Impaired Glucose Tolerance and Insulin Resistance Are Associated With Increased Adipose 11β-Hydroxysteroid Dehydrogenase Type 1 Expression and Elevated Hepatic 5α-Reductase Activity

Abstract

OBJECTIVE-The precise molecular mechanisms contributing to the development of insulin resistance, impaired glucose tolerance (IGT), and type 2 diabetes are largely unknown. Altered endogenous glucocorticoid metabolism, including 11␤-hydroxysteroid dehydrogenase type 1 (11␤-HSD1), which generates active cortisol from cortisone, and 5␣-reductase (5␣R), which inactivates cortisol, has been implicated. RESEARCH DESIGN AND METHODS-A total of 101 obese patients (mean age 48 Ϯ 7 years, BMI 34.4 Ϯ 4.3 kg/m 2 , 66 women, 35 men) underwent 75-g oral glucose tolerance testing (OGTT), body composition analysis (dual-energy X-ray absorptiometry), assessment of glucocorticoid metabolism (24-h urine steroid metabolite analysis by gas chromatography/mass spectrometry), and subcutaneous abdominal adipose tissue biopsies.RESULTS-A total of 22.7% of women had IGT compared with 34.2% of men. Two women and five men were diagnosed with type 2 diabetes. In women, adipose 11␤-HSD1 expression was increased in patients with IGT and correlated with glucose levels across the OGTT (R ϭ 0.44, P Ͻ 0.001) but was independent of fat mass. Total glucocorticoid secretion was higher in men with and without IGT (normal 13,743 Ϯ 863 vs. 7,453 Ϯ 469 g/24 h, P Ͻ 0.001; IGT 16,871 Ϯ 2,113 vs. 10,133 Ϯ 1,488 g/24 h, P Ͻ 0.05), and in women, it was higher in those with IGT (7,453 Ϯ 469 vs. 10,133 Ϯ 1,488 g/24 h, P Ͻ 0.001). In both sexes, 5␣R activity correlated with fasting insulin (men R ϭ 0.53, P ϭ 0.003; women R ϭ 0.33, P ϭ 0.02), insulin secretion across an OGTT (men R ϭ 0.46, P ϭ 0.01; women R ϭ 0.40, P ϭ 0.004), and homeostasis model assessment of insulin resistance (men R ϭ 0.52, P ϭ 0.004; women R ϭ 0.33, P ϭ 0.02).

Evaluating the Fat Distribution in Idiopathic Intracranial Hypertension Using Dual-Energy X-ray Absorptiometry Scanning

“…9,10 The scans were administered by a clinical scientist and trained radiographer. Patients with metal prosthetics or implants were included, and tissue overlying the prosthesis was excluded from analysis.…”

“…Regional fat mass was analysed as described previously. 9–11 The precision of total fat mass measures in terms of coefficients of variation (CV) was less than 3%, and for regional fat analyses it was less than 5%. Regional fat data were expressed as a percentage of the total body fat.…”

Diminished adrenal sensitivity and ACTH efficacy in obese premenopausal women

“…Increased clearance of cortisol might be caused by enhanced 5a-or 5b-reduction of the A-ring of cortisol in the liver, or changed activity of 11b-hydroxysteroid dehydrogenase 1 (11b-HSD1) decreasing the conversion of cortisone into cortisol (36,37). A drawback of these studies is that locally produced cortisol from cortisone and vice versa by 11b-HSD1, facilitating oxidation or reduction determined by local cell conditions, and subsequent release from fat, muscle, or splanchnic organs into the circulation, was not quantitated.…”

11β-Hydroxysteroid Dehydrogenase Type 1 and the Metabolic Syndrome

“…In contrast, in lean patients with T2DM (controlled by diet alone) a relatively small decrease in hepatic 11 -HSD1 activity, and no change in gluteal SAT enzyme activity, has been reported, but only by one group (Andrews et al, 2002;Andrews et al, 2003). Abdominal SAT 11 -HSD1 expression is higher in obese women with impaired glucose tolerance than in obese women with normal glucose tolerance, despite AT (total and regional) being similar between the two groups, and positively correlated with glucose area under curve levels across an oral glucose tolerance testing (Tomlinson et al, 2008). Whole-body 11 -HSD1 activity is increased in obese men with T2DM, compared to healthy normal-weight control subjects, whereas liver 11 -HSD1 activity is sustained, unlike in euglycemic obesity (R. Stimson et al, 2011).…”

“…Recently, more trustworthy results from various more tissue-specific measures were obtained (Andrews et al, 2002;Andrews et al, 2003;Desbriere et al, 2006;Gathercole & Stewart, 2010;Karlsson et al, 2010;Morton, 2010;Paulmyer-Lacroix et al, 2002;Rask et al, 2001;Rask et al, 2002;Sandeep et al, 2005;Stewart & Tomlinson, 2009;R. Stimson et al, 2011;Tomlinson et al, 2008;Valsamakis et al, 2004;Wamil & Seckl, 2007). After studies in men and women, representing a wide range of body compositions and insulin sensitivities (but without T2DM), 11 -HSD1 activity is found selectively increased in the abdominal subcutaneous AT (SAT) in obese humans (Rask et al, 2001;Rask et al, 2002;Sandeep et al, 2005), to a similar degree as the increase in transgenic overexpressing mice (Andrews et al, 2003), but impaired in the liver (Rask et al, 2001;Rask et al, 2002;.…”