title: Suppression of hepatic glucose production by human neutrophil alpha-defensins through a signaling pathway distinct from insulin.
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.
authors.affiliation: Division of Translational Biology, The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina 27709, USA.
authors.forename: Hui-Yu
authors.initials: HY
authors.lastname: Liu
authors.forename: Qu Fan
authors.initials: QF
authors.lastname: Collins
authors.forename: Fatiha
authors.initials: F
authors.lastname: Moukdar
authors.forename: Degen
authors.initials: D
authors.lastname: Zhuo
authors.forename: Jianmin
authors.initials: J
authors.lastname: Han
authors.forename: Tao
authors.initials: T
authors.lastname: Hong
authors.forename: Sheila
authors.initials: S
authors.lastname: Collins
authors.forename: Wenhong
authors.initials: W
authors.lastname: Cao
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D045744:Cell Line, Tumor; D002469:Cell Separation; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005943:Gluconeogenesis / Q000187:drug effects / Q000235:genetics; D005947:Glucose / Q000096:biosynthesis*; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism; D051381:Rats; D011924:Rats, Zucker; D015398:Signal Transduction / Q000187:drug effects*; D014158:Transcription, Genetic / Q000187:drug effects; D023084:alpha-Defensins / Q000494:pharmacology*
chemical_list: D001786:Blood Glucose; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D007328:Insulin; D023084:alpha-Defensins; C406413:human neutrophil peptide 1; C406416:human neutrophil peptide 2; D016392:Proto-Oncogene Proteins pp60(c-src); D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose