title: 11beta-hydroxysteroid dehydrogenase type 1 activity in lean and obese males with type 2 diabetes mellitus.
abstract: 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 11beta-hydroxysteroid dehydrogenase (11beta-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/m(2) (mean +/- sd)] and 38 normal controls (age, 41.4 +/- 14 yr; BMI, 38.2 +/- 12.8 kg/m(2)). 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 11beta-HSD1 activity between diabetic subjects and controls. In addition, 11beta-HSD1 activity was unaffected by BMI in diabetic subjects. However, in control subjects, increasing BMI was associated with a reduction in the urinary tetrahydrocortisol+5alpha-tetrahydrocortisol:tetrahydrocortisone ratio (P < 0.05) indicative of impaired 11beta-HSD1 activity. The degree of inhibition correlated tightly with visceral fat mass. Changes in 11beta-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 11beta-HSD1 activity in patients with diabetes may potentiate dyslipidemia, insulin resistance, and obesity. Inhibition of 11beta-HSD1 may therefore represent a therapeutic strategy in patients with type 2 diabetes mellitus and obesity.
authors.affiliation: Division of Medical Sciences, University of Birmingham, Queen Elizabeth Hospital, Edgbaston, Birmingham B15 2TH, United Kingdom.
authors.forename: G
authors.initials: G
authors.lastname: Valsamakis
authors.forename: A
authors.initials: A
authors.lastname: Anwar
authors.forename: J W
authors.initials: JW
authors.lastname: Tomlinson
authors.forename: C H L
authors.initials: CH
authors.lastname: Shackleton
authors.forename: P G
authors.initials: PG
authors.lastname: McTernan
authors.forename: R
authors.initials: R
authors.lastname: Chetty
authors.forename: P J
authors.initials: PJ
authors.lastname: Wood
authors.forename: A K
authors.initials: AK
authors.lastname: Banerjee
authors.forename: G
authors.initials: G
authors.lastname: Holder
authors.forename: A H
authors.initials: AH
authors.lastname: Barnett
authors.forename: P M
authors.initials: PM
authors.lastname: Stewart
authors.forename: S
authors.initials: S
authors.lastname: Kumar
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000378:metabolism*; D000328:Adult; D000367:Age Factors; D000368:Aged; D044466:Asian People; D015992:Body Mass Index; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology*; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000201:enzymology*; D013851:Thinness / Q000201:enzymology*; D044465:White People
chemical_list: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D006854:Hydrocortisone