Ludwig D S, Vidal-Puig A, O'Brien R M, Printz R L, Granner D K, Moller D E, Flier J S
Division of Endocrinology and Metabolism, Beth Israel Hospital, Boston, Massachusetts 02215, USA.
J Clin Endocrinol Metab. 1996 Feb;81(2):503-6. doi: 10.1210/jcem.81.2.8636258.
Expression of phosphoenolpyruvate carboxykinase (PEPCK), a rate-limiting enzyme in gluconeogenesis, is under dominant negative regulation by insulin. In this study, we sought to test the hypothesis that mutations in the PEPCK gene promoter may impair the ability of insulin to suppress hepatic glucose production, thereby contributing to both the insulin resistance and increased rate of gluconeogenesis characteristic of NIDDM. The proximal PEPCK promoter region in 117 patients with noninsulin-dependent diabetes mellitus and 20 obese Pima Indians was amplified by PCR and analyzed with single strand conformation polymorphism techniques. In addition, limited direct DNA sequencing was performed on the insulin response sequence and flanking regions. No DNA sequence polymorphisms were found in any patient. This result suggests that mutations in cis-acting PEPCK gene regulatory elements do not constitute a common cause of noninsulin-dependent diabetes mellitus. The significance of genetic variation in promoter regions to human disease is discussed.
磷酸烯醇式丙酮酸羧激酶（PEPCK）是糖异生过程中的一种限速酶，其表达受胰岛素的显性负调控。在本研究中，我们试图验证以下假说：PEPCK基因启动子的突变可能损害胰岛素抑制肝糖生成的能力，从而导致胰岛素抵抗以及非胰岛素依赖型糖尿病（NIDDM）特有的糖异生速率增加。采用聚合酶链反应（PCR）扩增了117例非胰岛素依赖型糖尿病患者和20例肥胖皮马印第安人的近端PEPCK启动子区域，并运用单链构象多态性技术进行分析。此外，对胰岛素反应序列及其侧翼区域进行了有限的直接DNA测序。在所有患者中均未发现DNA序列多态性。该结果表明，顺式作用的PEPCK基因调控元件突变并非非胰岛素依赖型糖尿病的常见病因。文中还讨论了启动子区域基因变异对人类疾病的意义。
