Majer M, Popov K M, Harris R A, Bogardus C, Prochazka M
Phoenix Epidemiology and Clinical Research Branch, National Institutes of Health, Phoenix, Arizona, 85016, USA.
Mol Genet Metab. 1998 Oct;65(2):181-6. doi: 10.1006/mgme.1998.2748.
Oxidative metabolism of glucose is regulated by pyruvate dehydrogenase (PDH) that can be inhibited by isoforms of PDH kinase (PDK). Recently, increased PDK activity has been implicated in the pathogenesis of insulin resistance and non-insulin-dependent diabetes mellitus (NIDDM) in obese subjects. Using quantitative RT-PCR, we measured mRNA of PDK2 and PDK4 isoforms in skeletal muscle biopsies from nondiabetic Pima Indians, a population with a high prevalence of NIDDM associated with obesity. PDK2 and PDK4 mRNAs were positively correlated with fasting plasma insulin concentration, 2-h plasma insulin concentration in response to oral glucose, and percentage body fat, whereas both isoforms were negatively correlated with insulin-mediated glucose uptake rates. Measurements of PDK2 and PDK4 mRNA during the hyperinsulinemic-euglycemic clamp and of PDK2 in cell culture indicated that both transcripts decrease in response to insulin. Increased fatty acid (FA) oxidation has been traditionally viewed as the cause for increased PDK activity contributing to insulin resistance in obese subjects. In contrast, our data indicate that insufficient downregulation of PDK mRNA in insulin-resistant individuals could be a cause of increased PDK expression leading to impaired glucose oxidation followed by increased FA oxidation.
葡萄糖的氧化代谢由丙酮酸脱氢酶（PDH）调节，而丙酮酸脱氢酶激酶（PDK）的同工型可抑制该酶。最近，PDK活性增加被认为与肥胖个体的胰岛素抵抗和非胰岛素依赖型糖尿病（NIDDM）的发病机制有关。我们使用定量逆转录聚合酶链反应（RT-PCR），测量了非糖尿病皮马印第安人骨骼肌活检样本中PDK2和PDK4同工型的mRNA，该人群中NIDDM与肥胖的患病率很高。PDK2和PDK4的mRNA与空腹血浆胰岛素浓度、口服葡萄糖后2小时血浆胰岛素浓度以及体脂百分比呈正相关，而这两种同工型均与胰岛素介导的葡萄糖摄取率呈负相关。在高胰岛素-正常血糖钳夹期间对PDK2和PDK4 mRNA的测量以及在细胞培养中对PDK2的测量表明，这两种转录本均对胰岛素产生反应而减少。传统观点认为，脂肪酸（FA）氧化增加是肥胖个体中PDK活性增加导致胰岛素抵抗的原因。相比之下，我们的数据表明，胰岛素抵抗个体中PDK mRNA下调不足可能是PDK表达增加的原因，导致葡萄糖氧化受损，随后FA氧化增加。
