Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

J. Biol. Chem. 283 (18): 12056-12063

© 2008 by The American Society for Biochemistry and Molecular Biology, Inc.

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

Hui-Yu Liu{ddagger}, Qu Fan Collins{ddagger}, Fatiha Moukdar{ddagger}, Degen Zhuo{ddagger}, Jianmin Han{ddagger}, Tao Hong{ddagger}, Sheila Collins{ddagger}§, , and Wenhong Cao{ddagger}1

{ddagger}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

Abstract: In this study, we tested the hypothesis that human neutrophil {alpha}-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. Revision received 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}

Leucine Facilitates Insulin Signaling through a G{alpha}i Protein-dependent Signaling Pathway in Hepatocytes.
X. Yang, S. Mei, X. Wang, X. Li, R. Liu, Y. Ma, L. Hao, P. Yao, L. Liu, X. Sun, et al. (2013)
J. Biol. Chem. 288, 9313-9320
   Abstract »    Full Text »    PDF »
A Novel Glycerophosphodiester Phosphodiesterase, GDE5, Controls Skeletal Muscle Development via a Non-enzymatic Mechanism.
Y. Okazaki, N. Ohshima, I. Yoshizawa, Y. Kamei, S. Mariggio, K. Okamoto, M. Maeda, Y. Nogusa, Y. Fujioka, T. Izumi, et al. (2010)
J. Biol. Chem. 285, 27652-27663
   Abstract »    Full Text »    PDF »
Hepatic Autophagy Is Suppressed in the Presence of Insulin Resistance and Hyperinsulinemia: INHIBITION OF FoxO1-DEPENDENT EXPRESSION OF KEY AUTOPHAGY GENES BY INSULIN.
H.-Y. Liu, J. Han, S. Y. Cao, T. Hong, D. Zhuo, J. Shi, Z. Liu, and W. Cao (2009)
J. Biol. Chem. 284, 31484-31492
   Abstract »    Full Text »    PDF »
Insulin Is a Stronger Inducer of Insulin Resistance than Hyperglycemia in Mice with Type 1 Diabetes Mellitus (T1DM).
H.-Y. Liu, S. Y. Cao, T. Hong, J. Han, Z. Liu, and W. Cao (2009)
J. Biol. Chem. 284, 27090-27100
   Abstract »    Full Text »    PDF »
Effect of dietary monosodium glutamate on trans fat-induced nonalcoholic fatty liver disease.
K. S. Collison, Z. Maqbool, S. M. Saleh, A. Inglis, N. J. Makhoul, R. Bakheet, M. Al-Johi, R. Al-Rabiah, M. Z. Zaidi, and F. A. Al-Mohanna (2009)
J. Lipid Res. 50, 1521-1537
   Abstract »    Full Text »    PDF »
Prolonged Exposure to Insulin Suppresses Mitochondrial Production in Primary Hepatocytes.
H.-Y. Liu, E. Yehuda-Shnaidman, T. Hong, J. Han, J. Pi, Z. Liu, and W. Cao (2009)
J. Biol. Chem. 284, 14087-14095
   Abstract »    Full Text »    PDF »
Inhibition of Gluconeogenesis in Primary Hepatocytes by Stromal Cell-derived Factor-1 (SDF-1) through a c-Src/Akt-dependent Signaling Pathway.
H.-Y. Liu, G.-B. Wen, J. Han, T. Hong, D. Zhuo, Z. Liu, and W. Cao (2008)
J. Biol. Chem. 283, 30642-30649
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882