A synthetic glucagon-like peptide-1 analog with improved plasma stability.
A synthetic glucagon-like peptide-1 analog with improved plasma stability.
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DOI：
10.1677/joe.0.1590093
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发表时间：
1998-10
期刊：
影响因子：
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通讯作者：
U. Ritzel;U. Leonhardt;M. Ottleben;A. Rühmann;K. Eckart;J. Spiess;G. Ramadori
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文献类型：
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作者：
U. Ritzel;U. Leonhardt;M. Ottleben;A. Rühmann;K. Eckart;J. Spiess;G. Ramadori
胰高血糖素样肽-1（GLP-1）是最强的内源性胰岛素刺激激素。在本研究中，在体外和体内评价了GLP-1类似物[Ser]GLP-1（7-36）酰胺（其中第二个N-末端氨基酸丙氨酸被丝氨酸取代）的血浆稳定性和生物活性。GLP-1与人或大鼠血浆孵育导致天然GLP-1（7-36）酰胺降解为GLP-1（9-36）酰胺，而血浆酶未显著降解[Ser]GLP-1（7-36）酰胺。使用葡萄糖响应性HIT-T15细胞，[Ser]GLP-1（7-36）酰胺显示出较强的促胰岛素活性，可被特异性GLP-1受体拮抗剂exendin-4（9-39）酰胺抑制。在大鼠中同时静脉注射[Ser]GLP-1（7-36）酰胺和葡萄糖诱导的血浆胰岛素水平增加是未修饰GLP-1（7-36）酰胺和葡萄糖的2倍，是葡萄糖单独给药的5倍。在静脉注射葡萄糖前1小时给予[Ser]GLP-1（7 - 36）酰胺时，其诱导的血浆胰岛素增加是GLP-1（7-36）酰胺的1.5倍。通过静脉注射毒蜥外泌肽-4（9-39）酰胺抑制[Ser]GLP-1（7-36）酰胺的促胰岛素作用。本数据表明，用丝氨酸替换第二个N-末端氨基酸丙氨酸改善了GLP-1（7-36）酰胺的血浆稳定性。体外和体内的促胰岛素作用没有受到这种修饰的显着损害。
Glucagon-like peptide-1 (GLP-1) is the most potent endogenous insulin-stimulating hormone. In the present study the plasma stability and biological activity of a GLP-1 analog, [Ser]GLP-1(7-36)amide, in which the second N-terminal amino acid alanine was replaced by serine, was evaluated in vitro and in vivo. Incubation of GLP-1 with human or rat plasma resulted in degradation of native GLP-1(7-36)amide to GLP-1(9-36)amide, while [Ser]GLP-1(7-36)amide was not significantly degraded by plasma enzymes. Using glucose-responsive HIT-T15 cells, [Ser]GLP-1(7-36)amide showed strong insulinotropic activity, which was inhibited by the specific GLP-1 receptor antagonist exendin-4(9-39)amide. Simultaneous i.v. injection of [Ser]GLP-1(7-36)amide and glucose in rats induced a twofold higher increase in plasma insulin levels than unmodified GLP-1(7-36)amide with glucose and a fivefold higher increase than glucose alone. [Ser]GLP-1(7-36)amide induced a 1.5-fold higher increase in plasma insulin than GLP-1(7-36)amide when given 1 h before i.v. application of glucose. The insulinotropic effect of [Ser]GLP-1(7-36)amide was suppressed by i.v. application of exendin-4(9-39)amide. The present data demonstrate that replacement of the second N-terminal amino acid alanine by serine improves the plasma stability of GLP-1(7-36)amide. The insulinotropic action in vitro and in vivo was not impaired significantly by this modification.