Mibefradil reduces blood glucose concentration in db/db mice |
| |
Authors: | Yujie Lu Min Long Shiwen Zhou Zihui Xu Fuquan Hu Ming Li |
| |
Institution: | IThird Military Medical University, Xinqiao Hospital, Department of Endocrinology, Chongqing, China. ;IIThird Military Medical University, Xinqiao Hospital, Clinical Pharmacology Institution, Chongqing, China. ;IIIThird Military Medical University, Xinqiao Hospital, Department of Microbiology Chongqing, China. ;IVTulane University, Department of Physiology, New Orleans/LA, United States. |
| |
Abstract: | OBJECTIVE:Numerous recent studies suggest that abnormal intracellular calcium concentration (Ca2+]i) is a common defect in diabetic animal models and patients. Abnormal calcium handling is an important mechanism in the defective pancreatic β-cell function in type 2 diabetes. T-type Ca2+ channel antagonists lower blood glucose in type 2 diabetes, but the mechanism remains unknown.METHODS:We examined the effect of the Ca2+ channel antagonist mibefradil on blood glucose in male db/db mice and phenotypically normal heterozygous mice by intraperitoneal injection.RESULTS:Mibefradil (15 mg/kg, i.p., b.i.d.) caused a profound reduction of fasting blood glucose from 430.92±20.46 mg/dl to 285.20±5.74 mg/dl in three days. The hypoglycemic effect of mibefradil was reproduced by NNC 55-0396, a compound structurally similar to mibefradil but more selective for T-type Ca2+ channels, but not by the specific L-type Ca2+ channel blocker nicardipine. Mibefradil did not show such hypoglycemic effects in heterozygous animals. In addition, triglycerides, basal insulin and food intake were significantly decreased by mibefradil treatment in the db/db mice but not in the controls. Western blot analysis, immunohistochemistry and immunofluorescence staining showed a significantly increased expression of T-type Ca2+ channel α-subunits Cav3.1 and Cav3.2 in liver and brain tissues from db/db mice compared to those from heterozygous animals.CONCLUSIONS:Collectively, these results suggest that T-type Ca2+ channels are potential therapeutic targets for antidiabetic drugs. |
| |
Keywords: | Diabetes Mellitus Hypoglycemic Effect Insulin Food Intake T-type Ca2+ Channel Antagonist |
本文献已被 ScienceDirect 等数据库收录! |
|