Central and opposing effects of IGF-I and IGF-binding protein-3 on systemic insulin action

Radhika H. Muzumdar, Xiaohui Ma, Sigal Fishman, Xiaoman Yang, Gil Atzmon, Patricia Vuguin, Francine H. Einstein, David Hwang, Pinchas Cohen, Nir Barzilai

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44 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2788-2796
Number of pages9
JournalDiabetes
Volume55
Issue number10
DOIs
StatePublished - Oct 1 2006

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ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Muzumdar, R. H., Ma, X., Fishman, S., Yang, X., Atzmon, G., Vuguin, P., Einstein, F. H., Hwang, D., Cohen, P., & Barzilai, N. (2006). Central and opposing effects of IGF-I and IGF-binding protein-3 on systemic insulin action. Diabetes, 55(10), 2788-2796. https://doi.org/10.2337/db06-0318