The role of Hepatic 11-β hydroxysteroid dehydrogenase Type 1 in Uraemia-induced Insulin Resistance.

Abstract

Insulin resistance and associated metabolic sequelae are common in Chronic Kidney Disease (CKD) and are positively and independently associated with increased cardiovascular mortality. However, the pathogenesis has yet to be fully elucidated. 11β-Hydroxysteroid Dehydrogenase type 1 (11β-HSD1) catalyses intracellular regeneration of active glucocorticoids, promoting insulin resistance in liver and other metabolic tissues. Using data from two experimental rat models of CKD (subtotal nephrectomy and adenine diet) which show early insulin resistance, we found that 11β-HSD1 mRNA and protein increase in hepatic and adipose tissue, together with increased hepatic 11β-HSD1 activity. This was associated with intrahepatic but not circulating glucocorticoid excess, and increased hepatic gluconeogenesis and lipogenesis. Oral administration of the 11β-HSD inhibitor carbenoxolone to uraemic rats for 2 weeks improved glucose tolerance and insulin sensitivity, improved insulin signalling, and reduced hepatic expression of gluconeogenic and lipogenic genes. Furthermore, 11β-HSD1−/− mice and rats treated with a specific 11β-HSD1 inhibitor (UE2316) were protected from metabolic disturbances despite similar renal dysfunction following adenine-induced experimental uraemia. Therefore, we demonstrate that elevated hepatic 11β-HSD1 is an important contributor to early insulin resistance and dyslipidaemia in uraemia. Specific 11β-HSD1 inhibitors potentially represent a novel therapeutic approach for management of insulin resistance in patients with CKD.