Chadwick W, Wilson G, van de Venter M, Oelofsen W, Roux S
Department of Biochemistry and Microbiology, Nelson Mandela Metropolitan University of Port Elizabeth, PO Box 77000, Port Elizabeth 6031, South Africa.
J Pharm Pharmacol. 2007 Jan;59(1):95-103. doi: 10.1211/jpp.59.1.0013.
This study displayed the physiological effects the tricyclic antidepressants amitriptyline or trimipramine have on glucose homoeostasis in male Wistar rats. An insulin secreting cell line (INS-1) was also used to determine effects tricyclic antidepressants have on insulin secretion and insulin displacement. Thirty rats each received a 1 mg kg-1 dose of amitriptyline or trimipramine for a period of 14 weeks; another 14 rats served as the control group. Blood glucose, serum insulin and muscle and liver glycogen levels were determined. Kidney, liver and muscle insulin degradation was measured and compared with insulin degrading enzyme concentrations in the latter two tissues. INS-1 cells were used to determine the effect 1 microM amitriptyline has on insulin secretion. Displacement studies for [3H]glibenclamide by amitriptyline or trimipramine were undertaken on INS-1 cells. A significant increase in blood glucose (P<0.01) was found for both test groups after 6 and 14 weeks of receiving the medication, which may be related to a significant decrease in liver and muscle glycogen levels (P<0.001). Serum insulin levels remained unchanged, although a significant increase in insulin degradation was observed in the muscle, liver and kidney, which may be related to a significant increase in insulin degrading enzyme (P<0.001) that was found. A significant increase in insulin secretion was observed for the INS-1 cells treated with amitriptyline, although no significant displacement for the [3H]glibenclamide was evident for amitriptyline or trimipramine. The significant alterations in glucose homoeostasis observed, as well as the significant changes associated with insulin secretion and degradation associated with amitriptyline or trimipramine treatment, imply that prolonged use of these medicines may lead to insulin resistance and full blown diabetes.
本研究展示了三环类抗抑郁药阿米替林或曲米帕明对雄性Wistar大鼠葡萄糖稳态的生理影响。还使用了一种胰岛素分泌细胞系（INS-1）来确定三环类抗抑郁药对胰岛素分泌和胰岛素置换的影响。每组30只大鼠接受1mg/kg剂量的阿米替林或曲米帕明，持续14周；另外14只大鼠作为对照组。测定了血糖、血清胰岛素以及肌肉和肝脏糖原水平。测量了肾脏、肝脏和肌肉的胰岛素降解情况，并与后两种组织中的胰岛素降解酶浓度进行了比较。使用INS-1细胞来确定1μM阿米替林对胰岛素分泌的影响。在INS-1细胞上进行了阿米替林或曲米帕明对[3H]格列本脲的置换研究。在接受药物治疗6周和14周后，两个试验组的血糖均显著升高（P<0.01），这可能与肝脏和肌肉糖原水平显著降低有关（P<0.001）。血清胰岛素水平保持不变，尽管在肌肉、肝脏和肾脏中观察到胰岛素降解显著增加，这可能与所发现的胰岛素降解酶显著增加有关（P<0.001）。在用阿米替林处理的INS-1细胞中观察到胰岛素分泌显著增加，尽管阿米替林或曲米帕明对[3H]格列本脲没有明显的置换作用。观察到的葡萄糖稳态的显著改变，以及与阿米替林或曲米帕明治疗相关的胰岛素分泌和降解的显著变化，意味着长期使用这些药物可能导致胰岛素抵抗和全面的糖尿病。
