Rosiglitazone decreases 11beta-hydroxysteroid dehydrogenase type 1 in subcutaneous adipose tissue.
OBJECTIVE
The peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist rosiglitazone increases insulin sensitivity, which, in animal models, is comparable to the effect of a reduction in 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) activity. We therefore investigated whether rosiglitazone-induced insulin sensitivity is associated with changes in 11beta-HSD1 activity in different tissues.


METHODS
An oral glucose tolerance test (OGTT) and a euglycaemic hyperinsulinaemic clamp were performed in seven male volunteers [age 59.3 +/- 3.0 years, body mass index (BMI) 29.3 +/- 4.1 kg/m(2)] with impaired glucose tolerance before and after 8 weeks of rosiglitazone treatment. To assess hepatic 11beta-HSD1 activity, serum cortisol levels were measured after oral administration of cortisone acetate. 11beta-HSD1 activity and mRNA expression were assessed in abdominal subcutaneous fat biopsies. Total-body 11beta-HSD activities were estimated by calculating the urinary ratios of glucocorticoid metabolites.


RESULTS
As expected, rosiglitazone improved insulin resistance and postprandial hyperglycaemia. In parallel, 11beta-HSD1 mRNA expression [100 +/- 0% (reference) vs. 68.5 +/- 9.3%, P < 0.01] and activity [0.18 +/- 0.02 vs. 0.13 +/- 0.02 pmol/min/mg, P < 0.05] decreased in abdominal subcutaneous fat, while an increase in hepatic 11beta-HSD1 activity was detected [the area under the curve (AUC) for the cortisol/cortisone ratio was 1319 +/- 76 vs. 955 +/- 59; P < 0.05]. No changes in BMI, waist-to-hip ratio (WHR) and whole-body 11beta-HSD1 activity were found.


CONCLUSIONS
Part of the beneficial effects of rosiglitazone may be mediated by a reduction in the 11beta-HSD1 mRNA expression and activity in subcutaneous abdominal fat.
Mai
Knut
K
Department of Endocrinology, Diabetes and Nutrition, Charite - University Medicine Berlin, Campus Benjamin Franklin, Berlin, Germany. knut.mai@charite.de
Andres
Janin
J
Bobbert
Thomas
T
Maser-Gluth
Christiane
C
Möhlig
Matthias
M
Bähr
Volker
V
Pfeiffer
Andreas F H
AF
Spranger
Joachim
J
Diederich
Sven
S
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000235:genetics / Q000378:metabolism; D000324:Adrenocorticotropic Hormone / Q000097:blood; D001786:Blood Glucose / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005951:Glucose Tolerance Test; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D006943:Hyperglycemia / Q000188:drug therapy* / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000008:administration & dosage; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000502:physiology; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D000077154:Rosiglitazone; D050151:Subcutaneous Fat / Q000187:drug effects* / Q000201:enzymology*; D045162:Thiazolidinediones / Q000008:administration & dosage*
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D000324:Adrenocorticotropic Hormone; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; C468386:HSD11B1 protein, human; D006854:Hydrocortisone