Reduced insulin clearance is linked to subclinical atherosclerosis in individuals at risk for type 2 diabetes mellitus

Hyperglycemia and insulin resistance contribute to vascular damage and are regulated by different pathophysiological processes. The aim of the study was to systematically investigate the relative contributions of multiple fasting state- and oral glucose tolerance test (oGTT)-derived glycemic traits to carotid intima-media thickness (cIMT), a surrogate parameter of subclinical atherosclerosis, in individuals with increased risk for type 2 diabetes mellitus (T2D). 667 volunteers (417 women and 250 men, mean age 44.1 years), who were free of cardiovascular disease (CVD), were included in this cross-sectional study. Glucose tolerance, insulin sensitivity, insulin secretion and insulin clearance were assessed by frequently sampled 75 g oGTT. cIMT was measured by high-resolution ultrasound. Insulin clearance was associated with cIMT in univariate analysis (r_s = -0.17, p < 0.0001) and in a stepwise regression analysis on 15 variables positing cIMT, age (r² = 0.3923, p < 0.0001), insulin clearance (r² = 0.4644, p < 0.0001), systolic blood pressure (r² = 0.4733, p < 0.0001), body mass index (BMI) (r² = 0.4804, p = 0.002), gender (r² = 0.4381, p = 0.013), and fasting insulin clearance (r² = 0.4857, p = 0.030) turned out to be significant determinants of cIMT. In a cross-validated model resulting from this analysis, insulin clearance was found to be an independent determinant of cIMT (r_s = -0.16, p < 0.001) even after adjusting for traditional CVD risk factors. Reduced insulin clearance may be an early marker of damage on the vasculature, independent of classical CVD risk factors. Reduced insulin clearance should be considered with regard to vascular insulin resistance.

Elko Randrianarisoa, Angela Lehn-Stefan, Anja Hieronymus, Robert Wagner, Jakub Machuzak, Kilian Rittig, Bernd Balletshofer, Andreas L. Birkenfeld, Andreas Peter, Norbert Stefan, Hans-Ulrich Häring, Martin Heni