Correlations of receptor binding and metabolic and mitogenic potencies of insulin analogs designed for clinical use
Correlations of receptor binding and metabolic and mitogenic potencies of insulin analogs designed for clinical use
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临床使用的胰岛素类似物的受体结合与代谢和有丝分裂效力的相关性
DOI：
10.2337/diabetes.49.6.999
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发表时间：
2000-06-01
期刊：
影响因子：
7.7
通讯作者：
Trüb, T
中科院分区：
文献类型：
--
作者：
Kurtzhals, P;Schäffer, L;Trüb, T
近年来，人胰岛素的类似物已经被工程化，目的是改善糖尿病患者的治疗。为了确保人激素的安全性不受分子修饰的影响，应仔细监测胰岛素类似物的毒理药理学特性。在本研究中，我比较了门冬胰岛素（B28 Asp人胰岛素）、赖脯胰岛素（B28 Lys、B29 Pro人胰岛素）、甘精胰岛素（A21 Gly、B31 Arg、B32 Arg人胰岛素）、地特胰岛素（NN 304）[B29 Lys（ε-十四烷酰基）、desB 30人胰岛素]和参比胰岛素类似物的胰岛素和IGF-I受体结合特性以及代谢和促有丝分裂效价。使用纯化的人受体测定受体亲和力，使用过表达人胰岛素受体的中国仓鼠卵巢细胞测定胰岛素受体解离速率，使用原代小鼠脂肪细胞评价代谢效价，并在人骨肉瘤细胞中测定促有丝分裂效价。代谢效力与胰岛素受体亲和力相关性良好。促有丝分裂效能一般与IGF-I受体亲和力的相关性优于与胰岛素受体解离率的相关性。2种速效胰岛素类似物门冬胰岛素和赖脯胰岛素的所有参数均与人胰岛素相似，但赖脯胰岛素的IGF-I受体亲和力略微升高。相比之下，2种长效胰岛素类似物甘精胰岛素和地特胰岛素与人胰岛素存在显著差异。与人胰岛素相比，B31 B32 diArg和A21 Gly取代的组合使甘精胰岛素的IGF-I受体亲和力和促有丝分裂效价增加6- 8倍。脂肪酸链与LysB 29的连接降低了地特胰岛素的受体亲和力以及代谢和促有丝分裂效价，但未改变促有丝分裂效价和代谢效价之间的平衡。甘精胰岛素的生长刺激潜力增加的安全性影响尚不清楚。地特胰岛素的体外效力降低可能解释了为什么这种类似物在人体中的摩尔基础上不如人胰岛素有效。
In recent years, analogs of human insulin have been engineered with the aim of improving therapy for people with diabetes. To ensure that the safety profile of the human hormone is not compromised by the molecular modifications, the toxico-pharmacological properties of insulin analogs should be carefully monitored. In this study, me compared the insulin and IGF-I receptor binding properties and metabolic and mitogenic potencies of insulin aspart (B28Asp human insulin), insulin lispro (B28Lys,B29Pro human insulin), insulin glargine (A21Gly,B31Arg,B32Arg human insulin), insulin detemir (NN304) [B29Lys(epsilon-tetradecanoyl),desB30 human insulin], and reference insulin analogs. Receptor affinities were measured using purified human receptors, insulin receptor dissociation rates were determined using Chinese hamster ovary cells overexpressing the human insulin receptor, metabolic potencies were evaluated using primary mouse adipocytes, and mitogenic potencies were determined in human osteosarcoma cells. Metabolic potencies correlated well with insulin receptor affinities. Mitogenic potencies in general correlated better with IGF-I receptor affinities than with insulin receptor off-rates. The 2 rapid-acting insulin analogs aspart and lispro resembled human insulin on all parameters, except for a slightly elevated IGF-I receptor affinity of lispro. In contrast, the 2 long-acting insulin analogs, glargine and detemir, differed significantly from human insulin. The combination of the B31B32diArg and A21Gly substitutions provided insulin glargine with a 6- to 8-fold increased IGF-I receptor affinity and mitogenic potency compared with human insulin. The attachment of a fatty acid chain to LysB29 provided insulin detemir with reduced receptor affinities and metabolic and mitogenic potencies but did not change the balance between mitogenic and metabolic potencies. The safety implications of the increased growth-stimulating potential of insulin glargine are unclear. The reduced in vitro potency of insulin detemir might explain why this analog is not as effective on a molar basis as human insulin in humans.