Haplotypes of PPARGC1A are associated with glucose tolerance, body mass index and insulin sensitivity in offspring of patients with type 2 diabetes.
OBJECTIVE
Decreased expression of the peroxisomal proliferator activated receptor gamma coactivator 1 alpha gene (PPARGC1A) is found in patients with type 2 diabetes, and variants in this gene have been linked with type 2 diabetes. Therefore, we investigated the effects of single nucleotide polymorphisms in PPARGC1A on body composition and glucose tolerance and on insulin sensitivity and secretion.


METHODS
Non-diabetic offspring (n=156, age 34.9+/-0.5 years [mean+/-SEM], BMI 26.2+/-0.4 kg/m2) underwent an OGTT and an IVGTT and the hyperinsulinaemic-euglycaemic clamp. The promoter and coding regions of PPARGC1A were sequenced.


RESULTS
Two haplotype blocks in PPARGC1A were observed, one in the promoter region (G-1774A, A-1679G, T-1422C, A-1278G, C-543A) and one in the coding region and 3' regions (Thr394Thr, Asp475Asp, Gly482Ser, Thr528Thr, Thr612Met, G+2381A). The coding region haplotype carrying the rare allele in codons 482 and 528 was associated with elevated glucose levels in an OGTT (p=0.024, adjusted for age, sex and BMI) and a haplotype carrying the rare alleles in codons 394 and 475 was associated with low BMI (p=0.033), high rates of whole-body glucose uptake (p=0.045) and low glucose levels in the OGTT (p=0.037).


CONCLUSIONS
We conclude that PPARGC1A is likely to contribute to the risk of diabetes in offspring of patients with type 2 diabetes.
Pihlajamäki
J
J
Department of Medicine, University of Kuopio, P.O. Box 1627, 70210, Kuopio, Finland. pihlajam@uku.fi
Kinnunen
M
M
Ruotsalainen
E
E
Salmenniemi
U
U
Vauhkonen
I
I
Kuulasmaa
T
T
Kainulainen
S
S
Laakso
M
M
D001786:Blood Glucose / Q000235:genetics* / Q000378:metabolism*; D015992:Body Mass Index; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005951:Glucose Tolerance Test; D006360:Heat-Shock Proteins / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000235:genetics*
D001786:Blood Glucose; D006360:Heat-Shock Proteins; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors