Insulin Resistance Predicts Mortality in Nondiabetic Individuals in the U.S.

OBJECTIVE

Insulin resistance is a suspected causative factor in a wide variety of diseases. We aimed to determine whether insulin resistance, estimated by the homeostasis model assessment for insulin resistance (HOMA-IR), is associated with all-cause or disease-specific mortality among nondiabetic persons in the U.S.

RESEARCH DESIGN AND METHODS

We determined the association between HOMA-IR and death certificate–based mortality among 5,511 nondiabetic, adult participants of the third U.S. National Health and Nutrition Examination Survey (1988–1994) during up to 12 years of follow-up, after adjustment for potential confounders (age, sex, BMI, waist-to-hip ratio, alcohol consumption, race/ethnicity, educational attainment, smoking status, physical activity, C-reactive protein, systolic and diastolic blood pressure, plasma total and HDL cholesterol, and triglycerides).

RESULTS

HOMA-IR was significantly associated with all-cause mortality (adjusted hazard ratio 1.16 [95% CI 1.01–1.3], comparing successive quartiles of HOMA-IR in a linear model and 1.64 [1.1–2.5], comparing the top [HOMA-IR >2.8] to the bottom [HOMA-IR ≤1.4] quartile). HOMA-IR was significantly associated with all-cause mortality only in subjects with BMI <25.2 kg/m² (the median value) but not in subjects with BMI ≥25.2 kg/m². Subjects in the second, third, and fourth quartile of HOMA-IR appeared to have higher cardiovascular mortality than subjects in the lowest quartile of HOMA-IR. HOMA-IR was not associated with cancer-related mortality.

CONCLUSIONS

HOMA-IR is associated with all-cause mortality in the nondiabetic U.S. population but only among persons with normal BMI. HOMA-IR is a readily available measure that can be used in the future to predict mortality in clinical or epidemiological settings.Insulin resistance is a condition in which normal amounts of insulin are not adequate to produce the expected biologic response in target tissues, including adipose tissue, muscle, and liver. Insulin resistance has been associated with a wide variety of adverse health outcomes, including type 2 diabetes (1), hypertension (2), cardiovascular disease (1), cerebrovascular disease (3), peripheral vascular disease (4), congestive heart failure (5), nonalcoholic fatty liver disease (6), dyslipidemia (low HDL cholesterol and high triglycerides) (7), and a variety of malignancies (8). Using a mathematical simulation model, Eddy et al. (9) recently estimated that insulin resistance was responsible for 42% of myocardial infarctions in the U.S. and was the most important single cause of coronary artery disease.Obesity is known to be a strong risk factor for insulin resistance, in particular ectopic as opposed to subcutaneous adiposity (10). In addition, factors unrelated to obesity are important contributors to insulin resistance, such as race, sex, physical activity, and genetic factors, while as-yet-unknown causes of insulin resistance also likely exist.The homeostasis model assessment for insulin resistance (HOMA-IR) estimates insulin resistance from fasting plasma glucose and serum insulin levels (11). There is good correlation between values of insulin resistance obtained using HOMA-IR and the euglycemic-hyperinsulinemic clamp method (12), the gold-standard test that is too costly and technically demanding to be used in epidemiologic studies or clinical practice. Given the combination of accuracy and ease of testing, HOMA-IR is considered an appropriate method for measurement of insulin resistance in epidemiologic studies (12).Our aim was to determine the association between HOMA-IR and mortality in nondiabetic people in the U.S. independently of other important predictors of mortality. This finding would be important in incorporating HOMA-IR into future models predicting mortality for clinical or epidemiological purposes, especially since HOMA-IR is readily available.