Effect of experimental elevation of free fatty acids on insulin secretion and insulin sensitivity in healthy carriers of the Pro12Ala polymorphism ofthe peroxisome proliferator-activated receptor-gamma(2) gene

The transcription of many genes involved in lipid metabolism is regulated b y the peroxisome proliferator-activated receptor-gamma (PPAR-gamma). The Pr o12Ala polymorphism in the PPAR-gamma (2), gene has been associated with re duced transcriptional activity in vitro and increased insulin sensitivity i n vivo. Although PPAR-gamma has been demonstrated in human beta -cells, it is unknown whether the Pro12Ala polymorphism plays a role in insulin secret ion. Moreover, it is also unknown if and how the effect of free fatty acids (FFAs) on insulin secretion and insulin sensitivity is modulated by the pr esence of this polymorphism. We therefore performed hyperglycemic clamps (8 mmol/l, 140 min, 5 g arginine bolus at min 120) in 10 healthy subjects wit h the (X/Ala) polymorphism and in 10 subjects without the polymorphism (Pro /Pro) basally and after 5 h infusion of Intralipid plus heparin. FFA concen trations increased hom 473 +/- 61 mu mol/l to 1,732 +/- 163 mu mol/l in the Pro/Pro and from 372 +/- 46 mu mol/l to 1,630 +/- 96 mu mol/l in the X/Ala group (P = 0.68). Basally, neither insulin sensitivity nor insulin secreti on were significantly different between the two groups. During infusion of Intralipid, first-phase insulin secretion remained unchanged in both groups (P = 0.21). In the Pro/Pro group, second-phase insulin secretion remained unchanged (444 +/- 67 vs. 471 +/- 93 pmol/min) and the response to arginine increased from 5,007 +/- 41 to 6,072 +/- 732 pmol/min. In contrast, in the X/Ala group, there was a decrease of both second-phase insulin secretion ( 533 +/- 58 to 427 +/- 48 pmol/min, P = 0.02 vs. Pro/Pro) and in the respons e to arginine (from 7,518 +/- 1,306 to 6,458 +/- 1,040 pmol/min, P = 0.014 vs. Pro/Pro). The insulin sensitivity index decreased comparably in Pro/Pro and X/Ala (to 71 +/- 8 vs. 74 +/- 9% of basal, P = 0.8). In conclusion, th ese results provide evidence that the Pro12Ala polymorphism in the PPAR-gam ma (2), gene might be involved in a differential regulation of insulin secr etion in response to increased FFAs in humans.