Evidence for greater oxidative substrate flexibility in male carriers of the Pro 12 Ala polymorphism in PPARgamma2.
The Pro12Ala polymorphism of the peroxisome proliferator-activated receptor gamma2 (PPARgamma2) 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 micromol/kg/min/pM) than in Pro/Pro (0.12 +/- 0.01 micromol/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.
Thamer
C
C
Department of Endocrinology and Metabolism, Eberhard-Karls-Universität, Tübingen, Germany.
Haap
M
M
Volk
A
A
Maerker
E
E
Becker
R
R
Bachmann
O
O
Machicao
F
F
Häring
H U
HU
Stumvoll
M
M
D000328:Adult; D002151:Calorimetry; D002153:Calorimetry, Indirect; D002241:Carbohydrates / Q000097:blood; D015309:Glucose Clamp Technique; D006801:Humans; D007328:Insulin / Q000097:blood; D008055:Lipids / Q000097:blood; D008297:Male; D010084:Oxidation-Reduction; D011110:Polymorphism, Genetic / Q000235:genetics*; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*
D002241:Carbohydrates; D007328:Insulin; D008055:Lipids; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors