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Increased In Vivo Regeneration of Cortisol in Adipose Tissue in Human Obesity and Effects of the 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitor Carbenoxolone
- Source :
- Diabetes. 54:872-879
- Publication Year :
- 2005
- Publisher :
- American Diabetes Association, 2005.
-
Abstract
- 11β-Hydroxysteroid dehydrogenase type 1 (11HSD1) regenerates cortisol from cortisone within adipose tissue and liver. 11HSD1 inhibitors may enhance insulin sensitivity in type 2 diabetes and be most efficacious in obesity when 11HSD1 is increased in subcutaneous adipose biopsies. We examined the regeneration of cortisol in vivo in obesity, and the effects of the 11HSD1 inhibitor carbenoxolone. We compared six lean and six obese men and performed a randomized, placebo-controlled crossover study of carbenoxolone in obese men. The obese men had no difference in their whole-body rate of regenerating cortisol (measured with 9,11,12,12-[2H4]cortisol tracer), but had more rapid conversion of [3H]cortisone to [3H]cortisol in abdominal subcutaneous adipose tissue (measured with microdialysis). During insulin infusion, adipose 11HSD1 activity fell markedly in lean but not in obese men. Carbenoxolone inhibited whole-body cortisol regeneration, but did not significantly inhibit adipose 11HSD1 and had no effects on insulin sensitivity (measured by [2H2]glucose infusion with or without hyperinsulinemia). Thus, in vivo cortisol generation is increased selectively within adipose tissue in obesity, perhaps reflecting resistance to insulin-mediated downregulation of 11HSD1. However, obese men are less susceptible than lean men to the insulin-sensitizing effects of carbenoxolone. To be useful in obese patients, 11HSD1 inhibitors will need to inhibit the enzyme more effectively in adipose tissue.
- Subjects :
- Adult
Male
medicine.medical_specialty
Hydrocortisone
Endocrinology, Diabetes and Metabolism
medicine.medical_treatment
Carbenoxolone
Adipose tissue
White adipose tissue
Double-Blind Method
11β-hydroxysteroid dehydrogenase type 1
Internal medicine
11-beta-Hydroxysteroid Dehydrogenase Type 1
Internal Medicine
Hyperinsulinemia
Humans
Insulin
Medicine
Obesity
Cross-Over Studies
biology
business.industry
Middle Aged
medicine.disease
Cortisone
Endocrinology
Adipose Tissue
biology.protein
business
medicine.drug
Subjects
Details
- ISSN :
- 1939327X and 00121797
- Volume :
- 54
- Database :
- OpenAIRE
- Journal :
- Diabetes
- Accession number :
- edsair.doi.dedup.....d8da51c21699c20a6035fcaaad3b3031