Metabolic Syndrome/Insulin Resistance/Pre-Diabetes ORIGINAL ARTICLE Insulin Sensitivity, Insulinemia, and Coronary Artery Disease The Insulin Resistance Atherosclerosis Study 1 5 MARIAN REWERS, MD, PHD JOE V. SELBY, MD, MPH tery disease (CAD). On the other hand, 2 6 DANIEL ZACCARO, MS RICHARD BERGMAN, PHD hyperinsulinemia (a marker of low in- 2 7 RALPH D’AGOSTINO,JR., PHD PETER SAVAGE, MD sulin sensitivity) has been related to CAD 3 STEVEN HAFFNER, MD, MPH FOR THE INSULIN RESISTANCE in numerous prospective (6–12) and 4 MOHAMMED F. SAAD, MD ATHEROSCLEROSIS STUDY INVESTIGATORS cross-sectional studies (13). Insulinemia is generally inversely related to insulin sensitivity, but the relationship is not lin- ear (14), and it is usually absent in dia- OBJECTIVE — The aim of this study was to evaluate whether low insulin sensitivity (Si) measured using a modified frequently sampled intravenous glucose tolerance test with minimal betic individuals (15,16) who account for model analysis is associated with coronary artery disease (CAD) independent of other cardio- a significant proportion of people with vascular risk factors. low insulin sensitivity. The Insulin Resis- tance Atherosclerosis Study (IRAS) (17) RESEARCH DESIGN AND METHODS — We studied 1,482 women and men, age and others (18,19) have previously 40–69 years old, African American (28%), Hispanic (34%), or non-Hispanic white (38%), with shown that low insulin sensitivity is asso- normal (45%), impaired (23%), or diabetic (32%) glucose tolerance. CAD defined as confirmed ciated with atherosclerosis, defined by the past myocardial infarction, coronary artery bypass graft, coronary angioplasty, or presence of a major Q-wave was found in 91 participants. intima-media thickening of the carotid ar- teries. In this study, we test the hypothesis RESULTS — The odds ratio (OR) for CAD was greatest among individuals in the two lowest that low insulin sensitivity is also cross- quintiles of Si (2.4, 95% CI 1.0–5.6 and 4.7, 2.1–10.7) compared with the highest Si quintile. sectionally associated with clinical CAD, After adjusting for demographic and cardiovascular risk factors, a decrement from the 75th to independent of insulin levels and other ϭ 25th percentile in Si was associated with a 56% increase in CAD (P 0.028). Similar increments cardiovascular risk factors. in fasting or 2-h insulin levels were associated with, respectively, only 15 (NS) and 3% (NS) increases in CAD. The association between Si and CAD was partially mediated by insulin, HDL cholesterol and triglyceride levels, hypertension, diabetes, and obesity, but not LDL cholesterol RESEARCH DESIGN AND or cigarette smoking. METHODS — The design of IRAS, a four-center epidemiological study explor- CONCLUSIONS — Low Si is associated with CAD independently of and stronger than ing relationships among insulin sensitiv- plasma insulin levels. Part of the association is accounted for by dyslipidemia, hypertension, ity, insulin levels, cardiovascular risk diabetes, and obesity. factors, and cardiovascular disease across Diabetes Care 27:781–787, 2004 a broad range of glucose tolerance, has been previously published (20). Briefly, IRAS evaluated 1,624 women and men ow insulin sensitivity underlies the measurement of insulin sensitivity is tech- aged 40–69 years, representing normal metabolic syndrome that includes nically difficult, and only a few relatively (44%), impaired (23%), and diabetic glu- L central obesity, dyslipidemia, hyper- small studies (3–5) have demonstrated a cose tolerance (33%). Of the 479 diabetic glycemia, hypertension, impaired fibrino- strong association between insulin sensi- patients included in this report, 294 were lysis, and atherosclerosis (1,2). However, tivity measured directly and coronary ar- previously diagnosed (average duration ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● of diabetes 6.9 Ϯ 6.4 years). Of those, From the 1Barbara Davis Center, University of Colorado HSC, Denver, Colorado; the 2Department of Public 73% were taking oral hypoglycemic 3 Health Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina; the Department of agents, whereas the remaining were Medicine, University of Texas HS, San Antonio, Texas; the 4Department of Medicine, University of California Los Angeles, Los Angeles, California; the 5Department of Physiology and Biophysics, University of Southern treated with diet alone. Individuals with California, Los Angeles, California; the 6Kaiser Research Center, Northern California, Division of Research, impaired glucose tolerance (IGT) and Oakland, California; and the 7Division of Epidemiology and Clinical Applications, National Heart, Lung, and type 2 diabetes were over-sampled to Blood Institute, Bethesda, Maryland. achieve sufficient