Insulin-like growth factor-II and insulin-like growth factor binding protein-2 prospectively predict longitudinal elevation of HDL-cholesterol in type 2 diabetes

Abstract

Introduction: Associations of insulin-like growth factor-II (IGF-II) and insulin-like growth factor binding protein-2 (IGFBP-2) with cardiovascular risk have been inadequately studied. We hypothesized that IGF-II and IGFBP-2 associate with longitudinal trends in lipid profiles in type 2 diabetes patients. Subjects and methods: Four hundred and eighty nine subjects with type 2 diabetes (age 27-87 years) from the Salford Diabetes Cohort were studied. Longitudinal clinical information was extracted for an eight-year period (2002)(2003)(2004)(2005)(2006)(2007)(2008)(2009) from an integrated electronic dataset of primary care and hospital data. Results: There were 294 male subjects and mean age was 62.9 years. At baseline, IGF-II concentration was 602 ng/mL. HDL cholesterol at baseline was associated with log-IGF-II concentration in a model adjusted for age, gender, baseline body-mass index (BMI), estimated glomerular filtration rate (eGFR) and lipid-lowering therapy. IGFBP-1 and IGFBP-2 were associated with high HDL-cholesterol. A higher circulating IGF-II concentration at baseline was also associated with longitudinal increase in HDL-cholesterol in mixed-effects regression analyses independent of IGF-I, IGFBP-1, IGFBP-2, IGFBP-3, age, gender, eGFR, BMI and lipid-lowering therapy. Log-transformed baseline concentrations of IGFBP-1 and IGFBP-2 were also associated with longitudinal elevation in HDL-cholesterol. No association was observed for IGF-II or IGFBP-2 with longitudinal LDL cholesterol trends. Conclusion: Our analyses based on 'real world' data demonstrate that higher baseline IGF-II and IGFBP-2 predict increased HDL concentration over time, implicating IGF-II in modulation of circulating HDL-cholesterol concentrations.

Circulating IGFBP-2 levels are incrementally linked to correlates of the metabolic syndrome and independently associated with VLDL triglycerides

“…When similar analyses were conducted for HDL-C, IGFBP-2 did not remain independently associated with this variable. This observation contrasts with a recent study showing that IGFBP-2 levels can predict longitudinal changes in HDL-C over an 8-year period in a population with type 2 diabetes [21]. This discordance might be attributable to the crosssectional nature of the present study and to the different populations examined.…”

“…Notably, individuals in the low IGFBP-2 group displayed an increased number of VLDL particles, elevated plasma TG as reflected by elevated TG in all lipoprotein subfractions, lower HDL-C and smaller HDL particles. These findings are consistent with and extend reports of negative associations between circulating levels of IGFBP-2 and plasma TG and HDL-C concentrations [17,21].…”

“…IGFBP-2 has been negatively associated with circulating TG and cholesterol levels [13,16,17,21]. However, only a limited number of studies have investigated the impact of IGFBP-2 on lipid metabolism [21].…”

“…However, only a limited number of studies have investigated the impact of IGFBP-2 on lipid metabolism [21]. In order to dissociate the interaction of IGFBP-2 with lipids beyond its relation with insulin sensitivity and fat mass, the present study aimed at exploring the associations between circulating levels of IGFBP-2 and several features of the plasma lipoprotein/lipid profile in a cohort of men covering a large range of adiposity.…”

Changes in IGFBP-2 levels following a one-year lifestyle modification program are independently related to improvements in plasma apo B and LDL apo B levels

“…In addition, we did not assess the levels of IGFBP-2 fragments [35,36] or those of other IGFBPs possibly modified by the lifestyle regimen, which could have both influenced the changes in IGFBP-2 as a compensatory feedback. Nonetheless, these data complement the numerous transversal studies showing that total IGFBP-2 levels are closely linked to insulin sensitivity, fat mass and components of the lipoprotein-lipid profile [8,9,11,34,[37][38][39] and suggest that these associations are within a time continuum as well. The molecular mechanism responsible for the stimulation of IGFBP-2 production upon lifestyle modifications remain to be tested in humans.…”