Insulin resistance, insulin response, and obesity as indicators of metabolic risk

Context: Insulin resistance (IR) and obesity, especially abdominal obesity, are regarded as central pathophysiological features of a cluster of cardiovascular risk factors (CVRFs), but their relative roles remain undefined. Moreover, the differential impact of IR viz. insulin response has not been evaluated. Objective: The objective of this study was to dissect out the impact of obesity, abdominal obesity, and IR/insulin response on CVRF. Design: This was a cross-sectional study. Setting: The study was conducted at 21 research centers in Europe. Subjects: The study included a cohort of 1308 nondiabetic subjects [ 718 women and 590 men, age 30-60 yr, body mass index (BMI) 17-44 kgm(-2)]. Main Outcome Measures: We measured IR (by a standardized euglycemic insulin clamp), waist girth, insulin response to an oral glucose tolerance test, and major CVRF, and analyzed their associations by multivariate models and factor analysis. Results: BMI was positively related to all CVRFs. Waist circumference was related to higher blood pressure and serum triglycerides and lower high- density lipoprotein- cholesterol, IR to reduced glucose tolerance, higher free fatty acids, triglyceride and low-density lipoprotein-cholesterol, and lower high-density lipoprotein-cholesterol, and insulin response to higher heart rate, blood pressure and fasting glucose, and the same dyslipidemic profile as IR (P <= 0.05 for all). By factor analysis, three main factors (related to IR, age, and fatness, respectively) appeared to underlie this pattern of associations. Each of BMI, waist girth, IR, and insulin response was independently associated with total CVRF load (all P < 0.001). Conclusions: When IR, fat mass and distribution, and insulin response are measured simultaneously in a large cohort, no one factor stands out as the sole driving force of the CVRF cluster, each being associated with one or more physiological pathways according to known cause-effect relationships.