Central and opposing effects of IGF-I and IGF-binding protein-3 on systemic insulin action.
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 x kg(-1) x 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 (approximately 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.
Muzumdar
Radhika H
RH
Division of Pediatric Endocrinology, Children's Hospital at Montefiore, New York, USA.
Ma
Xiaohui
X
Fishman
Sigal
S
Yang
Xiaoman
X
Atzmon
Gil
G
Vuguin
Patricia
P
Einstein
Francine H
FH
Hwang
David
D
Cohen
Pinchas
P
Barzilai
Nir
N
D000818:Animals; D005947:Glucose / Q000096:biosynthesis; D015309:Glucose Clamp Technique; D006019:Glycolysis / Q000187:drug effects; D007031:Hypothalamus / Q000378:metabolism; D007262:Infusions, Intravenous; D007276:Injections, Intraventricular; D007328:Insulin / Q000502:physiology*; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000008:administration & dosage / Q000235:genetics / Q000502:physiology*; D007334:Insulin-Like Growth Factor I / Q000502:physiology*; D008099:Liver / Q000378:metabolism; D008297:Male; D019913:Nuclear Localization Signals / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley
D007328:Insulin; D018972:Insulin-Like Growth Factor Binding Protein 3; D019913:Nuclear Localization Signals; D007334:Insulin-Like Growth Factor I; D005947:Glucose