Gefel D, Hendrick G K, Mojsov S, Habener J, Weir G C
Joslin Diabetes Center, Boston, Massachusetts 02215.
Endocrinology. 1990 Apr;126(4):2164-8. doi: 10.1210/endo-126-4-2164.
Glucagon-like peptide 1-(7-37) [GLP-I-(7-37)] is a 31-amino acid hormone which may have an important role in the regulation of insulin secretion, It is processed from preproglucagon and found in the pancreas, brain, and, in highest quantity, intestine. In previous studies we found that GLP-I-(7-37) is a potent insulin secretagogue, and its effect was indistinguishable from that of GLP-I-(7-36) amide at concentrations of 10(-11) M. Herein we report insulinotropic effects of additional GLP-I analogs. GLP-I-(7-34) had no stimulatory effect on insulin release at 10(-10) M, but had a partial effect at 10(-9) M and was as active as GLP-I-(7-37) at 10(-8) M. GLP-I-(7-33) had no effect at any concentration tested. GLP-I-(8-37) caused no significant effect on insulin release at 10(-9) and 10(-8) M, but did have an effect at the high concentration of 10(-7) M. Similar results were found with cAMP formation in the beta TC1 line. In this system GLP-I-(7-34) was less potent than GLP-I-(7-37) at a concentration of 5 x 10(-9) M. GLP-I-(7-33) had only about 0.1% the potency of GLP-I-(7-37); thus, there is good agreement between cAMP formation in the beta-cell line and insulin secretion from the perfused pancreas experiments. We conclude that histidine in the 7 position in the N-terminus of GLP-I-(7-37) is crucial for cAMP formation and insulin secretion, and that removal of the last three C-terminus residues of GLP-I-(7-37) results in only partial loss of activity; the residue in the 34 position is, however, essential for the insulinotropic action.
胰高血糖素样肽1-(7 - 37)[GLP-I-(7 - 37)]是一种由31个氨基酸组成的激素，它可能在胰岛素分泌调节中发挥重要作用。它由前胰高血糖素加工而来，存在于胰腺、大脑中，在肠道中的含量最高。在之前的研究中我们发现，GLP-I-(7 - 37)是一种强效的胰岛素促分泌剂，在10(-11) M的浓度下，其作用与GLP-I-(7 - 36)酰胺难以区分。在此我们报告其他GLP-I类似物的促胰岛素作用。GLP-I-(7 - 34)在10(-10) M时对胰岛素释放没有刺激作用，但在10(-9) M时有部分作用，在10(-8) M时与GLP-I-(7 - 37)活性相当。GLP-I-(7 - 33)在任何测试浓度下都没有作用。GLP-I-(8 - 37)在10(-9)和10(-8) M时对胰岛素释放没有显著影响，但在10(-7) M的高浓度时有作用。在βTC1细胞系中cAMP形成实验也得到了类似结果。在这个系统中，在5×10(-9) M的浓度下，GLP-I-(7 - 34)的效力低于GLP-I-(7 - 37)。GLP-I-(7 - 33)的效力仅约为GLP-I-(7 - 37)的0.1%；因此，β细胞系中cAMP形成与灌注胰腺实验中胰岛素分泌之间存在良好的一致性。我们得出结论，GLP-I-(7 - 37) N端第7位的组氨酸对于cAMP形成和胰岛素分泌至关重要，去除GLP-I-(7 - 37) C端最后三个残基仅导致部分活性丧失；然而，第34位的残基对于促胰岛素作用是必不可少的。
