1804-P: The Good and the Bad of Verapamil vs. Other Calcium Channel Blockers in the Context of Diabetes

Introduction and Objective: We have previously discovered that the L-type calcium channel blocker (CCB) anti-hypertensive, verapamil, lowers beta cell expression of pro-apoptotic, pro-inflammatory thioredoxin-interacting protein (TXNIP) by decreasing cellular calcium levels and targeting the calcineurin signaling pathway. Combined with the identification of increased beta cell TXNIP as an important factor in the pathogenesis of type 1 (T1D) and type 2 diabetes (T2D), this has provided the basis for multiple preclinical and clinical studies demonstrating the beneficial anti-diabetic effects of verapamil and TXNIP inhibition. However, as a non-dihydropyridine, verapamil primarily targets calcium channels in the heart and pancreas and thus is also associated with cardiac side effects, i.e., heart block, arrhythmias, as well as inhibition of beta cell insulin secretion. Nonetheless, recent findings have suggested that verapamil is superior to other CCBs, especially dihydropyridines, in lowering the incidence of T2D. To find an explanation for this, the goal of our studies was now to determine whether dihydropyridines such as nifedipine affect beta cell TXNIP differently from verapamil. Methods: INS-1 beta-like cells were treated with or without nifedipine or verapamil and the effects on TXNIP expression were assessed by qPCR. Results: Surprisingly, nifedipine led to a significant increase in beta cell TXNIP expression in contrast to the reduction observed with verapamil. On the other hand, verapamil led to an acute impairment in glucose homeostasis as assessed by glucose tolerance tests in C57BL/6J mice. Conclusion: While dihydropyridines, which act primarily on vascular smooth muscle cells, lack the cardiac side effects and functional beta cell inhibition of verapamil, they are unable to control beta cell TXNIP. Given the central role of TXNIP in diabetes development, this may explain the higher T2D incidence observed with dihydropyridines versus verapamil and underlines the need for more specific, non-CCB TXNIP inhibitors. Disclosure G. Jing: None. G. Xu: None. A. Shalev: Other - Co-founder, CSO/CMO; Current; TIXiMED, Inc.