Familial hyperproinsulinemia. Two cohorts secreting indistinguishable type II intermediates of proinsulin conversion.
Familial hyperproinsulinemia. Two cohorts secreting indistinguishable type II intermediates of proinsulin conversion.
复制标题
家族性高胰岛素原血症。
DOI：
10.1172/jci111264
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发表时间：
1984
期刊：
影响因子：
--
通讯作者：
Tager,HS
中科院分区：
文献类型：
--
作者：
Robbins,DC;Shoelson,SE;Rubenstein,AH;Tager,HS
家族性高胰岛素原血症是一种遗传性综合征，其中个体分泌大量9，000-mol wt胰岛素原样物质，已在两个不相关的队列中确定。对两个队列中每个队列的材料进行的单独分析表明，胰岛素原样肽是一种转化中间体，其中一种情况下C肽仍与胰岛素B链连接，而另一种情况下C肽仍与胰岛素A链连接。为了重新调查这一明显的差异，我们现在已经使用化学，生物化学，免疫化学和物理技术来比较平行的免疫亲和层析纯化的，胰岛素原样肽从两个家庭的成员的血清分离的结构。我们的研究结果表明，受影响的个人在这两个队列分泌两个链的中间体的胰岛素原转化，其中的羧基末端的C-肽是延长胰岛素A链和胰岛素B链的氧化亚硫酸分解释放。通过反相高效液相色谱法，使用两种不同的缓冲系统的转换中间体的分析表明，胰岛素原相关的肽从两个家庭的cumps在一个单一的位置非常接近的正常的中间des-Arg 31，Arg 32-胰岛素原。此外，用乙酸酐处理这些肽阻止了胰蛋白酶催化的C肽从胰岛素A链上的裂解，结果证明了两种异常形式中存在Lys 64和不存在Arg 65。我们的结论是，个人从两个队列与家族性高胰岛素原血症的秘密非常相似或相同的中间体的胰岛素原转换中的C-肽仍然连接到胰岛素A链，其中Arg 65已被替换为另一个氨基酸残基。
Familial hyperproinsulinemia, a hereditary syndrome in which individuals secrete high amounts of 9,000-mol wt proinsulin-like material, has been identified in two unrelated cohorts. Separate analysis of the material from each of the two cohorts had suggested that the proinsulin-like peptide was a conversion intermediate in which the C-peptide remained attached to the insulin B-chain in one case, whereas it was a conversion intermediate in which the C-peptide remained attached to the insulin A-chain in the other. To reinvestigate this apparent discrepancy, we have now used chemical, biochemical, immunochemical, and physical techniques to compare in parallel the structures of the immunoaffinity chromatography-purified, proinsulin-like peptides isolated from the serum of members of both families. Our results show that affected individuals in both cohorts secrete two-chained intermediates of proinsulin conversion in which the COOH-terminus of the C-peptide is extended by the insulin A-chain and from which the insulin B-chain is released by oxidative sulfitolysis. Analysis of the conversion intermediates by reverse-phase high-performance liquid chromatography using two different buffer systems showed that the proinsulin-related peptides from both families elute at a single position very near that of the normal intermediate des-Arg31, Arg32-proinsulin. Further, treatment of these peptides with acetic anhydride prevented trypsin-catalyzed cleavage of the C-peptide from the insulin A-chain, a result demonstrating the presence of Lys64 and the absence of Arg65 in both abnormal forms. We conclude that individuals from both cohorts with familial hyperproinsulinemia secret very similar or identical intermediates of proinsulin conversion in which the C-peptide remains attached to the insulin A chain and in which Arg65 has been replaced by another amino acid residue.