A Defensin Defense Against Diabetes?

Science Signaling  06 May 2008:
Vol. 1, Issue 18, pp. ec164
DOI: 10.1126/stke.118ec164

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]