Polymorphisms in the gene encoding adiponectin receptor 1 are associated with insulin resistance and high liver fat.
OBJECTIVE
The adipokine adiponectin has insulin-sensitising, anti-atherogenic and anti-inflammatory properties. Recently, the genes for mouse and human adiponectin receptor-1 (ADIPOR1) and -2 (ADIPOR2) have been cloned. The aim of this study was to investigate whether genetic variants of the genes encoding ADIPOR1 and ADIPOR2 play a role in human metabolism.


METHODS
We screened ADIPOR1 and ADIPOR2 for polymorphisms and determined their association with glucose metabolism, lipid metabolism, an atherogenic lipid profile and inflammatory markers in 502 non-diabetic subjects. A subgroup participated in a longitudinal study; these subjects received diet counselling and increased their physical activity.


RESULTS
We identified six variants of ADIPOR1 and seven variants of ADIPOR2. A single-nucleotide polymorphism (SNP) in the putative promoter region 8503 bp upstream of the translational start codon (-8503 G/A) of ADIPOR1 (frequency of allele A=0.31) was in almost complete linkage disequilibrium with another SNP (-1927 T/C) in intron 1. Subjects carrying the -8503 A and -1927 C alleles had lower insulin sensitivity, as estimated from a 75 g OGTT (p=0.04) and determined during a euglycaemic clamp (n=295, p=0.04); they also had higher HbA(1)c levels (p=0.02) and, although the difference was not statistically significant, higher liver fat (n=85, determined by proton magnetic resonance spectroscopy, p=0.056) (all p values are adjusted for age, sex and percentage of body fat). In the longitudinal study (n=45), the -8503 A and -1927 C alleles were associated with lower insulin sensitivity (p=0.03) and higher liver fat (p=0.02) at follow-up compared with the -8503 G and -1927 T alleles, independently of basal measurements, sex and baseline and follow-up percentage of body fat.


CONCLUSIONS
The present findings suggest that the -8503 G/A SNP in the promoter or the -1927 T/C SNP in intron 1 of ADIPOR1 may affect insulin sensitivity and liver fat in humans.
Stefan
N
N
Department of Internal Medicine, Division of Endocrinology, Metabolism and Pathobiochemistry, University of Tübingen, Germany. norbert.stefan@med.uni-tuebingen.de
Machicao
F
F
Staiger
H
H
Machann
J
J
Schick
F
F
Tschritter
O
O
Spieth
C
C
Weigert
C
C
Fritsche
A
A
Stumvoll
M
M
Häring
H U
HU
D000273:Adipose Tissue / Q000473:pathology; D000328:Adult; D050218:Body Fat Distribution; D003430:Cross-Sectional Studies; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000473:pathology; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005858:Germany; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics*; D007438:Introns; D008055:Lipids / Q000737:chemistry; D008099:Liver / Q000473:pathology*; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D054419:Receptors, Adiponectin; D011956:Receptors, Cell Surface / Q000235:genetics*
C475418:ADIPOR1 protein, human; C475420:ADIPOR2 protein, human; D008055:Lipids; D054419:Receptors, Adiponectin; D011956:Receptors, Cell Surface