistance in male mice revealed essentially no difference between PrPC KO and control mice. The only exception was an increase in serum insulin concentration in male PrPC KO mice 5 minutes after glucose injection. Conclusions: This report is the first to show that PrPC in β-cells is involved in glucoregulation. A further understanding of the role of PrPC in regulating β-cell function will provide valuable insight into the mechanisms of blood glucose regulation.