Evidence for Greater Oxidative Substrate Flexibility in Male Carriers of the Pro 12 Ala Polymorphism in PPARγ₂

Abstract

The Pro12Ala polymorphism of the peroxisome proliferator-activated receptor γ₂ (PPARγ₂) gene is associated with reduced type 2 diabetes risk and increased insulin sensitivity. It is possible that the oxidative shift from lipid to glucose as a fuel is more efficient in Ala allele carriers. To test this hypothesis, we examined carbohydrate and lipid oxidation by indirect calorimetry in lean, glucose tolerant subjects with (X/Ala, n = 25) and without the Pro12Ala polymorphism (Pro/Pro, n = 73) basally and after insulin stimulation during a 2-hour eugylcaemic hyperinsulinaemic clamp. Insulin sensitivity was non-significantly greater in X/Ala (0.13 ± 0.01 µmol/kg/min/pM) than in Pro/Pro (0.12 ± 0.01 µmol/kg/min/pM, p = 0.27). Basally, there were no lipid nor carbohydrate oxidation differences between the groups. Interestingly, the decrease in lipid oxidation during insulin stimulation was significantly greater in male X/Ala (- 0.51 ± 0.06 mg/kg/min) than in male Pro/Pro (- 0.35 ± 0.04 mg/kg/min, p = 0.03). No difference was observed in females. Analogously, the change in carbohydrate oxidation in male X/Ala (1.34 ± 0.2 mg/kg/min) was significantly greater than in male Pro/Pro (1.03 ± 0.12 mg/kg/min, p = 0.05). The respiratory quotient increased more, but not significantly more, in male X/Ala (0.11 ± 0.01) than in male Pro/Pro subjects (0.08 ± 0.01, p = 0.08) but similarly in females. These results indicate that the mechanism by which the Ala allele improves insulin sensitivity might involve enhanced suppression of lipid oxidation permitting more efficient (predominantly non-oxidative) glucose disposal. It is unclear why this could be demonstrated only in males, although gender differences in substrate oxidation are well documented.

Indirect Calorimetry - Lipid Oxidation - Carbohydrate Oxidation - Insulin Resistance - Type 2 Diabetes

References

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