We recently described novel regulatory roles for protein histidine phosphorylation of key islet proteins [e.g., nucleoside diphosphate kinase and succinyl thiokinase] in insulin secretion from the islet cell [Diabetologia 44:89-94, 2001 and Arch. Biochem. Biophys. 398:160-169, 2002]. In this context, we also characterized an ATP- and GTP-sensitive, novel protein histidine kinase in isolated cells that catalyzed the histidine phosphorylation of islet [endogenous] proteins as well as exogenously added histone 4 and we implicated this kinase in the activation of islet endogenous G- proteins [Biochem. Pharmacol. 63:2091-2100, 2002]. In the present study, we describe abnormalities in ATP-or GTP-mediated histidine phosphorylation of nucleoside diphosphate kinase in islets derived from the Goto-Kakizaki [GK] rat, a model for non-insulin-dependent diabetes. Further, we provide evidence for a marked reduction in the activities of ATP- or GTP-sensitive histidine kinases in GK rat islets. Based on these observations, we propose that alterations in protein histidine phosphorylation could contribute toward insulin secretory abnormalities demonstrable in the diabetic islet.