Haplotypes of PPARGC1A are associated with glucose tolerance, body mass index and insulin sensitivity in offspring of patients with type 2 diabetes

Diabetologia. 2005 Jul;48(7):1331-4. doi: 10.1007/s00125-005-1800-9. Epub 2005 May 24.


Aims/hypothesis: 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/interpretation: We conclude that PPARGC1A is likely to contribute to the risk of diabetes in offspring of patients with type 2 diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blood Glucose / genetics*
  • Blood Glucose / metabolism*
  • Body Mass Index
  • Diabetes Mellitus, Type 2 / genetics*
  • Female
  • Gene Expression Regulation
  • Gene Frequency
  • Genetic Predisposition to Disease
  • Genetic Variation
  • Glucose Tolerance Test
  • Heat-Shock Proteins / genetics*
  • Humans
  • Linkage Disequilibrium
  • Male
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Promoter Regions, Genetic
  • Transcription Factors / genetics*


  • Blood Glucose
  • Heat-Shock Proteins
  • PPARGC1A protein, human
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Transcription Factors