Severe defect in proglucagon processing in islet A-cells of prohormone convertase 2 null mice
Severe defect in proglucagon processing in islet A-cells of prohormone convertase 2 null mice
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DOI：
10.1074/jbc.m103362200
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发表时间：
2001-07-20
影响因子：
4.8
通讯作者：
Steiner, DF
中科院分区：
文献类型：
--
作者：
Furuta, M;Zhou, A;Steiner, DF
编码激素原转化酶2 （PC2）基因缺失的纯合小鼠通常是健康的，但有轻度低血糖和平坦的葡萄糖耐量曲线。他们的胰岛显示明显的α (A)细胞增生，提示胰高血糖素加工可能存在缺陷(Furuta， M., Yano， H., Zhou， A., Rouille, Y ., Holst， J., Carroll， R., Ravazzola， M., Orci， L., Furuta， H., and Steiner， D. (1997) Proc. Natl。学会科学。美国94,6646-6651)。在本报告中，我们通过脉冲追逐标记研究了这些小鼠离体胰岛中胰高血糖素原的生物合成和加工，发现胰高血糖素原在持续8小时的追逐期基本上没有加工。在敏感的结构域间位点（残基71和72）似乎只发生了很小比例的裂解。因此，这些观察结果最终证明了PC2对胰岛a细胞中胰高血糖素产生的重要性。超微结构和免疫细胞化学研究表明，在增生和肥厚的a细胞中，在不典型的分泌颗粒中存在大量的胰高血糖素，形态学证据表明，在PC2缺失的胰岛中，胰高血糖素分泌率很高。这些发现提供了强有力的证据，表明活性胰高血糖素是维持正常血糖水平所必需的，在任何时候都能平衡胰岛素的作用。
Mice homozygous for a deletion in the gene encoding prohormone convertase 2 (PC2) are generally healthy but have mild hypoglycemia and flat glucose-tolerance curves. Their islets show marked alpha (A)-cell hyperplasia, suggesting a possible defect in glucagon processing (Furuta, M., Yano, H., Zhou, A., Rouille, Y,, Holst, J., Carroll, R., Ravazzola, M., Orci, L., Furuta, H., and Steiner, D. (1997) Proc. Natl. Acad. Sci. U.S.A. 94, 6646-6651). In this report we have examined the biosynthesis and processing of proglucagon in isolated islets from these mice via pulse-chase labeling and find that proglucagon undergoes essentially no processing in chase periods up to 8 h in duration. Only a small percent of cleavage at the sensitive interdomain site (residues 71 and 72) appears to occur. These observations thus conclusively demonstrate the essentiality of PC2 for the production of glucagon in the islet A-cells, Ultrastructural and immunocytochemical studies indicate the presence of large amounts of proglucagon in atypical appearing secretory granules in the hyperplastic and hypertrophic A-cells, along with morphological evidence of high rates of proglucagon secretion in PC2 null islets. These findings provide strong evidence that active glucagon is required to maintain normal blood glucose levels, counterbalancing the action of insulin at all times.