An 11-Beta Hydroxysteroid Dehydrogenase Type 1 Inhibitor, JTT-654 Ameliorates Insulin Resistance and Non-obese Type 2 Diabetes

Abstract

Hydroxysteroid dehydrogenase type 1 (11β-HSD1) is the only enzyme that converts inactive glucocorticoids to active forms and plays an important role in the regulation of glucocorticoid action in target tissues. JTT-654 is a selective 11β-HSD1 inhibitor and we investigated its pharmacological properties in cortisone-treated rats and non-obese type 2 diabetic Goto-Kakizaki (GK) rats because Asians, including Japanese, are more likely to have non-obese type 2 diabetics. Systemic cortisone treatment increased fasting plasma glucose and insulin levels and impaired insulin action on glucose disposal rate and hepatic glucose production assessed by hyperinsulinemic-euglycemic clamp, but all these effects were attenuated by JTT-654 administration. Cortisone treatment also reduced basal and insulin-stimulated glucose oxidation in adipose tissue, increased plasma glucose levels after administration of the pyruvate, the substrate of gluconeogenesis, and increased liver glycogen content. Administration of JTT-654 also inhibited all of these effects. Cortisone treatment decreased basal and insulin-stimulated 2-deoxy-D-[1-3 H]-glucose uptake in 3T3-L1 adipocytes and increased the release of free fatty acids and glycerol, a gluconeogenic substrate, from 3T3-L1 adipocytes, and JTT-654 significantly attenuated these effects. In GK rats, JTT-654 treatment significantly reduced fasting plasma glucose and insulin levels, enhanced insulin-stimulated glucose oxidation in adipose tissue, and suppressed hepatic gluconeogenesis as assessed by pyruvate administration. These results demonstrated that glucocorticoid was involved in the pathology of diabetes in GK rats, as in cortisone-treated rats, and that JTT-654 ameliorated the diabetic conditions. Our results suggest that JTT-654 ameliorates insulin resistance and non-obese type 2 diabetes by inhibiting adipose tissue and liver 11β-HSD1.

A 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitor, 11b-0048, effectively suppresses the expression of 11β-HSD1 activated in cultured keratinocytes and in diabetic murine skin

“…In patients with NASH and type 2 DM, the AZD4017 group showed improvement in liver steatosis compared to the placebo group 38 . 'TT-654' demonstrated an improvement in insulin resistance and obesity in Goto-Kakizaki rats, a DM model, by inhibiting adipose tissue and liver 11β-HSD1 39 . Consequently, 11β-HSD1 inhibitors are being investigated for a range of metabolic disorders, including type 2 DM, though clinical studies on their effects in the skin are limited.…”