Altered activity of 11β-hydroxysteroid dehydrogenase types 1 and 2 in skeletal muscle confers metabolic protection in subjects with type 2 diabetes

Context: There is little information regarding the regulation of 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) enzymes in skeletal muscle in the setting of type 2 diabetes. Objective: Our objective was to investigate whether there is differential mRNA expression and enzyme activity of 11 beta-HSD1 and 11 beta-HSD2 in the skeletal muscle of diabetic subjects compared with controls at baseline and in response to dexamethasone. Design: Participants underwent muscle biopsy of vastus lateralis at baseline and after dexamethasone. Setting: The study took place at a university teaching hospital. Participants: Twelve subjects with type 2 diabetes and 12 age-and sex-matched controls participated. Intervention: Subjects were given oral dexamethasone, 4 mg/d for 4 d. Main Outcome Measures: We assessed 11 beta-HSD1, 11 beta-HSD2, and H6PDH mRNA levels by quantitative RT-PCR and enzyme activity by percent conversion of [H-3] cortisone and [H-3] cortisol, respectively. Results: At baseline, mRNA levels were similar in diabetic and control subjects for 11 beta-HSD1, 11 beta-HSD2, and H6PDH. 11 beta-HSD1 activity was reduced in diabetic subjects (percent conversion of [H-3] cortisone to [H-3] cortisol was 11.4 +/- 2.5% vs. 18.5 +/- 2.2%; P = 0.041), and 11 beta-HSD2 enzyme activity was higher in diabetic subjects (percent conversion of [H-3] cortisone to [H-3] cortisol was 17.2 +/- 2.6% vs. 9.2 +/- 1.3%; P +/- 0.012). After dexamethasone, 11 beta-HSD1 mRNA increased in both groups (P < 0.001), whereas 11 beta-HSD2 mRNA decreased (P = 0.002). 11 beta-HSD1 activity increased in diabetic subjects (P = 0.021) but not in controls, whereas 11 beta-HSD2 activity did not change in either group. At baseline, there was a significant negative correlation between 11 beta-HSD1 and 11 beta-HSD2 enzyme activity (r = -0.463; P = 0.026). Conclusions: The activities of skeletal muscle 11 beta-HSD1 and 11 beta-HSD2 are altered in diabetes, which together may reduce intracellular cortisol generation, potentially conferring metabolic protection.