Effects of aging on insulin synthesis and secretion. Differential effects on preproinsulin messenger RNA levels, proinsulin biosynthesis, and secretion of newly made and preformed insulin in the rat.
Effects of aging on insulin synthesis and secretion. Differential effects on preproinsulin messenger RNA levels, proinsulin biosynthesis, and secretion of newly made and preformed insulin in the rat.
复制标题
DOI：
10.1172/jci113291
复制
发表时间：
1988
期刊：
影响因子：
--
通讯作者：
S. Y. Wang;P. Halban;J. Rowe
中科院分区：
文献类型：
--
作者：
S. Y. Wang;P. Halban;J. Rowe
人类和啮齿动物的衰老与葡萄糖刺激的胰岛β细胞(B细胞)胰岛素分泌显著下降有关。胰岛素分泌是生物合成蛋白分泌途径上一系列步骤的最终结果，包括胰岛素基因转录、转录本加工成胰岛素原mRNA、mRNA的翻译、新生成的胰岛素原在分泌囊泡中的分离和加工、胰岛素原向胰岛素的转化、囊泡向质膜的运输以及胞吐作用。我们利用Fischer大鼠，一种被广泛研究的啮齿动物衰老模型，研究了AGE在这一途径的三个阶段的影响：胰岛素原mRNA水平，胰岛素原合成，以及新合成和预制胰岛素的分泌。幼年(4-5个月)和老年(21-22个月)动物的胰腺重量、总胰岛素含量、胰岛大小和每个胰岛的平均胰岛素含量相同。年龄对喂饲动物全胰腺和胰岛在5.5 mM葡萄糖中培养16h的胰岛素原mRNA水平无明显影响。用5.5 mM葡萄糖预先孵育分离的胰岛，比较胰岛素原的生物合成和新合成胰岛素的分泌。经16.7 mM葡萄糖脉冲标记后，免疫沉淀法测定，与4-5mo胰岛相比，7mo胰岛胰岛素原合成减少16%，21-22mo胰岛减少39%，但总蛋白质合成没有减少。在2.8 mM葡萄糖条件下，4-5个月和21-22个月的胰岛在释放预制胰岛素和新生成的胰岛素方面没有差异。当追逐16.7 mM葡萄糖时，与年轻胰岛相比，老年胰岛新生成的胰岛素的分泌显著减少。在年轻和老年胰岛中，新合成的胰岛素优先于预制的胰岛素的释放。然而，由于在衰老的胰岛中，预先形成的胰岛素的分泌比新生成的胰岛素的分泌减少得更多，所以与年轻的成年胰岛相比，新生成的胰岛素相对于总免疫反应性胰岛素释放的比例增加了两到三倍。衰老对胰岛素合成-分泌途径中这些步骤的不同影响可能是由于将葡萄糖刺激转化为B细胞对葡萄糖的广泛反应的信号的不同损害。
Aging in men and rodents is associated with a marked decline in glucose stimulated insulin secretion by pancreatic beta cells (B cells). Secreted insulin is the end result of a series of steps along the biosynthetic protein-secretion pathway, including insulin gene transcription, processing of transcripts to preproinsulin mRNA, translation of mRNA, segregation and processing of newly made proinsulin in secretory vesicles, proinsulin to insulin conversion, transport of vesicles to the plasma membrane, and exocytosis. We have examined the influence of age at three stages along this pathway: preproinsulin mRNA levels, proinsulin synthesis, and secretion of newly made and preformed insulin, using Fischer rats, a widely studied rodent model of aging. Pancreatic weights and total insulin contents, islet sizes, and mean insulin content per islet were the same in young adult (4-5 mo) and senescent (21-22 mo) animals. There was no effect of age on preproinsulin mRNA levels in whole pancreata of fed animals, or in isolated islets cultured for 16 h in 5.5 mM glucose. Proinsulin biosynthesis and the secretion of newly made insulin were compared in isolated islets preincubated in 5.5 mM glucose. After a pulse label at 16.7 mM glucose, proinsulin synthesis, assayed by immunoprecipitation, was decreased 16% in 7 mo islets and 39% in 21-22 mo islets, compared with 4-5 mo islets, though total protein synthesis was not reduced. When chased at 2.8 mM glucose, 4-5 month and 21-22 mo islets showed no difference in release of preformed or newly made insulin. When chased at 16.7 mM glucose, there was a significant decrease in the secretion of newly made insulin in the old islets compared with the young islets. There was preferential release of newly made insulin over preformed insulin in both young and old islets. However, since secretion of preformed insulin was decreased much more than secretion of newly made insulin in senescent islets, these displayed a two- to threefold increase in the proportion of newly made insulin relative to total immunoreactive insulin released compared with young adult islets. The differential effects of aging on these steps in the insulin synthesis-secretion pathway may be due to varying impairments in signals transducing the glucose stimulus into the wide range of B cell responses to glucose.