The Gly40Ser mutation in the human glucagon receptor gene associated with NIDDM results in a receptor with reduced sensitivity to glucagon
The Gly40Ser mutation in the human glucagon receptor gene associated with NIDDM results in a receptor with reduced sensitivity to glucagon
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DOI：
10.2337/diabetes.45.6.725
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发表时间：
1996-06-01
期刊：
影响因子：
7.7
通讯作者：
Nishimura, E
中科院分区：
文献类型：
--
作者：
Hansen, LH;Abrahamsen, N;Nishimura, E
胰岛激素胰高血糖素刺激肝脏葡萄糖产生，并且还被证明可以增强葡萄糖诱导的胰岛素分泌。由于胰高血糖素是葡萄糖稳态的关键调节剂，因此其受体被认为是参与NIDDM发病机制的候选基因。我们先前报道了胰高血糖素受体基因外显子2中的单个杂合错义突变，将甘氨酸变成丝氨酸在本研究中，在用野生型或Gly 40 Ser突变的人胰高血糖素受体cDNA稳定转染的幼仓鼠肾细胞和大鼠胰岛素瘤细胞（RIN-5AH）中检查该突变受体的信号传导特性。使用I-125标记的胰高血糖素进行竞争测定，并且在两种细胞类型中，发现Gly 40 Ser突变体受体与胰高血糖素的结合亲和力比野生型受体低大约三倍。在两种细胞类型中，与表达野生型的细胞相比，表达突变体受体的细胞中响应胰高血糖素的cAMP产生减少。最后，表达突变型受体的RIN细胞的胰高血糖素刺激的胰岛素分泌减少，使得与表达野生型受体的细胞相比，剂量-反应曲线向右移动。这些结果表明，这种位于胰高血糖素受体胞外区的单点突变降低了靶组织对胰高血糖素的敏感性。
The pancreatic islet hormone, glucagon, stimulates hepatic glucose production and has also been shown to potentiate glucose-induced insulin secretion, Because glucagon is a key regulator of glucose homeostasis, its receptor, which mediates the actions of glucagon, was considered a candidate gene involved in the pathogenesis of NIDDM, We have previously reported that a single heterozygous missense mutation in exon 2 of the glucagon receptor gene, which changes a glycine to a serine (Gly40Ser), is associated with NIDDM in a French population, In the present study, the signaling properties of this mutant receptor were examined in baby hamster kidney cells and rat insulinoma cells (RIN-5AH) stably transfected with either the wild type or Gly40Ser mutant human glucagon receptor cDNAs, Competition assays using I-125-labeled glucagon were performed, and in both cell types, the Gly40Ser mutant receptor was found to bind glucagon with an approximately threefold lower affinity compared with the wild type receptor, In both cell types, the production of cAMP in response to glucagon was decreased in cells expressing the mutant receptor compared with those expressing the wild type, Finally, glucagon-stimulated insulin secretion by RIN cells expressing the mutant receptor was decreased such that the dose-response curve was shifted to the right in comparison to that obtained with cells expressing the wild type receptor. These results indicate that this single-point mutation located in the extracellular region of the glucagon receptor decreases the sensitivity of target tissues to glucagon.