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Pro12Ala Polymorphism in the Peroxisome Proliferator–Activated Receptor-₂ Gene Is Associated With Increased Antilipolytic Insulin Sensitivity

Department of Endocrinology and Metabolism, Eberhard-Karls-Universität, Tübingen, Germany

The Pro12Ala polymorphism of the peroxisome proliferator–activated receptor (PPAR)-₂ is associated with reduced transcriptional activity in vitro and increased insulin sensitivity in humans in vivo. The mechanism by which this polymorphism influences insulin sensitivity in humans is unclear. PPAR-₂ is mainly expressed in adipocytes, and free fatty acids released from adipose tissue are key mediators of peripheral insulin resistance. Therefore, we examined insulin suppression of lipolysis in 51 subjects without (Pro/Pro) and 17 subjects with the polymorphism (X/Ala). Both groups were lean (BMI <27.0 kg/m²) and matched for age, BMI, waist-to-hip ratio, and sex. The isotopically (infusion of d₅ glycerol) determined glycerol rate of appearance was used as an index of lipolysis. Insulin sensitivity of lipolysis was expressed as the insulin concentration resulting in half-maximal suppression (EC₅₀). This was directly determined during a three-step hyperinsulinemic-euglycemic clamp (n = 21) or estimated indirectly during a standard hyperinsulinemic-euglycemic clamp (n = 47). The insulin sensitivity index (ISI) of glucose disposal was 0.095 ± 0.006 µmol · kg^-1 · min^-1 · pmol^-1 · l^–1 in the control group and 0.129 ± 0.008 µmol · kg^-1 · min^-1 · pmol^-1 · l^–1 in the X/Ala group (P = 0.003). The EC₅₀ was 56 ± 2 pmol/l in the control group and 44 ± 3 pmol/l in the X/Ala group (P = 0.001). The EC₅₀ of lipolysis and ISI was significantly correlated (r = 0.42, P = 0.002). In conclusion, in lean subjects, the Pro12Ala polymorphism is associated with increased insulin sensitivity of glucose disposal and suppression of lipolysis. This result suggests that an altered transcriptional activity of PPAR-₂ in X/Ala subjects either causes a more efficient suppression of lipolysis in adipose tissue, which in turn results in improved insulin-stimulated glucose disposal in muscle, or, alternatively, beneficially affects insulin signaling in both tissues independently of one another.

Abbreviations: EC₅₀, insulin concentration resulting in half-maximal suppression; FFA, free fatty acid; GIR, mean infusion rate of exogenous glucose; ISI, insulin sensitivity index; MCR, metabolic clearance rate of glucose; PPAR, peroxisome proliferator–activated receptor; R_a, rate of appearance

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