11?-Hydroxysteroid dehydrogenase Type 1: genetic polymorphisms are associated with Type 2 diabetes in Pima Indians independently of obesity and expression in adipocyte and muscle

Abstract

Aims/hypothesis. The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) modulates tissuespecific glucocorticoid concentrations by generating active cortisol. We have shown that adipose tissue 11β-HSD1 mRNA levels were associated with adiposity and insulinaemia. Here we conducted further expression and genetic association studies in Pima Indians. Methods. The 11β-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 11β-HSD1 mRNA concentrations were correlated positively with adiposity and insulinaemia, and were additionally negatively correlated with insulin-mediated glucose uptake rates; nevertheless, the adipocyte 11β-HSD1 expression did not correlate with genotypes of the donors. The muscle 11β-HSD1 mRNA concentrations did not correlate with any anthropometric or metabolic variables. Conclusions/interpretation. We confirmed that adipocyte 11β-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.

Adipose tissue expression of 11beta-Hydroxysteroid dehydrogenase type 1 in cushing's syndrome and in obesity

“…In two populations, polymorphisms were associated with an increased risk of diabetes and hypertension, but not obesity (38,39). A polymorphism was also found that predicts lower 11βHSD1 expression and protection against diabetes (40).…”

Obesity and corticosteroids: 11β-Hydroxysteroid type 1 as a cause and therapeutic target in metabolic disease

“…Further, human 11 -HSD1 mRNA levels did not correlate with any metabolic parameters, unlike adipose 11 -HSD1 in obese PIMA Indians (Nair et al, 2004). However, a number of studies have highlighted the importance of skeletal muscle as a potential site of activity of the enzyme in humans (Whorwood et al, 2001, Abdallah et al, 2005, Jang et al 2006, 2007 which may reflect a species difference.…”

Relationship of 11.BETA.-hydroxysteroid dehydrogenase type 1 and hexose-6-phosphate dehydrogenase gene polymorphisms with metabolic syndrome and type 2 diabetes

“…Polymorphisms of HSD11B1 were reported to be associated with type 2 diabetes and insulin resistance in Pima Indians [17]. However, several other studies have failed to find evidence of an association between HSD11B1 polymorphisms and type 2 diabetes, obesity, or metabolic syndrome [18][19][20][21].…”

“…Two SNPs in the HSD11B1 gene [IVS3-29G/T (rs12086634) in intron 3 and IVS4-11120A/G (rs1000283) in intron 5] and two SNPs in the H6PD gene [R453Q (rs6688832) and P554L (rs17368528) in exon 5] were analyzed. We selected these four SNPs after consulting previously published studies suggesting a positive association of these SNPs with metabolic disease [17,26,27] and reviewing the allele frequencies of the Asian population and locations using the international HapMap project (http://www.hapmap.org/). LD coefficient r 2 between rs12086634 and rs1000283, and rs6688832 and rs17368528 were 0.00 and 0.62 respectively (http://www.broad.mit.edu/mpg/haploview/).…”