A Potential Inverse Association Between Insulin-Like Growth Factor I and Hypertension in a Cross-Sectional Study

Purpose

Elevated circulating insulin-like growth factor I (IGF-I) levels increasingly are being implicated as a potential risk factor for the development of some cancers; however, relatively few epidemiologic studies have focused on potential relationships between circulating IGF-I levels and cardiovascular risk factors or cardiovascular disease. Hence, our objective is to examine relationships between IGF-I levels; body mass index (BMI); fasting insulin level; IGF binding protein 1 (IGFBP-1), IGFBP-2, and IGFBP-3 levels; and an array of traditional cardiovascular risk factors.

Methods

Our analysis included 715 men and women aged 30 to 62 years who participated in the Västerbotten Intervention Project cohort. IGF-I and IGFBP-1, -2, and -3 were measured in stored plasma samples. Cardiovascular risk factors of interest included glucose level (fasting and 2-hour postload), lipid levels (total cholesterol, high-density lipoprotein cholesterol, and triglycerides), blood pressure (systolic and diastolic), and hypertension status. All presented results were adjusted for age, sex, and laboratory batch.

Results

IGF-I quartile was associated inversely with 2-hour glucose level and diastolic blood pressure. There was a stepwise inverse graded association between increasing IGF-I quartile and hypertension, with an odds ratio of 0.51 (95% confidence interval, 0.29–0.90) for hypertension comparing the fourth IGF-I quartile with the first. Further adjusting for BMI and IGFBP-3 level simultaneously strengthened the inverse association, with an odds ratio of 0.42 (95% confidence interval, 0.22–0.80) for hypertension comparing the fourth with the first IGF-I quartile.

Conclusions

Contrary to positive associations between IGF-I levels and some cancers, our results suggest that IGF-I level may be related inversely to prevalent hypertension, a risk factor for cardiovascular disease.

Introduction

Elevated circulating insulin-like growth factor I (IGF-I) levels increasingly are being implicated as a potential risk factor for the development of some cancers, including breast, colon, and prostate 1, 2, 3, 4, 5, 6. These findings have led to speculation about means of decreasing IGF-I levels for cancer prevention or whether growth hormone (GH) supplementation might lead to harmful effects in terms of increased cancer risk. However, little is known about relationships of circulating IGF-I and IGF-binding proteins (IGFBPs) with chronic disease end points other than cancer or overall mortality. Cardiovascular disease is the leading cause of death in developed and developing countries; however, despite biologically plausible mechanisms, relatively few epidemiologic studies focused on potential relationships between circulating IGF-I levels and cardiovascular risk factors or cardiovascular disease.

IGF-I, as a member of the family of insulin-like peptides also including insulin and IGF-II, is part of an extremely complex system that involves endocrine, paracrine, and autocrine interactions between the IGFs, at least six identified IGFBPs, and cellular receptors 7, 8, 9. IGF-I production is suspected to be ubiquitous with circulating IGF-I produced primarily as an endocrine factor by the liver. IGF-I levels are associated with pubescent growth, peak during puberty, and slowly decrease throughout adult life. It is not entirely known how circulating IGF-I levels and IGFBPs may be quantitatively related to IGF-I bioactivity in tissues. IGFBPs are known to serve as IGF transport proteins in the plasma, prolong IGF half-life, provide a means of tissue and cell-type localization, and directly modulate interactions between IGFs and their receptors 8, 9. Approximately 75% of circulating IGF-I is found in a 150-kd ternary complex composed of IGF-I, IGFBP-3, and an acid-labile subunit. Circulating levels of the first three IGFBPs (IGFBP-1 to -3), but not the remaining two, clearly are influenced by alterations in nutritional status. Three transmembrane tyrosine kinase receptors bind IGFs, and although IGF-I binds with the greatest affinity to IGF receptor type 1 (IGF-R1), IGF-I binds at lower affinity to both IGF-R2 and the insulin receptor. Finally, hybrid insulin/IGF-I–Rs are known to form 10, 11.

Regulation of circulating levels of IGF-I and IGFBP-1, -2, and -3 is mediated largely along two nutritionally influenced axes; one is related primarily to GH, and the other, to insulin. GH provides the key stimulus for synthesis of IGF-I and IGFBP-3 8, 12, 13, and circulating levels of these peptides are correlated. Conversely, insulin enhances GH-stimulated synthesis of IGF-I and IGFBP-3 by increasing levels of GH receptors 14, 15, 16 and stimulating cellular uptake of amino acids for protein synthesis. In addition, insulin increases the bioactivity of IGF-I by inhibiting the synthesis of IGFBP-1 and -2, reflected in the inverse correlation between levels of insulin and these binding proteins.

Hence, IGF-I and IGFBP-1, -2, and -3 can be subdivided as components of one of two axes: the GH/IGF-I axis, including IGF-I and IGFBP-3; and the obesity–insulin-resistance axis, including IGFBP-1 and -2. Because IGFBP-1 and -2, as inverse correlates of insulin and body mass index (BMI), are expected to be and previously have been associated inversely with components of insulin resistance syndrome 17, 18, namely, hypertension, diabetes, and dyslipidemia, the current report focuses on the GH/IGF-I axis.

Results are presented from a large cross-sectional study of the relationship of plasma IGF-I level, BMI, fasting insulin level, and IGFBP-1, -2, and -3 levels with an array of traditional cardiovascular risk factors, including plasma glucose levels (fasting and 2-hour post–glucose load), lipid levels (total and high-density lipoprotein [HDL] cholesterol, as well as triglycerides), systolic and diastolic blood pressure, and hypertension status.