Mibefradil reduces blood glucose concentration in db/db mice

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.

A New Computer Model for Evaluating the Selective Binding Affinity of Phenylalkylamines to T-Type Ca2+ Channels

“…As the only type of voltage-gated Ca 2+ channels that are activated at or near resting membrane potentials, T-type Ca 2+ channels (TCCs) play an important role in regulating [Ca 2+ ] i homeostasis in a variety of tissues, including pancreatic β-cells and tumor cells [ 1 , 2 , 3 , 4 ]. Therefore, TCC antagonists could be potentially useful for the treatment of chronic diseases associated with Ca 2+ dysregulation [ 5 , 6 , 7 ].…”

Enhanced expression of β cell Ca V 3.1 channels impairs insulin release and glucose homeostasis

“…These data suggest that the pathologically enhanced expression of β cell Ca V 3.1 channels serves as a causal factor for defective insulin secretion from human and rodent islets, regardless of obvious interspecies differences in expression of Ca V 3.1 channels in healthy β cells (6,7,10,12,13). This is well supported by the findings of the appearance of T-type Ca 2+ currents in diabetic mouse β cells, elevation of these Ca 2+ currents in diabetic rat β cells, and, in particular, amelioration of hyperglycemia by systemic inhibition of these Ca 2+ currents in diabetic mice (6,7,12,14,15,20). Taken together, the findings indicate the significance of up-regulation of β cell Ca V 3.1 channels in the pathogenesis of human diabetes.…”

“…proteins through dephosphorylation of FoxO1 (17)(18)(19). Systemic administration of Ca V 3 channel blockers significantly ameliorates hyperglycemia in diabetic mice (20). However, the causal role and transcriptomic impact of a pathological elevation of β cell Ca V 3.1 channels in the development of diabetes is not known.…”

Pan-organ model integration of metabolic and regulatory processes in type 1 diabetes

“…In addition, a drug repurposing analysis found that Mibefradil and Amlodipine could reverse the expression of the genes associated with the differentially active reactions in T1D (Table S6). Encouragingly, studies investigating experimental rodent models of diabetes have shown that calcium blockers improve blood glucose levels and diabetes-associated nephropathy (Lu et al, 2014;Ma et al, 2004). Taken together, these findings suggest the existence of a continuum between diabetes and neurodegenerative disorders, possibly involving a strong metabolic component.…”