Increasing Circulating IGFBP1 Levels Improves Insulin Sensitivity, Promotes Nitric Oxide Production, Lowers Blood Pressure, and Protects Against Atherosclerosis

Abstract

Low concentrations of insulin-like growth factor (IGF) binding protein-1 (IGFBP1) are associated with insulin resistance, diabetes, and cardiovascular disease. We investigated whether increasing IGFBP1 levels can prevent the development of these disorders. Metabolic and vascular phenotype were examined in response to human IGFBP1 overexpression in mice with diet-induced obesity, mice heterozygous for deletion of insulin receptors (IR+/−), and ApoE−/− mice. Direct effects of human (h)IGFBP1 on nitric oxide (NO) generation and cellular signaling were studied in isolated vessels and in human endothelial cells. IGFBP1 circulating levels were markedly suppressed in dietary-induced obese mice. Overexpression of hIGFBP1 in obese mice reduced blood pressure, improved insulin sensitivity, and increased insulin-stimulated NO generation. In nonobese IR+/− mice, overexpression of hIGFBP1 reduced blood pressure and improved insulin-stimulated NO generation. hIGFBP1 induced vasodilatation independently of IGF and increased endothelial NO synthase (eNOS) activity in arterial segments ex vivo, while in endothelial cells, hIGFBP1 increased eNOS Ser1177 phosphorylation via phosphatidylinositol 3-kinase signaling. Finally, in ApoE−/− mice, overexpression of hIGFBP1 reduced atherosclerosis. These favorable effects of hIGFBP1 on insulin sensitivity, blood pressure, NO production, and atherosclerosis suggest that increasing IGFBP1 concentration may be a novel approach to prevent cardiovascular disease in the setting of insulin resistance and diabetes.

High concentrations of pyridoxal stimulate the expression of IGFBP1 in HepG2 cells through upregulation of the ERK/c-Jun pathway

“…The ERK/c-Jun pathway may be involved in the induction of IGFBP1 by PL. Vitamin B6 and IGFBP1 are hypothesized as protective factors against cancers and cardiovascular disease (7,15,22,35). Thus, it is of interest to examine whether vitamin B6 intake causes a higher production of IGFBP1 in the liver, resulting in higher circulating IGFBP1, which in turn leads to lower development of these diseases.…”

“…Previous studies have suggested that IGFBP1 may be a tumor suppressor (16)(17)(18)(19). Low serum IGFBP1 levels are associated with a number of chronic diseases, including colon cancer, cardiovascular disease and diabetes (20)(21)(22). A previous study showed that increased circulating IGFBP1 levels improve insulin sensitivity, lower blood pressure and protect against atherosclerosis (22).…”

“…Low serum IGFBP1 levels are associated with a number of chronic diseases, including colon cancer, cardiovascular disease and diabetes (20)(21)(22). A previous study showed that increased circulating IGFBP1 levels improve insulin sensitivity, lower blood pressure and protect against atherosclerosis (22). IGFBP1 is rapidly induced during liver regeneration and is implicated in the maintenance of hepatocyte differentiation and metabolism (23,24).…”

Beneficial Effect of a Low Dose of Ethanol on Liver Function and Serum Urate in Rats Fed a High-Fat Diet

“…Recent studies suggest IGFBP-1 plays a role as a protective factor against liver injury, type 2 diabetes, hypertension, atherosclerosis, and cancer (23)(24)(25). Adiponectin is also known to be a protective factor against such diseases, including liver injury (26).…”

Selective Enhancement of Insulin Sensitivity in the Endothelium In Vivo Reveals a Novel Proatherosclerotic Signaling Loop

“…Systolic blood pressure was measured using tailcuff plethysmography in conscious mice, as previously described. 15,16 Mice were pre-warmed for 10 minutes in a thermostatically controlled restrainer (CODA2 System, XBP1000; Kent Scientific). Three training sessions were performed during the week before measurements were taken.…”