Activation of Protein Kinase C-ζ in Pancreatic β-Cells In Vivo Improves Glucose Tolerance and Induces β-Cell Expansion via mTOR Activation

Abstract

TG mice displayed increased plasma insulin, improved glucose tolerance, and enhanced insulin secretion with concomitant upregulation of islet insulin and glucokinase expression. In addition, TG mice displayed increased β-cell proliferation, size, and mass compared with wild-type littermates. The increase in β-cell proliferation was associated with upregulation of cyclins D1, D2, D3, and A and downregulation of p21. Phosphorylation of D-cyclins, known to initiate their rapid degradation, was reduced in TG mouse islets. Phosphorylation/inactivation of GSK-3β and phosphorylation/activation of mTOR, critical regulators of D-cyclin expression and β-cell proliferation, were enhanced in TG mouse islets, without changes in Akt phosphorylation status. Rapamycin treatment in vivo eliminated the increases in β-cell proliferation, size, and mass; the upregulation of cyclins Ds and A in TG mice; and the improvement in glucose tolerance-identifying mTOR as a novel downstream mediator of PKC-ζ-induced β-cell replication and expansion in vivo. CONCLUSIONS PKC:-ζ, through mTOR activation, modifies the expression pattern of β-cell cycle molecules leading to increased β-cell replication and mass with a concomitant enhancement in β-cell function. Approaches to enhance PKC-ζ activity may be of value as a therapeutic strategy for the treatment of diabetes.