A Defensin Defense Against Diabetes?

The treatment of diabetes has focused on either replacing insulin or increasing sensitivity to it. Noting that plasma concentrations of human neutrophil α-defensins (HNPs) activate Akt, a component of the insulin signaling pathway, and that severe bacterial infections (which are associated with increased plasma HNPs) are often accompanied by hypoglycemia, Liu et al . investigated the role of HNPs in regulating hepatic glucose production. Intravenous administration of HNP-1 decreased blood glucose concentration in both wild-type mice and Zucker diabetic fatty rats [ZDF rats, a model of type II (insulin-resistant) diabetes]. Under conditions in which hyperinsulinemia was maintained in ZDF rats by means of the continuous infusion of insulin, HNP-1 increased the rate of glucose infusion required to maintain euglycemia. Radioisotopic analysis indicated that this depended on a decrease in glucose production, rather than an increase in uptake by skeletal muscle. HNP-1 inhibited pharmacologically stimulated gluconeogenesis and glycogenolysis in isolated mouse hepatocytes and also inhibited the pharmacologically stimulated increase in mRNAs encoding the gluconeogenic enzymes glucose-6-phosphatase and phosphoenoylpyruvate carboxyl kinase (PEPCK) and activation of a gene reporter under the control of the PEPCK promoter. Like insulin, HNP-1 and -2 stimulated phosphorylation of Akt and FoxO1 in hepatoma cells and primary mouse hepatocytes. Whereas insulin stimulated the phosphorylation of IRS1 but not that of c-Src, HNP-1 stimulated the phosphorylation of c-Src but not that of IRS-1. Furthermore, c-Src activation was required for the effects of HNP-1 on glucose-6-phosphatase mRNA expression and gluconeogenesis but not for those of insulin. Thus, the authors conclude that HNP-1 can inhibit hepatic glucose production through a pathway distinct from that mediated by insulin, a finding that may have implications for the treatment of diabetes. H.-Y. Liu, Q. F. Collins, F. Moukdar, D. Zhuo, J. Han, T. Hong, S. Collins, W. Cao, Suppression of hepatic glucose production by human neutrophil α-defensins through a signaling pathway distinct from insulin. J. Biol. Chem . 283 , 12056-12063 (2008). [Abstract] [Full Text]