共价连接的胰岛素二聚体：其作为胰岛素清除的部分竞争性拮抗剂在体内的代谢及生物学效应

Covalently-linked insulin dimers: their metabolism and biological effects in vivo as partial competitive antagonists of insulin clearance.

作者信息

Tatnell M A, Jones R H, Sönksen P H

出版信息

Diabetologia. 1984 Jul;27(1):27-31. doi: 10.1007/BF00253497.

Abstract

The biological properties of three covalently-linked insulin dimers were studied in greyhounds. Constant infusions showed that the plasma distribution kinetics were slower for the dimers than for insulin. The metabolic clearance rates of the three dimers (10.3 +/- 0.4, 8.8 +/- 0.5, 8.2 +/- 0.5 ml X min-1 X kg-1; mean +/- SEM) were significantly lower than that of insulin (19 +/- 0.8 ml X min-1 X kg-1), and their hypoglycaemic effects (11.2%, 3% and 0.3%) were markedly reduced compared with their lipogenic potencies in vitro (80%, 30% and 13%, respectively). A low dose infusion of insulin or an equipotent dose of one of the dimers significantly prolonged the effects of an insulin bolus on plasma glucose but not on non-esterified fatty acids. The apparent distribution space (106.4 +/- 11.9 ml/kg) and clearance rate (14.7 +/- 0.5 ml X min-1 X kg-1) of an insulin bolus were significantly reduced by one dimer (44.5 +/- 8.4 ml/kg and 10.7 +/- 2.8 ml X min-1 X kg-1) but not by the equipotent insulin infusion (102.7 +/- 8.2 ml/kg and 16.4 +/- 0.07 ml X min-1 X kg-1). The apparent partial competitive antagonism of insulin by the dimers that has been reported in vitro can be observed in vivo, in that antagonism of insulin metabolism was directly demonstrated with one of the dimers.

摘要

在灵缇犬身上研究了三种共价连接的胰岛素二聚体的生物学特性。持续输注显示，二聚体的血浆分布动力学比胰岛素慢。三种二聚体的代谢清除率（10.3±0.4、8.8±0.5、8.2±0.5 ml·min⁻¹·kg⁻¹；平均值±标准误）显著低于胰岛素（19±0.8 ml·min⁻¹·kg⁻¹），并且与它们在体外的生脂能力（分别为80%、30%和13%）相比，它们的降血糖作用（11.2%、3%和0.3%）明显降低。低剂量输注胰岛素或等剂量的一种二聚体可显著延长胰岛素推注对血浆葡萄糖的作用，但对非酯化脂肪酸无此作用。一种二聚体显著降低了胰岛素推注的表观分布容积（106.4±11.9 ml/kg）和清除率（14.7±0.5 ml·min⁻¹·kg⁻¹）（分别为44.5±8.4 ml/kg和10.7±2.8 ml·min⁻¹·kg⁻¹），但等剂量的胰岛素输注则没有（102.7±8.2 ml/kg和16.4±0.07 ml·min⁻¹·kg⁻¹）。体外报道的二聚体对胰岛素的明显部分竞争性拮抗作用在体内也可观察到，因为其中一种二聚体直接证明了对胰岛素代谢的拮抗作用。