Stumvoll M, Wahl H G, Löblein K, Becker R, Machicao F, Jacob S, Häring H
Department of Endocrinology and Metabolism, Eberhard-Karls-Universität, Tübingen, Germany.
Diabetes. 2001 Apr;50(4):876-81. doi: 10.2337/diabetes.50.4.876.
The Pro12Ala polymorphism of the peroxisome proliferator-activated receptor (PPAR)-gamma2 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-gamma2 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 micromol x kg(-1) x min(-1) x pmol(-1) x l(-1) in the control group and 0.129+/-0.008 micromol x kg(-1) x min(-1) x pmol(-1) x 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-gamma2 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.
过氧化物酶体增殖物激活受体（PPAR）-γ2的Pro12Ala多态性与体外转录活性降低以及人类体内胰岛素敏感性增加相关。这种多态性影响人类胰岛素敏感性的机制尚不清楚。PPAR-γ2主要在脂肪细胞中表达，而从脂肪组织释放的游离脂肪酸是外周胰岛素抵抗的关键介质。因此，我们检测了51名无该多态性（Pro/Pro）的受试者和17名有该多态性（X/Ala）的受试者中胰岛素对脂解的抑制作用。两组均体型偏瘦（体重指数<27.0kg/m²），且在年龄、体重指数、腰臀比和性别方面相匹配。用同位素法（输注d5甘油）测定的甘油出现率作为脂解的指标。脂解的胰岛素敏感性用导致半数最大抑制的胰岛素浓度（EC50）表示。这在三步高胰岛素-正常血糖钳夹期间直接测定（n = 21），或在标准高胰岛素-正常血糖钳夹期间间接估算（n = 47）。对照组葡萄糖处置的胰岛素敏感性指数（ISI）为0.095±0.006μmol·kg⁻¹·min⁻¹·pmol⁻¹·l⁻¹，X/Ala组为0.129±0.008μmol·kg⁻¹·min⁻¹·pmol⁻¹·l⁻¹（P = 0.003）。对照组的EC50为56±2pmol/l，X/Ala组为44±3pmol/l（P = 0.001）。脂解的EC50与ISI显著相关（r = 0.42，P = 0.002）。总之，在体型偏瘦的受试者中，Pro12Ala多态性与葡萄糖处置的胰岛素敏感性增加和脂解抑制相关。这一结果表明，X/Ala受试者中PPAR-γ2转录活性的改变要么导致脂肪组织中脂解的抑制更有效，进而改善肌肉中胰岛素刺激的葡萄糖处置，要么相互独立地对两个组织中的胰岛素信号传导产生有益影响。
