Abstract 3944: IGFBP-1: A Vasculoprotective Peptide in Obesity and Insulin Resistance
Insulin, insulin-like growth factor-I (IGF-I) and IGF binding protein-1 (IGFBP-1) are thought to play complimentary roles in glucose homeostasis. Reduced levels of IGF-I and IGFBP-1 have been implicated in the development of cardiovascular disease; raising levels of IGFBP-1 may be atheroprotective. We characterized longitudinal changes in the insulin/IGF-I/IGFBP-1 axis during the development of dietary-induced obesity in mice and examined the effects of IGFBP-1 overexpression on this metabolic and vascular phenotype. Male C57 Bl/6 mice (WT) and transgenic mice overexpressing human IGFBP-1 (TG) received a high fat (HF) or chow diet from weaning (n= 6–16). Insulin and IGF-I tolerance tests were performed, fasting IGF-I and IGFBP-1 levels were measured by ELISA. Hepatic IGFBP-1 expression was measured by real-time RT-PCR. Vascular insulin and IGF-I sensitivities were assessed ex-vivo in aortic rings. Systolic blood pressure (SBP) was recorded by tail-cuff plethysmography. After 8–16 weeks feeding, WT fed HF had a higher body weight and fat pad mass than chow fed and demonstrated decreased insulin sensitivity (p<0.01). The hypoglycaemic effect of IGF-I was decreased (p<0.001) and circulating IGF-I levels were higher (298ng/ml vs. 404ng/ml, p<0.05). IGFBP-1 expression and protein levels were significantly lower in HF than chow fed animals (p<0.01). TG fed HF had similar body weights and adiposity to WT but insulin resistance was attenuated (TG 41.8% decrease in blood glucose at 30 mins. vs. WT 32.3%, p<0.02). Whilst insulin and IGF-I did not alter the effect of phenylephrine on aortic rings of WT HF fed mice, TG mice had significant blunting of vasoconstriction (p<0.05) demonstrating preserved vascular insulin and IGF-I sensitivities. In addition obese WT mice had significantly higher SBP than chow fed mice (p<0.01); however TG littermates had similar SBP to both WT and TG chow fed controls. These data demonstrate that IGFBP-1 levels decrease and IGF-I levels increase as obesity develops, with an accompanying decrease in IGF-I sensitivity. Overexpression of human IGFBP-1 protects against the development of hypertension and the development of insulin resistance in both peripheral tissues and the vasculature despite the development of obesity.