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Insulin Resistance, Insulin Response, and Obesity as Indicators of Metabolic Risk

Department of Internal Medicine and Consiglio Nazionale delle Ricerche Institute of Clinical Physiology (E.F., A.N.), University of Pisa, I-56100 Pisa, Italy; Institut National de la Santé et de la Recherche Médicale (B.B.), U 780-IFR69, F-94807 Villejuif, France; Academic Medical Unit (S.W.C.), The Royal London Hospital, London E1 1BB, United Kingdom; Extramuraal Geneeskundig Onderzoek (EMGO) Institute (J.M.D.), Vrije Universiteit Medical Center, 1081 BV Amsterdam, The Netherlands; Consiglio Nazionale delle Ricerche Institute of Biomedical Engineering (A.M.), I-35127 Padova, Italy; Department of Medicine (J.N.), Trinity College, Dublin 2, Ireland; Department of Medicine (M.W.), University of Newcastle upon Tyne, Newcastle upon Tyne NE2 4HQ, United Kingdom; and Department of Endocrinology M (H.B.-N.), Odense University Hospital, DK-5000 Odense, Denmark

Address all correspondence and requests for reprints to: Ele Ferrannini, M.D., Department of Internal Medicine, Via Roma, 67-I-56100 Pisa, Italy. E-mail: ferranni{at}ifc.cnr.it.

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 kg·m^–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.

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