Department of Physiology, Faculty of Medicine, American University of Beirut, Beirut 11-236, Lebanon.
Can J Physiol Pharmacol. 2010 Jan;88(1):54-63. doi: 10.1139/Y09-095.
This study focused on the regulation and affinity modulation of the insulin receptor of coronary endothelium and cardiomyocytes in nondiabetic and STZ-induced type 1 diabetic rats. Male rats were divided into the following 9 groups: nondiabetic (N), nondiabetic treated with exendin-4 (NE), nondiabetic treated with dipeptidyl peptidase IV (DPP-IV) inhibitor (NDp), diabetic (D), diabetic treated with insulin (DI), diabetic treated with exendin-4 (DE), diabetic co-treated with insulin and exendin-4 (DIE), diabetic treated with DPP-IV inhibitor (DDp), and diabetic co-treated with insulin and DPP-IV inhibitor (DIDp). After the rats were treated for 1 month, a first-order Bessel function was employed to estimate the insulin binding affinity (with time constant tau = 1/k-n) to its receptors on the coronary endothelium and cardiomyocytes using CHAPS-untreated and CHAPS-treated heart perfusion, respectively. The results showed that diabetes (D) decreased the tau value on the coronary endothelium and increased it on cardiomyocytes compared with the nondiabetic group (N). Treatment with insulin and (or) exendin-4, a glucagon-like peptide-1 (GLP-1) analogue, increased tau on the coronary endothelium only. On the coronary endothelium, tau values of DI and DIDp were normalized. Western blots of the insulin receptor showed upregulation in D, downregulation in DI, and normalization in DE and DDp. Immunohistochemistry and RT-PCR findings indicated atrial natriuretic factor (ANF) in all diabetic ventricles, thus ascertaining hypertrophy. Therefore, negative myocardial effects related to the insulin receptor were diminished in diabetic rats treated with DPP-IV inhibitor and, more efficiently, by exendin-4.
本研究聚焦于非糖尿病和链脲佐菌素诱导的 1 型糖尿病大鼠的冠状动脉内皮细胞和心肌细胞胰岛素受体的调节和亲和力调节。雄性大鼠分为以下 9 组：非糖尿病（N）、给予 exendin-4（NE）处理的非糖尿病、给予二肽基肽酶 IV（DPP-IV）抑制剂处理的非糖尿病（NDp）、糖尿病（D）、给予胰岛素处理的糖尿病（DI）、给予 exendin-4 处理的糖尿病（DE）、胰岛素和 exendin-4 联合处理的糖尿病（DIE）、给予 DPP-IV 抑制剂处理的糖尿病（DDp）、胰岛素和 DPP-IV 抑制剂联合处理的糖尿病（DIDp）。在大鼠处理 1 个月后，采用一阶贝塞尔函数（first-order Bessel function），分别使用 CHAPS 未处理和 CHAPS 处理的心脏灌注，来估计胰岛素与其在冠状动脉内皮细胞和心肌细胞上的受体的结合亲和力（结合时间常数 tau=1/k-n）。结果显示，与非糖尿病组（N）相比，糖尿病（D）降低了冠状动脉内皮上的 tau 值，增加了心肌细胞上的 tau 值。胰岛素和（或）胰高血糖素样肽-1（GLP-1）类似物 exendin-4 的治疗仅增加了冠状动脉内皮上的 tau 值。在冠状动脉内皮上，DI 和 DIDp 的 tau 值恢复正常。胰岛素受体的 Western blot 显示 D 组上调，DI 组下调，DE 和 DDp 组恢复正常。免疫组化和 RT-PCR 结果表明，所有糖尿病心室均存在心房利钠肽（ANF），从而证实了心肌肥厚。因此，糖尿病大鼠用 DPP-IV 抑制剂治疗，更有效地用 exendin-4 治疗，可减轻与胰岛素受体相关的负性心肌效应。
