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[摘要]：Although loss of functional beta-cell mass is a hallmark of diabetes, no treatment approaches that halt this process are currently available. We recently identified thioredoxin-interacting protein (TXNIP) as an attractive target in this regard. Glucose and diabetes upregulate beta-cell TXNIP expression, and TXNIP overexpression induces beta-cell apoptosis. In contrast, genetic ablation of TXNIP promotes endogenous beta-cell survival and prevents streptozotocin (STZ)- and obesity-induced diabetes. Finding an oral medication that could inhibit beta-cell TXNIP expression would therefore represent a major breakthrough. We were surprised to discover that calcium channel blockers inhibited TXNIP expression in INS-1 cells and human islets and that orally administered verapamil reduced TXNIP expression and beta-cell apoptosis, enhanced endogenous insulin levels, and rescued mice from STZ- induced diabetes. Verapamil also promoted beta-cell survival and improved glucose homeostasis and insulin sensitivity in BTBR ob/ob mice. Our data further suggest that this verapamil-mediated TXNIP repression is conferred by reduction of intracellular calcium, inhibition of calcineurin signaling, and nuclear exclusion and decreased binding of carbohydrate response element-binding protein to the E-box repeat in the TXNIP promoter. Thus, for the first time, we have identified an oral medication that can inhibit proapoptofic beta-cell TXNIP expression, enhance beta-cell survival and function, and prevent and even improve overt diabetes. Diabetes 61:848-856, 2012 |
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