Kubota A, Yamada Y, Hayami T, Yasuda K, Someya Y, Ihara Y, Kagimoto S, Watanabe R, Taminato T, Tsuda K, Seino Y
Department of Metabolism and Clinical Nutrition, Kyoto University Faculty of Medicine, Japan.
Diabetes. 1996 Dec;45(12):1701-5. doi: 10.2337/diab.45.12.1701.
Gastric inhibitory polypeptide (GIP) potently stimulates insulin secretion from pancreatic islets in the presence of glucose as an incretin. Because the insulinotropic effect of GIP is reduced in NIDDM, it should be clarified whether defects in the GIP receptor gene contribute to the impaired insulin secretion in NIDDM. Using genomic DNA samples from Japanese NIDDM and non-NIDDM subjects, we have investigated the entire coding region of the GIP receptor gene by polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP). We have identified two missense mutations, Gly198-->Cys (Gly198Cys) in exon 7 and Glu354-->Gln (Glu354Gln) in exon 12. Investigation of the function of GIP receptor with either of these mutations reveals a half-maximal stimulation value of GIP-induced cAMP response in Chinese hamster ovary cells expressing the GIP receptor with Gly198Cys of 6.3 +/- 1.2 x 10(-10) mol/l (n = 3), which was considerably higher than that of the normal GIP receptor, 9.4 +/- 3.8 x 10(-12) mol/l GIP (n = 3), whereas that of the GIP receptor with Glu354Gln was not significantly different from that of the normal GIP receptor. To assess the possible role of the GIP receptor gene in genetic susceptibility to NIDDM, we have examined the allelic frequencies of Gly198Cys and Glu354Gln in NIDDM and control subjects. Association studies show no relationship between NIDDM and either of the two mutations.
胃抑制多肽（GIP）作为一种肠促胰岛素，在有葡萄糖存在的情况下能强烈刺激胰岛分泌胰岛素。由于NIDDM（非胰岛素依赖型糖尿病）患者中GIP的促胰岛素作用降低，因此需要明确GIP受体基因缺陷是否导致了NIDDM患者胰岛素分泌受损。我们使用来自日本NIDDM患者和非NIDDM患者的基因组DNA样本，通过聚合酶链反应-单链构象多态性（PCR-SSCP）技术研究了GIP受体基因的整个编码区。我们鉴定出两个错义突变，分别是外显子7中的Gly198→Cys（Gly198Cys）和外显子12中的Glu354→Gln（Glu354Gln）。对携带这两种突变之一的GIP受体功能进行研究发现，在中国仓鼠卵巢细胞中表达带有Gly198Cys突变的GIP受体时，GIP诱导的cAMP反应的半数最大刺激值为6.3±1.2×10⁻¹⁰mol/L（n = 3），这显著高于正常GIP受体的9.4±3.8×10⁻¹²mol/L GIP（n = 3），而带有Glu354Gln突变的GIP受体的该值与正常GIP受体的无显著差异。为了评估GIP受体基因在NIDDM遗传易感性中的可能作用，我们检测了NIDDM患者和对照受试者中Gly198Cys和Glu354Gln的等位基因频率。关联研究表明NIDDM与这两种突变均无关联。
