Pro12Ala polymorphism in the peroxisome proliferator-activated receptor-gamma(2) gene is associated with increased antilipolytic insulin sensitivity

The Pro12Ala polymorphism of the peroxisome proliferator-activated receptor (PPAR)-gamma (2) is associated with reduced transcriptional activity in vi tro and increased insulin sensitivity in humans in vivo. The mechanism by w hich this polymorphism influences insulin sensitivity in humans is unclear. PPAR-gamma (2) is mainly expressed in adipocytes, and free fatty acids rel eased from adipose tissue are key mediators of peripheral insulin resistanc e. Therefore, we examined insulin suppression of lipolysis in 51 subjects w ithout (Pro/Pro) and 17 subjects with the polymorphism (X/Ala). Both groups were lean (BMI <27.0 kg/m(2)) and matched for age, BMI, waist-to-hip ratio , and sex. The isotopically (infusion of d(5) 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-m aximal 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 sensitiv ity index (ISI) of glucose disposal was 0.095 <plus/minus> 0.006 mu mol . k g(-1) . min(-1) . pmol(-1) . l(-1) in the control group and 0.129 +/- 0.008 mu mol . 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 EC,, of Lipolysis and ISI was significant ly correlated (r = 0.42, P = 0.002). In conclusion, in lean subjects, the P ro12Ala polymorphism is associated with increased insulin sensitivity of gl ucose disposal and suppression of Lipolysis. This result suggests that an a ltered transcriptional activity of PPAR-gamma (2) in X/Ala subjects either causes a more efficient suppression of Lipolysis in adipose tissue, which i n turn results in improved insulin-stimulated glucose disposal in muscle, o r, alternatively, beneficially affects insulin signaling in both tissues in dependently of one another.