Mibefradil reduces blood glucose concentration in db/db mice

  • Yujie Lu Third Military Medical University; Department of Endocrinology; Xinqiao Hospital
  • Min Long Third Military Medical University; Department of Endocrinology; Xinqiao Hospital
  • Shiwen Zhou Third Military Medical University; Clinical Pharmacology Institution; Xinqiao Hospital
  • Zihui Xu Third Military Medical University; Department of Endocrinology; Xinqiao Hospital
  • Fuquan Hu Third Military Medical University; Department of Microbiology; Xinqiao Hospital
  • Ming Li Tulane University; Department of Physiology

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.

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Published
2014-01-01
How to Cite
Lu, Y., Long, M., Zhou, S., Xu, Z., Hu, F., & Li, M. (2014). Mibefradil reduces blood glucose concentration in db/db mice. Clinics, 69(1), 61-67. https://doi.org/10.1590/clin.v69i1.77070
Section
Basic Research