| Background and Objective：Diabetes Mellitus (DM) is an endocrine disease withreduced leptin sensitivity in peripheral tissues caused by chronic high blood glucoseaccompanied (or not) by the defect of insulin secretion of islet β cell. Several studies havedemonstrated disordered intracellular Ca2+regulation within diabeties. Recent studiesshowed that β cell membrane ATP dependent Ca2+channel and K+Channel are critical toleptin secretion. Ca2+channel play a role in the secretion of glucose induced leptin inhuman and rodents. Ca2+channel blocker regulates the function of target organ via amechanism of blocking membrane calcium channel to inhibit the influx of extracellularCa2+in order to lower intracellular Ca2+level. Presently, there are a few reports on theeffect on diabetes of L type Ca2+channel blockers, however none has been reported ofutilizing T type Ca2+blocker in lowering blood glucose. This study plans to intervene db/dbmice by T type Ca2+channel blocker Mibefradil, NNC55-0396and L type Ca2+channelblocker Nicardipine respectively, compare the lowering effect on blood glucose and furtherstudy on the role of Mibefradil on biochemical criterion of blood plasma and the expressionof T type Ca2+channel specific subunit Cav3.1and Cav3.2. A preliminary study on themechanism is planned as well.Methods：24wild-type non-diabetic mice and24db-/db-diabetic mice were randomlyseparated into8groups by random method（6mice per group）: wild-type control group,wild-type Mibefradil group, wild-type NNC group, wild Nicardipine group, db/db controlgroup, db/db Mibefradil group, db/db NNC group and db/db Nicardipine group. Mibefradil,NNC and Nicardipine group were given30mg/kg per injection and nicardpin group weregiven25mg/kg per injection. Intraperitoneal injection of saline were given to db/db andwild-type mice at same dose at day and night for7days. Both control groups were givenintraperitoneal injection of saline in an identical manner. Changes of levels of plasmaglucose, body weight, average blood pressure, heart rate and insulin tolerance test were compared after drug administration. Focus was given to observe the difference on levels ofinsulin, glycosylated hemoglobin and total cholesterol after drug intervention, as well asdetect the expression level of T type Ca2+specific subunits Cav3.1and Cav3.2byimmunohistochemistry and western-blot method.Results：(1) Compared to db/db control mice，fasting blood glucose of db/dbMibefradil group and NNC group mice had been obviously lowered（P<0.01）after treatment,and the hypoglycemic effect of Mibefradil was earlier detected than NNC, the effect wasalso more significant, but no significant difference was found in db/db Nicardipine group(P>0.05). In contrast, no significant difference was found in wild-type control group orwild-type drug intervention group (P>0.05)(2) Compare to db/db control mice, body weight of db/db Mibefradil group and db/dbNNC group had been obviously lowered (P<0.05) after treatment, the therapeutic effect ofMibefradil was detected earlier than NNC; no significant difference was found in db/dbNicardipine group (P>0.05). In contrast, no significant difference was found in wild-typecontrol group or wild-type drug intervention group (P>0.05).(3) Compare to db/db control mice, the level of24h food intake, basal insulin,glycosylated hemoglobin and cholesterol of db/db Mibefradil group had been obviouslylowered (P <0.05). In contrast, no significant difference was found in wild-type controlgroup or wild Mibefradil group (P>0.05).(4) Compare to wild type control mice, over expression of Cav3.1and Cav3.2proteinhad been observed in tissues in liver and brain of db/db mice (P<0.05), however, nodifference was found after Mibefradil treatment.Conclusion： Mibefradil can reduce blood glucose in a short period of time. Differentfrom traditional Glucose metabolic pathways, Mibefradil works via regulating on voltagedependent Ca2+channel. |
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