Thrifty Genotype, Thrifty Phenotype, or Both?
The Pro12Ala polymorphism in the PPARγ2 gene has been associated with reduced risk of type 2 diabetes and insulin resistance. Recently, an association between dizygotic twinning and PPARγ gene polymorphisms has been proposed. We investigated the phenotypic appearance of the two polymorphisms (Pro12Ala and exon 6 C→T) in PPARγ among elderly twins (207 monozygotic [MZ] and 342 dizygotic [DZ]) and evaluated whether they could explain previously reported differences in plasma glucose and insulin profiles among MZ and DZ twins. We demonstrated a significant impact of the Pro12Ala polymorphism on glucose tolerance, diabetic status, homeostasis model assessment for insulin resistance, and plasma insulin profiles in twins. No impact of the silent exon 6 polymorphism on glucose homeostasis or plasma insulin profiles was found. Independent of the polymorphisms, we observed a significant impact of zygosity status per se on the plasma insulin profile after oral glucose ingestion, with the MZ twins being more hyperinsulinemic, indicating insulin resistance, than the DZ twins. Nonsignificantly higher glucose concentrations were observed among MZ compared with DZ twins. We demonstrated an association between the Ala allele and reduced risk of diabetes and insulin resistance in twins. However, the differences in metabolic profiles among MZ and DZ twins were not explained by differences in frequencies of the genetic variants and may be due to intrauterine environmental factors operating in twins independent of genotype. Accordingly, our study simultaneously supports a role for both the intrauterine environment (thrifty phenotype) and for genetics (thrifty genotype) in the etiology of insulin resistance and perhaps glucose intolerance in twins.
Address correspondence and reprint requests to Dr. Pernille Poulsen, Department of Endocrinology, Odense University Hospital, Sdr. Boulevard, 5000 Odense, Denmark. E-mail:; or Dr. Allan Vaag, Steno Diabetes Center, Niels Steensensvej, 2820 Gentofte, Denmark. E-mail: .
Received for publication 28 August 2001 and accepted in revised form 7 October 2002.
P.P. and G.A. contributed equally to this work.
AUC, area under the curve; DZ, dizygotic; HOMA, homeostasis model assessment; IGT, impaired glucose tolerance; MZ, monozygotic; NGT, normal glucose tolerance; OGTT, oral glucose tolerance test; PPAR, peroxisome proliferator–activated receptor.