Single Nucleotide Polymorphisms in the Peroxisome Proliferator–Activated Receptor δ Gene Are Associated With Skeletal Muscle Glucose Uptake

doi:10.2337/diabetes.54.12.3587

Single Nucleotide Polymorphisms in the Peroxisome Proliferator–Activated Receptor δ Gene Are Associated With Skeletal Muscle Glucose Uptake

¹Department of Medicine, University of Kuopio, Kuopio, Finland
²Positron Emission Tomography Centre, University of Turku, Turku, Finland
³Department of Medicine, University of Turku, Turku, Finland

Address correspondence and reprint requests to Markku Laakso, MD, Academy Professor, Department of Medicine, University of Kuopio, 70210 Kuopio, Finland. E-mail: markku.laakso{at}kuh.fi

Abstract

The peroxisome proliferator–activated receptors (PPARs) belong to a superfamily of nuclear receptors. It includes PPAR-δ, a key regulator of fatty acid oxidation and energy uncoupling, universally expressed in different tissues. The PPAR-δ gene (PPARD) maps to 6p21.2-p21.1 and has 11 exons and spans 35 kbp. We investigated the effects of single nucleotide polymorphisms (SNPs) of PPARD on whole-body, skeletal muscle, and subcutaneous adipose tissue glucose uptake in 129 healthy individuals using the hyperinsulinemic-euglycemic clamp technique combined with fluorine-18–labeled fluorodeoxyglucose ([¹⁸F]FDG) and positron emission tomography (PET). Three of six SNPs of PPARD and their haplogenotypes were significantly associated with whole-body insulin sensitivity. [¹⁸F]FDG-PET scanning indicated that SNPs of PPARD primarily affected insulin sensitivity by modifying glucose uptake in skeletal muscle but not in adipose tissue. Our results give evidence that SNPs of PPARD regulate insulin sensitivity particularly in skeletal muscle.