Cathepsin K: a novel association with glucose intolerance, insulin resistance, and subclinical atherosclerosis in T2DM

Background: Cathepsin K (CatK) contributes to vessel collagene remodelling and high CatK concentrations have been found in atherosclerotic lesions. CatK ablation in a murine model determined an amelioration of diabetes-induced hyperglycemia and cardiovascular structural/functional abnormalities. To date, it is unknown whether glucose tolerance status affects circulating levels of CatK, and if CatK is involved with the cardiovascular complications associated with type 2 diabetes (T2DM). Methods: We assayed the levels of serum CatK in a cohort of 544 well-characterized Caucasian adults. assessing subclinical cardiovascular organ damage defined by carotid artery intima-media thickness (c-IMT) and left ventricular mass index (LVMI) in our T2DM cohort. Results: CatK levels were significantly higher in individuals with T2DM (2.3 ± 0.8 ng/ml; N = 263) compared to normoglycemia (NGT; 1.2 ± 0.5 ng/ml; N = 146) or predabetes (IFG/IGT; 1.2 ± 0.3 ng/ml; N = 135). Consistent with the literature, CatK levels correlated with age (r = - 0.190, p = 0.001), 2 h-PG (r = - 0.118, p = 0.048) and c-IMT (r = 0.157, p < 0.01) in the subset without T2DM. In the T2DM group, CatK positively correlated with FPI (r = 0.277; p < 0.001), HOMA-IR (r = 0.269; p < 0.001) and c-IMT (r = 0.155; p = 0.013). Multiple logistic regression analysis, adjusted for potential confounders, revealed that a one-quintile increment in CatK levels was associated with a 6.5-fold increased odds of T2DM. Furthermore, multiple linear regression analysis in T2DM patients, including sex, age, BMI, hypotensive therapy, and HOMA-IR (or alternatively HbA1c or FPI) as covariates, identified age and CatK as the strongest determinants of c-IMT. CatK levels did not correlate with LVMI in either the T2DM or non-T2DM cohorts. Conclusions: Our data show that the variability of CatK circulating levels is associated with glucose tolerance status, and with early signs of atherosclerosis in a population with T2DM as well as in non-diabetic individuals. These findings, combined with the established role of CatK in vascular remodeling, suggest that CatK may play a role in the early etiopathogenesis of cardiovascular complications in T2DM.