Deppe C, Breiner M, Brandenburg D, Joost H G
Institut für Pharmakologie und Toxikologie, RWTH Aachen, Germany.
Naunyn Schmiedebergs Arch Pharmacol. 1994 Aug;350(2):213-7. doi: 10.1007/BF00241099.
The effects of 7 covalently dimerized insulin derivatives on glucose transport in differentiated 3T3-L1 cells were investigated. Symmetric cross-linkage at lysine B29 with a bridge of 2 (oxalyl), 8 (suberoyl) or 12 (dodecanedioyl) carbon atoms produced derivatives with essentially unaltered receptor binding affinity but largely reduced intrinsic activity. Regardless of the chain length, these derivatives inhibited the effect of submaximal insulin concentrations. Insulin derivatives cross-linked at phenylalanine B1 or asymmetrically at B1/B29 were full agonists of the insulin receptor. When lysine B29 was cross-linked with the inactive desoctapeptide(B23-B30)insulin at phenylalanine B1, the intrinsic activity of the resulting dimer was lower than that of insulin, but higher than that of the symmetric B29-dimers. It is concluded that linkage at the B29-lysines, and not at the B1-phenylalanine, leads to partial agonism of dimerized insulin derivatives, regardless of the length of the crosslinker.
研究了7种共价二聚化胰岛素衍生物对分化的3T3-L1细胞中葡萄糖转运的影响。在赖氨酸B29处通过含2个（草酰基）、8个（辛二酰基）或12个（十二烷二酰基）碳原子的桥进行对称交联，得到的衍生物受体结合亲和力基本未改变，但内在活性大幅降低。无论链长如何，这些衍生物均抑制次最大胰岛素浓度的作用。在苯丙氨酸B1处交联或在B1/B29处不对称交联的胰岛素衍生物是胰岛素受体的完全激动剂。当赖氨酸B29与无活性的去八肽（B23-B30）胰岛素在苯丙氨酸B1处交联时，所得二聚体的内在活性低于胰岛素，但高于对称的B29-二聚体。得出的结论是，无论交联剂长度如何，在B29-赖氨酸处而非B1-苯丙氨酸处的连接会导致二聚化胰岛素衍生物产生部分激动作用。
