11beta-Hydroxysteroid dehydrogenase Type 1: genetic polymorphisms are associated with Type 2 diabetes in Pima Indians independently of obesity and expression in adipocyte and muscle.
OBJECTIVE
The enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) modulates tissue-specific glucocorticoid concentrations by generating active cortisol. We have shown that adipose tissue 11beta-HSD1 mRNA levels were associated with adiposity and insulinaemia. Here we conducted further expression and genetic association studies in Pima Indians.


METHODS
The 11beta-HSD1 mRNA concentrations were measured in abdominal subcutaneous adipocytes (n=61) and skeletal muscle tissues (n=64). Single nucleotide polymorphisms in the HSD11B1 gene were genotyped in a larger group of full-blooded Pima Indians.


RESULTS
Two representative SNPs (SNP1, n=706; SNP5, n=839) were associated with Type 2 diabetes mellitus (p=0.01), although neither SNP was associated with obesity. Among subjects with normal glucose tolerance, SNP1 (n=127) and SNP5 (n=159) were associated with insulin-mediated glucose uptake rates (p=0.03 and p=0.04), and SNP1 was further associated with fasting, 30-min, and 2-h plasma insulin concentrations (p=0.002, p=0.002 and p=0.03). Adipocyte 11beta-HSD1 mRNA concentrations were correlated positively with adiposity and insulinaemia, and were additionally negatively correlated with insulin-mediated glucose uptake rates; nevertheless, the adipocyte 11beta-HSD1 expression did not correlate with genotypes of the donors. The muscle 11beta-HSD1 mRNA concentrations did not correlate with any anthropometric or metabolic variables.


CONCLUSIONS
We confirmed that adipocyte 11beta-HSD1 mRNA concentrations were associated with adiposity, and showed that genetic variations in the HSD11B1 gene were associated with Type 2 diabetes mellitus, plasma insulin concentrations and insulin action, independent of obesity. The variable adipose expression might not be a primary consequence of these HSD11B1 SNPs. Therefore, it is possible that the HSD11B1 gene is under tissue-specific regulation, and has tissue-specific consequences.
Nair
S
S
National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona, USA.
Lee
Y H
YH
Lindsay
R S
RS
Walker
B R
BR
Tataranni
P A
PA
Bogardus
C
C
Baier
L J
LJ
Permana
P A
PA
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D017667:Adipocytes / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology; D000328:Adult; D001130:Arizona; D015992:Body Mass Index; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D005838:Genotype; D006801:Humans; D007198:Indians, North American; D007262:Infusions, Intravenous; D007328:Insulin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D007333:Insulin Resistance / Q000502:physiology; D008297:Male; D018482:Muscle, Skeletal / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology; D009765:Obesity / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D006113:United Kingdom
D007328:Insulin; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1