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G Xu, J Chen, G Jing and A Shalev
Abstract
Although loss of functional β-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 β-cell TXNIP expression, and TXNIP overexpression induces β-cell apoptosis. In contrast, genetic ablation of TXNIP promotes endogenous β-cell survival and prevents streptozotocin (STZ)- and obesity-induced diabetes. Finding an oral medication that could inhibit β-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 β-cell apoptosis, enhanced endogenous insulin levels, and rescued mice from STZ-induced diabetes. Verapamil also promoted β-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 proapoptotic β-cell TXNIP expression, enhance β-cell survival and function, and prevent and even improve overt diabetes.
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Concepts
Gene, Diabetes mellitus, Insulin resistance, Calcium channel blocker, Glucose, DNA, Gene expression, Insulin
MeSH headings
Administration, Oral, Animals, Apoptosis, Calcium Channel Blockers, Carrier Proteins, Cell Line, Diabetes Mellitus, Experimental, Insulin-Secreting Cells, Male, Mice, Mice, Inbred C57BL, Mice, Obese, RNA, Messenger, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Thioredoxins, Verapamil
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