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J. Biol. Chem., Vol. 283, Issue 18, 12056-12063, May 2, 2008

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Suppression of Hepatic Glucose Production by Human Neutrophil -Defensins through a Signaling Pathway Distinct from Insulin^*

Hui-Yu Liu, Qu Fan Collins, Fatiha Moukdar, Degen Zhuo, Jianmin Han, Tao Hong, Sheila Collins^¶, and Wenhong Cao^¶1

From the Division of Translational Biology, The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina 27709 and the Departments of Psychiatry and Behavioral Sciences and ^¶Medicine (Endocrinology), Duke University Medical Center, Durham, North Carolina 27710

In this study, we tested the hypothesis that human neutrophil -defensins (HNPs) inhibit hepatic glucose production through a signaling pathway distinct from insulin. The effect of HNP-1 on fasting blood glucose levels and the expression of hepatic gluconeogenic genes was first examined. Using hyperinsulinemic-euglycemic clamps, we determined the effect of HNP-1 on endogenous glucose production, hepatic expression of key gluconeogenic genes and glucose uptake in skeletal muscle in Zucker diabetic fatty rats. In isolated primary hepatocytes, we studied the effect of HNP-1 and -2 on glucose production, expression of gluconeogenic genes, and phosphorylation of Akt, c-Src, and FoxO1. Our results show that HNP-1 reduced blood glucose levels of both normal mice and Zucker diabetic fatty rats predominantly through suppression of hepatic glucose production. HNPs inhibited glycogenolysis and gluconeogenesis in isolated hepatocytes. HNPs also suppressed expression of key gluconeogenic genes including phosphoenoylpyruvate carboxyl kinase and glucose-6-phosphatase. To investigate the mechanism, we found that HNPs stimulated phosphorylation of Akt and FoxO1 without activating IRS1. Nevertheless, HNPs activated c-Src. Blockade of c-Src activity with either a chemical inhibitor PP2 or an alternative inhibitor CSK prevented the inhibitory effect of HNPs on gluconeogenesis. Together, our results support the hypothesis that HNPs can suppress hepatic glucose production through an intracellular mechanism distinct from the classical insulin signaling pathway.

Received for publication, February 7, 2008 , and in revised form, February 29, 2008.

^* This work was supported by an Investigator Development Fund from the Hamner Institutes for Health Sciences (to W. C.), American Heart Association Grant SDG-0530244N (to W. C.), National Institutes of Health Grant R01DK076039 (to W. C.), and funds from the American Diabetes Association (to S. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom should be addressed: Division of Translational Biology, The Hamner Institutes for Health Sciences, 6 Davis Dr., Research Triangle Park, NC 27709. E-mail: wcao{at}thehamner.org.

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