11β-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.

Increased In Vivo Regeneration of Cortisol in Adipose Tissue in Human Obesity and Effects of the 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitor Carbenoxolone

“…This observation is consistent with the results of previous studies that have suggested that elevated glucose production is not a feature of obesity alone (49), although among diabetic subjects, the increased glucose production rate is exaggerated by obesity (50). A recent study, albeit relying on urinary cortisol-to-cortisone metabolite ratios, has suggested that the downregulation of 11HSD1 in the liver with increasing obesity is less pronounced in type 2 diabetic patients (19). The incremental effect on hepatic insulin sensitivity with carbenoxolone was greater in lean healthy subjects (32) and diabetic patients (33) than we found here in obese patients.…”

“…The conventional measure of 11HSD1 is the ratio of urinary cortisol to cortisone metabolites, which is inconsistently altered in obesity (11)(12)(13)(14)(15)(16) and diabetes (17)(18)(19). However, this ratio may be confounded by the activity of other enzymes (e.g., 11HSD type 2, 5␣-and 5␤-reductase) that differ in obesity, and is insensitive to the tissue-specific changes in 11HSD1 that have been observed in animals.…”

Neuroendocrine mechanisms in insulin resistance

“…In the liver no alterations were found in type 2 diabetes whereas a downregulation was found in obese individuals (62). Even though there are many questions to resolve about regulation of 11β-HSD-1, it may be an attractive drug target for future treatments of obesity and diabetes.…”

11β-Hydroxysteroid dehydrogenase and the pre-receptor regulation of corticosteroid hormone action

“…reduced hepatic glucose output, reduced adipocyte differentiation). Of interest is that a BMI-related reduction in 11 -HSD1 activity is not observed in type 2 diabetes mellitus (Valsamakis et al 2004). Further prospective studies are required to evaluate the consequences of this upon the development of diabetes in obese subjects.…”