Insulin Sensitivity and Carotid Intima-Media Thickness

Abstract

Objective— Despite a wealth of experimental data in animal models, the independent association of insulin resistance with early carotid atherosclerosis in man has not been demonstrated. Approach and Results— We studied a European cohort of 525 men and 655 women (mean age, 44±8 years) free of conditions known to affect carotid wall (diabetes mellitus, hypertension, and dyslipidemia). All subjects received an oral glucose tolerance test, a euglycemic hyperinsulinemic clamp (M/I as a measure of insulin sensitivity), and B-mode carotid ultrasound. In 833 participants (380 men), the carotid ultrasound was repeated after 3 years. In men, baseline intima-media thickness in the common carotid artery (CCA-IMT) was significantly higher ( P <0.05) in the lowest M/I tertile, whereas in women CCA-IMT was higher ( P <0.0005) in the highest fasting plasma glucose tertile (after adjustment for established risk factors). In multiple regression models, with CCA-IMT as the dependent variable and with risk factors and univariate metabolic correlates as independent variables, circulating free fatty acids and the leptin:adiponectin ratio replaced M/I as independent metabolic determinants of CCA-IMT in men. The strongest metabolic determinant of CCA-IMT in women was fasting plasma glucose. Three-year CCA-IMT changes were not associated with any cardio-metabolic risk factor. Conclusions— In young-to-middle aged apparently healthy people, the association of CCA-IMT with insulin sensitivity and its metabolic correlates differs between men and women. Lower insulin sensitivity is associated with higher IMT only in men; this association seems to be mediated by circulating free fatty acids and adipocytokines. In women, CCA-IMT is independently associated with fasting plasma glucose.

Contrasting associations of insulin resistance with diabetes, cardiovascular disease and all-cause mortality in the elderly: PROSPER long-term follow-up

“…It is a limitation of our study that we did not have such measures, although no large cohorts with prospective data that we are aware of have data on both insulin sensitivity measured by clamping techniques and sufficient numbers of CVD events to allow adequately powered statistical analysis. The multinational Relationship between Insulin Sensitivity and Cardiovascular Disease (RISC) Study recently reported weak cross-sectional associations of insulin sensitivity (measured by euglycaemic clamps) with carotid intima-media thickness in men but not in women, and, potentially more importantly, insulin sensitivity was not associated with 3 year changes in carotid intima-media thickness [21]. We also did not measure model-based insulin sensitivity or use data from OGTT; a recent meta-analysis suggests that correlation with euglycaemic-clamp-derived insulin sensitivity is r=−0.60 for log HOMA-IR, r=0.57 for model-based insulin sensitivity, and around r=0.70 for various OGTT-based measures [22].…”

Association between insulin resistance and the development of cardiovascular disease

“…Even though a wealth of studies support the notion that CVD is related to insulin resistance [4, 9, 31, 73–76], there are some controversial reports as well. A study performed by Kozakova et al reported the association of insulin sensitivity with risk of CVD in young to middle aged men, where as in women, atherosclerosis and plaque formation were independently associated with fasting plasma glucose levels [77]. In addition to insulin resistance, the compensatory hyperinsulinemia associated with insulin resistance can play a critical role in the formation of atherosclerotic plaques by changing the gene expression pattern associated with estrogen receptor, as reported in animal models [78].…”

Carotid Intima-Media Thickness for Atherosclerosis

“…In a systematic review, patients with diabetes mellitus or impaired glucose tolerance were found to have a greater carotid IMT than control subjects 61) . Associations were also found between the carotid IMT, insulin resistance, and metabolic syndrome [62][63][64][65][66] .…”