Cathepsin S inhibition lowers blood glucose levels in mice

Aims/hypothesis Cathepsin S (CatS) belongs to a family of proteases that have been implicated in several disease processes. We previously identified CatS as a protein that is markedly overexpressed in adipose tissue of obese individuals and downregulated after weight loss and amelioration of glycaemic status induced by gastric bypass surgery. This prompted us to test whether the protease contributes to the pathogenesis of type 2 diabetes using mouse models with CatS inactivation. Methods CatS knockout mice and wild-type mice treated with orally active small-molecule CatS inhibitors were fed chow or high-fat diets and explored for change in glycaemic status. Results CatS deletion induced a robust reduction in blood glucose, which was preserved in diet-induced obesity and with ageing and was recapitulated with CatS inhibition in obese mice. In vivo testing of glucose tolerance, insulin sensitivity and glycaemic response to gluconeogenic substrates revealed that CatS suppression reduced hepatic glucose production despite there being no improvement in insulin sensitivity. This phenotype relied on downregulation of gluconeogenic gene expression in liver and a lower rate of hepatocellular respiration. Mechanistically, we found that the protein 'regulated in development and DNA damage response 1' (REDD1), a factor potentially implicated in reduction of respiratory chain activity, was overexpressed in the liver of mice with CatS deficiency. Conclusions/interpretation Our results revealed an unexpected metabolic effect of CatS in promoting pro-diabetic alterations in the liver. CatS inhibitors currently proposed for treatment of autoimmune diseases could help to lower hepatic glucose output in obese individuals at risk for type 2 diabetes.