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11ß-Hydroxysteroid Dehydrogenase Type 1 Activity in Lean and Obese Males with Type 2 Diabetes Mellitus

Division of Medical Sciences (G.V., A.A., J.W.T., P.G.M., R.C., A.H.B., P.M.S., S.K.), University of Birmingham, Queen Elizabeth and Birmingham Heartlands Hospitals, Birmingham B15 2TH, United Kingdom; Department of Radiology (A.K.B.), Birmingham Heartlands Hospital, Birmingham B9 5SS, United Kingdom; Steroid Laboratory (C.H.L.S.), Children’s Hospital Oakland Research Institute, Oakland, California 94609-1809; Regional Endocrine Unit (P.J.W.), Southampton University Medical School, Southampton SO16 0XW, United Kingdom; and Regional Endocrine Laboratory (G.H.), Department of Clinical Biochemistry, University Hospital Birmingham National Health Service Trust, Birmingham B29 6JD, United Kingdom

Address all correspondence and requests for reprints to: Prof. P. M. Stewart, Division of Medical Sciences, University of Birmingham, Queen Elizabeth Hospital, Edgbaston, Birmingham B15 2TH, United Kingdom. E-mail: p.m.stewart{at}bham.ac.uk.

Glucocorticoids play an important role in the pathogenesis of obesity and insulin resistance. Impaired conversion of cortisone (E) to cortisol (F) by the type 1 isoenzyme of 11ß-hydroxysteroid dehydrogenase (11ß-HSD) in obesity may represent a protective mechanism preventing ongoing weight gain and glucose intolerance. We have studied glucocorticoid metabolism in 33 male subjects with type 2 diabetes mellitus [age, 44.2 ± 13 yr; body mass index (BMI), 31.1 ± 7.5 kg/m² (mean ± SD)] and 38 normal controls (age, 41.4 ± 14 yr; BMI, 38.2 ± 12.8 kg/m²).

Circulating F:E ratios were elevated in the diabetic group and correlated with serum cholesterol and homeostasis model assessment-S. There was no difference in 11ß-HSD1 activity between diabetic subjects and controls. In addition, 11ß-HSD1 activity was unaffected by BMI in diabetic subjects. However, in control subjects, increasing BMI was associated with a reduction in the urinary tetrahydrocortisol+5-tetrahydrocortisol:tetrahydrocortisone ratio (P < 0.05) indicative of impaired 11ß-HSD1 activity. The degree of inhibition correlated tightly with visceral fat mass. Changes in 11ß-HSD1 activity could not be explained by circulating levels of adipocytokines.

Impaired E to F metabolism in obesity may help preserve insulin sensitivity and prevent diabetes mellitus. Failure to down-regulate 11ß-HSD1 activity in patients with diabetes may potentiate dyslipidemia, insulin resistance, and obesity. Inhibition of 11ß-HSD1 may therefore represent a therapeutic strategy in patients with type 2 diabetes mellitus and obesity.

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