statistical power in Address correspondence and reprint requests to Marian Rewers, MD, PhD, Barbara Davis Center, Uni- these subgroups. Nondiabetic IRAS par- versity of Colorado Health Sciences Center, B-140, 4200 E 9th Ave., Denver, CO 80262. E-mail: marian. [email protected]. ticipants had, however, fasting blood glu- Received for publication 1 September 2003 and accepted in revised form 1 December 2003. cose levels similar to those in nondiabetic Abbreviations: CAD, coronary artery disease; ECG, electrocardiogram; FSIGT, frequently sampled in- individuals of the same ethnic group in travenous glucose tolerance test; HOMA, homeostasis model assessment; IGT, impaired glucose tolerance; the general population (20). IRAS clinics IRAS, Insulin Resistance Atherosclerosis Study. A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion in Oakland and Los Angeles, California, factors for many substances. studied non-Hispanic whites and African © 2004 by the American Diabetes Association. Americans recruited from Kaiser Perma- DIABETES CARE, VOLUME 27, NUMBER 3, MARCH 2004 781 The Insulin Resistance Atherosclerosis Study nente health maintenance organizations. firmed by review of medical records or a viously described (17), but it was The centers in San Antonio, Texas and major Q-wave on IRAS examination elec- statistically not significant (P Ͼ 0.05). San Luis Valley, Colorado recruited non- trocardiogram (ECG). The IRAS Events Hispanic whites and Hispanics from on- Committee (M.R., S.H., and J.S.) re- RESULTS — This report includes 91% going population-based studies (21,22). viewed using standard criteria (28) all (1,482 of 1,624) of the study participants Race and ethnicity were assessed by self- events reported to occur before the IRAS who completed the FSIGT. Univariate report using the U.S. census definitions; examination. Myocardial infarction was comparison of the characteristics of the African-Americans comprised 29%, His- confirmed in 39 (72%) of 54, coronary 91 case subjects and 1,391 control sub- panics 34%, and non-Hispanic whites artery bypass graft in 19 of 21, and per- jects studied (Table 1) confirmed known 37% of the study participants. Exclusion cutaneous transluminal coronary angio- associations between CAD and type 2 di- criteria included insulin treatment in the plasty in 7 of 9 of case subjects. Standard, abetes, male sex, older age, central obesity past 5 years, fasting glucose Ն16.7 resting 12-lead ECG was performed using (higher waist-to-hip ratio), dyslipidemia mmol/l [300 mg/dl], unstable angina, de- the MAC/PC electrocardiograph (Mar- (low HDL cholesterol and high triglycer- compensated congestive heart failure, or quette Electronics, Milwaukee, WI). ECG ides), hypertension, and cigarette smok- serious illness within the past month. All tracings were read centrally using NOVA- ing. Case subjects had significantly lower study protocols were approved by institu- CODE ECG software and the Minnesota Si levels than control subjects. Fasting in- tional review boards, and informed con- Code (29) and revealed a major Q-wave sulin levels were only on the borderline of sent was obtained from all participants. (Minnesota code 1.1–1.2, except for being higher among case subjects than 1.28) in 59 of the participants. Of the control subjects. There was no difference Measurement of glucose tolerance, 1,482 IRAS participants who completed in the levels of 2-h insulin between case insulin, and insulin sensitivity FSIGT, 91 (47 nondiabetic and 44 dia- subjects and control subjects. An oral glucose tolerance test with glu- betic participants) had at least one of To explore the linearity of the rela- cose tolerance classification according to these events and were classified as case tionship between Si and the CAD, the ORs the WHO criteria (23) and a frequently subjects. of CAD were estimated by quintiles of the sampled intravenous glucose tolerance Si distribution, adjusting for age, sex, eth- test (FSIGT) were performed on two sep- Other measurements nicity, and clinic (Fig. 1). Adjusted CAD arate days 2–28 days apart. Participants Resting systolic and diastolic blood pres- ORs for quintiles of fasting and 2-h insu- were asked to refrain from heavy exercise sure were measured three times, and the lin levels were included for comparison. and alcohol consumption for 24 h and second and third measurements were av- The quintile of highest Si or lowest fasting fast for 12 h before each visit and abstain eraged. Hypertension was defined as sys- insulin or 2-h insulin levels served as the from smoking the morning of examina- tolic blood pressure Ն140 or diastolic reference. The ORs for CAD were greatest Ն tion. Plasma glucose was measured with blood pressure 90 mmHg or if they among individuals