The insulin-like growth factor-1 receptor is a negative regulator of nitric oxide bioavailability and insulin sensitivity in the endothelium.

Abstract

OBJECTIVE:

In mice, haploinsufficiency of the IGF-1 receptor (IGF-1R(+/-)), at a whole-body level, increases resistance to inflammation and oxidative stress, but the underlying mechanisms are unclear. We hypothesized that by forming insulin-resistant heterodimers composed of one IGF-1Rαβ and one insulin receptor (IR), IRαβ complex in endothelial cells (ECs), IGF-1R reduces free IR, which reduces EC insulin sensitivity and generation of the antioxidant/anti-inflammatory signaling radical nitric oxide (NO).

RESEARCH DESIGN AND METHODS:

Using a number of complementary gene-modified mice with reduced IGF-1R at a whole-body level and specifically in EC, and complementary studies in EC in vitro, we examined the effect of changing IGF-1R/IR stoichiometry on EC insulin sensitivity and NO bioavailability.

RESULTS:

IGF-1R(+/-) mice had enhanced insulin-mediated glucose lowering. Aortas from these mice were hypocontractile to phenylephrine (PE) and had increased basal NO generation and augmented insulin-mediated NO release from EC. To dissect EC from whole-body effects we generated mice with EC-specific knockdown of IGF-1R. Aortas from these mice were also hypocontractile to PE and had increased basal NO generation. Whole-body and EC deletion of IGF-1R reduced hybrid receptor formation. By reducing IGF-1R in IR-haploinsufficient mice we reduced hybrid formation, restored insulin-mediated vasorelaxation in aorta, and insulin stimulated NO release in EC. Complementary studies in human umbilical vein EC in which IGF-1R was reduced using siRNA confirmed that reducing IGF-1R has favorable effects on NO bioavailability and EC insulin sensitivity.

CONCLUSIONS:

These data demonstrate that IGF-1R is a critical negative regulator of insulin sensitivity and NO bioavailability in the endothelium.

• Authors: Afroze Abbas, Helen Imrie, Hema Viswambharan, Piruthivi Sukumar, Adil Rajwani, Richard M Cubbon, Matthew Gage, Jessica Smith, Stacey Galloway, Nadira Yuldeshava, Matthew Kahn, Shouhong Xuan, Peter J Grant, Keith M Channon, David J Beech, Stephen B Wheatcroft, Mark T Kearney
• Journal: Diabetes (Diabetes) Vol. 60 Issue 8 Pg. 2169-78 (Aug 2011) ISSN: 1939-327X [Electronic] United States
• PMID: 21677284 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Phenylephrine
• Nitric Oxide
• Nitric Oxide Synthase Type III
• Nos3 protein, mouse
• Receptor, IGF Type 1
• Receptor, Insulin
• Glucose

Topics

• Animals
• Aorta (drug effects)
• Biological Availability
• Down-Regulation
• Endothelial Cells (metabolism)
• Glucose (metabolism)
• Glucose Intolerance (genetics)
• Humans
• Insulin Resistance
• Male
• Mice
• Mice, Inbred C57BL
• Nitric Oxide (metabolism)
• Nitric Oxide Synthase Type III (metabolism)
• Phenylephrine (pharmacology)
• Receptor, IGF Type 1 (deficiency, genetics, physiology)
• Receptor, Insulin (genetics, physiology)
• Signal Transduction
• Umbilical Veins (cytology)
• Vasoconstriction (drug effects)