Serum Cathepsin S Is Associated With Decreased Insulin Sensitivity and the Development of Type 2 Diabetes in a Community-Based Cohort of Elderly Men

OBJECTIVE

To investigate associations between serum cathepsin S, impaired insulin sensitivity, defective insulin secretion, and diabetes risk in a community-based sample of elderly men without diabetes.

RESEARCH DESIGN AND METHODS

Serum cathepsin S, insulin sensitivity (euglycemic-hyperinsulinemic clamp), and insulin secretion (early insulin response during an oral glucose tolerance test) were measured in 905 participants of the Uppsala Longitudinal Study of Adult Men (mean age, 71 years). Thirty participants developed diabetes during 6 years of follow-up.

RESULTS

After adjustment for age, anthropometric variables, and inflammatory markers, higher cathepsin S was associated with decreased insulin sensitivity (regression coefficient per SD increase −0.09 95% CI −0.14 to −0.04], P = 0.001), but no association with early insulin response was found. Moreover, higher cathepsin S was associated with a higher risk for developing diabetes (odds ratio per SD increase 1.48 1.08–2.01], P = 0.01).

CONCLUSIONS

Cathepsin S activity appears to be involved in the early dysregulation of glucose and insulin metabolism.Adipokines, inflammatory cytokines secreted from adiopose tissue, have been suggested to play a key role in the development of insulin resistance and diabetes (1). Cathepsin S is a potent cysteine protease that is highly expressed and secreted in adipose tissue of obese individuals (2) and has been suggested to be an important regulator of inflammatory activity (3). We thus hypothesized that cathepsin S levels would be involved in the early dysregulation of glucose and insulin metabolism before development of diabetes. Accordingly, we investigated the association between serum cathepsin S and the two major underlying causes of diabetes—impaired insulin sensitivity and impaired insulin secretion—in a community-based sample of elderly men without diabetes. In secondary analyses, we also investigated the longitudinal association between serum cathepsin S and the incidence of diabetes.