HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Muzumdar, R. H. Articles by Barzilai, N. Search for Related Content PubMed PubMed Citation Articles by Muzumdar, R. H. Articles by Barzilai, N. Social Bookmarking                What's this?

Central and Opposing Effects of IGF-I and IGF-Binding Protein-3 on Systemic Insulin Action

¹ Division of Pediatric Endocrinology, Children’s Hospital at Montefiore, Bronx, New York
² Diabetes Research and Training Center, Department of Medicine, Albert Einstein College of Medicine, Bronx, New York
³ Department of Obstetrics and Gynecology and Women’s Health, Albert Einstein College of Medicine, Bronx, New York
⁴ Mattel Children’s Hospital, University of California at Los Angeles, Los Angeles, California

Address correspondence and reprint requests to Nir Barzilai, MD, Institute for Aging Research, Department of Medicine, Belfer Bldg. #701, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461. E-mail: barzilai{at}aecom.yu.edu

Abbreviations: aCSF, artificial cerebrospinal fluid; ELISA, enzyme-linked immunosorbent assay; FFA, free fatty acid; G-6-P, glucose-6-phosphate; G6Pase, glucose-6-phosphatase; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; HGP, hepatic glucose production; ICV, intracerebroventricular; IGFBP, IGF-binding protein; NLS, nuclear localization signal; PEP, phosphoenolpyruvate; RXR, retinoid X receptor; SA, specific activity; TGO, total glucose output; UDPG, uridine diphosphate glucose

IGF-I is recognized as an insulin sensitizer at the liver and muscle, while recent evidence suggests that IGF-binding protein (IGFBP)-3 acts as an insulin antagonist. As there is a paucity of IGF-I receptors in the liver and as the IGF-IGFBP system in the central nervous system is emerging as physiologically relevant, we examined whether the effects of IGF-I and IGFBP-3 on insulin action are mediated through central mechanisms. Intracerebroventricular (ICV) infusion of IGF-I during the insulin clamp (3 mU · kg^–1 · min^–1) resulted in significant improvement in hepatic insulin action (50%, P < 0.05). In contrast, ICV infusion of IGFBP-3 significantly impaired insulin action at the liver (45% increase in hepatic glucose production, P < 0.01). While IGF-I marginally increased peripheral glucose uptake, IGFBP-3 significantly decreased peripheral glucose uptake (30%, P < 0.01). As the nuclear localization signal mutant IGFBP-3, which has a normal affinity to IGFs but binds other IGFBP-3 partners poorly and fails to normally internalize, has reduced central activity on metabolism, we conclude that the effects of IGFBP-3 on the hypothalamus involve activity mediated by interfacing with other molecules in addition to IGFs. Marked, opposing, and independent physiological effects of IGF-I and IGFBP-3 through central mechanisms may have implications on potential strategies in specific modulation of peripheral insulin action.

CiteULike    Del.icio.us    Digg    Reddit    Technorati    What's this?