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Altered Activity of 11ß-Hydroxysteroid Dehydrogenase Types 1 and 2 in Skeletal Muscle Confers Metabolic Protection in Subjects with Type 2 Diabetes

Department of Endocrinology and Diabetes (C.J., V.R.O., W.J.I., F.P.A.), St. Vincent’s Hospital, Melbourne 3065, Australia; Department of Medicine (C.J., R.J.D., W.J.I., F.P.A.), University of Melbourne, Melbourne 3010, Australia; and Laboratory of Molecular Hypertension (Z.K.), Baker Heart Research Institute, Melbourne 3004, Australia

Address all correspondence and requests for reprints to: Christina Jang, M.B., B.S., FRACP, Department of Endocrinology and Diabetes, St. Vincent’s Hospital, Melbourne, 41 Victoria Parade, Fitzroy 3065, Australia. E-mail: christina.jang{at}svhm.org.au.

Context: There is little information regarding the regulation of 11ß-hydroxysteroid dehydrogenase (11ß-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 11ß-HSD1 and 11ß-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 11ß-HSD1, 11ß-HSD2, and H6PDH mRNA levels by quantitative RT-PCR and enzyme activity by percent conversion of [³H]cortisone and [³H]cortisol, respectively.

Results: At baseline, mRNA levels were similar in diabetic and control subjects for 11ß-HSD1, 11ß-HSD2, and H6PDH. 11ß-HSD1 activity was reduced in diabetic subjects (percent conversion of [³H]cortisone to [³H]cortisol was 11.4 ± 2.5% vs. 18.5 ± 2.2%; P = 0.041), and 11ß-HSD2 enzyme activity was higher in diabetic subjects (percent conversion of [³H]cortisone to [³H]cortisol was 17.2 ± 2.6% vs. 9.2 ± 1.3%; P = 0.012). After dexamethasone, 11ß-HSD1 mRNA increased in both groups (P < 0.001), whereas 11ß-HSD2 mRNA decreased (P = 0.002). 11ß-HSD1 activity increased in diabetic subjects (P = 0.021) but not in controls, whereas 11ß-HSD2 activity did not change in either group. At baseline, there was a significant negative correlation between 11ß-HSD1 and 11ß-HSD2 enzyme activity (r = –0.463; P = 0.026).

Conclusions: The activities of skeletal muscle 11ß-HSD1 and 11ß-HSD2 are altered in diabetes, which together may reduce intracellular cortisol generation, potentially conferring metabolic protection.