Inhibition of 11β-HSD1 by LG13 improves glucose metabolism in type 2 diabetic mice.

11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) controls the production of active glucocorticoid (GC) and has been proposed as a new target for the treatment of type 2 diabetes. We have previously reported that a natural product, curcumin, exhibited moderate inhibition and selectivity on 11β-HSD1. By analyzing the models of protein, microsome, cells and GCs-induced mice in vitro and in vivo, this study presented a novel curcumin analog, LG13, as a potent selective 11β-HSD1 inhibitor. In vivo, Type 2 diabetic mice were treated with LG13 for 42 days to assess the pharmacological benefits of 11β-HSD1 inhibitor on hepatic glucose metabolism. In vitro studies revealed that LG13 selectively inhibited 11β-HSD1 with IC50 values at nanomolar level and high selectivity over 11β-HSD2. Targeting 11β-HSD1, LG13 could inhibit prednisone-induced adverse changes in mice, but had no effects on dexamethasone-induced ones. Further, the 11β-HSD1 inhibitors also suppressed 11β-HSD1 and GR expression, indicating a possible positive feedback system in the 11β-HSD1/GR cycle. In type 2 diabetic mice induced by high fat diet plus low-dosage STZ injection, oral administration with LG13 for 6 weeks significantly decreased fasting blood glucose, hepatic glucose metabolism, structural disorders, and lipid deposits. LG13 exhibited better pharmacological effects in vivo than insulin sensitizer pioglitazone and potential 11β-HSD1 inhibitor PF-915275. These pharmacological and mechanistic insights on LG13 also provide us novel agents, leading structures, and strategy for the development of 11β-HSD1 inhibitors treating metabolic syndromes.