Mibefradil reduces blood glucose concentration in db/db mice.
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.
Department of Endocrinology, Xinqiao Hospital, Third Military Medical University, Chongqing, China, Third Military Medical University, Xinqiao Hospital, Department of Endocrinology, Chongqing, China.
Yujie
Y
Lu
Department of Endocrinology, Xinqiao Hospital, Third Military Medical University, Chongqing, China, Third Military Medical University, Xinqiao Hospital, Department of Endocrinology, Chongqing, China.
Min
M
Long
Clinical Pharmacology Institution, Xinqiao Hospital, Third Military Medical University, Chongqing, China, Third Military Medical University, Xinqiao Hospital, Clinical Pharmacology Institution, Chongqing, China.
Shiwen
S
Zhou
Department of Endocrinology, Xinqiao Hospital, Third Military Medical University, Chongqing, China, Third Military Medical University, Xinqiao Hospital, Department of Endocrinology, Chongqing, China.
Zihui
Z
Xu
Department of Microbiology, Xinqiao Hospital, Third Military Medical University, Chongqing, China, Third Military Medical University, Xinqiao Hospital, Department of Microbiology Chongqing, China.
Fuquan
F
Hu
Department of Physiology, Tulane University, New Orleans/LA, United States, Tulane University, Department of Physiology, New Orleans/LA, United States.
Ming
M
Li
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects*; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000627:therapeutic use*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D004195:Disease Models, Animal; D004435:Eating; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000627:therapeutic use; D007150:Immunohistochemistry; D007274:Injections, Intraperitoneal; D008099:Liver / Q000187:drug effects; D008297:Male; D008488:Medical Illustration; D020748:Mibefradil / Q000008:administration & dosage / Q000627:therapeutic use*; D051379:Mice; D015203:Reproducibility of Results; D013997:Time Factors; D016896:Treatment Outcome
D001786:Blood Glucose; D002121:Calcium Channel Blockers; D007004:Hypoglycemic Agents; D020748:Mibefradil