Rosella G, Zajac J D, Baker L, Kaczmarczyk S J, Andrikopoulos S, Adams T E, Proietto J
Department of Medicine, University of Melbourne, Royal Melbourne Hospital, Victoria, Australia.
Mol Endocrinol. 1995 Oct;9(10):1396-404. doi: 10.1210/mend.9.10.8544847.
The effects of an overexpressed, non-insulin-responsive gluconeogenic enzyme, phosphoenolpyruvate carboxykinase (GTP) (PEPCK; EC 4.1.1.32), on glucose homeostasis were investigated. Transgenic rats harboring a metallothionein-driven PEPCK gene (lacking the entire PEPCK upstream-regulatory region) expressed transgene PEPCK mRNA in the key gluconeogenic tissues, liver and kidney. Female transgenic rats, studied at 10 weeks of age, showed mild fasting hyperglycemia (6.9 +/- 0.2 vs. 5.9 +/- 0.1 mM P = 0.002 n = 6), hyperinsulinemia (92.2 +/- 4.0 vs. 54.0 +/- 6.6 pM, P = 0.001, n = 6), impaired glucose tolerance and increased weight gain (178.3 +/- 3.2 vs. 153.4 +/- 2.5 g, P = 0.001, n = 16 and n = 13 transgenic and control rats, respectively). Despite hyperinsulinemia at this age, kidneys of transgenic rats maintained a significant 20% elevation of total PEPCK enzyme activity, while total liver PEPCK activity was not reduced. This study suggests that an insulin-resistant step in the gluconeogenic pathway can lead to glucose intolerance and an increase in weight. These rats offer the unique opportunity to study the metabolic consequences of chronic, mild excess glucose supply, as seen in non-insulin-dependent diabetes.
研究了一种过表达的、非胰岛素反应性糖异生酶——磷酸烯醇丙酮酸羧激酶（GTP）（PEPCK；EC 4.1.1.32）对葡萄糖稳态的影响。携带金属硫蛋白驱动的PEPCK基因（缺少整个PEPCK上游调控区）的转基因大鼠在关键的糖异生组织肝脏和肾脏中表达转基因PEPCK mRNA。对10周龄的雌性转基因大鼠进行研究，结果显示其存在轻度空腹高血糖（6.9±0.2对5.9±0.1 mM，P = 0.002，n = 6）、高胰岛素血症（92.2±4.0对54.0±6.6 pM，P = 0.001，n = 6）、糖耐量受损以及体重增加（转基因大鼠和对照大鼠分别为178.3±3.2对153.4±2.5 g，P = 0.001，n = 16和n = 13）。尽管在这个年龄存在高胰岛素血症，但转基因大鼠的肾脏中总PEPCK酶活性仍显著升高20%，而肝脏中的总PEPCK活性并未降低。这项研究表明，糖异生途径中胰岛素抵抗步骤可导致糖耐量受损和体重增加。这些大鼠为研究慢性轻度葡萄糖供应过剩的代谢后果提供了独特的机会，这在非胰岛素依赖型糖尿病中可见。
