Preventing Beta-Cell Loss and Diabetes With CCBs
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.
Loss of pancreatic β-cell mass is a key factor in the pathogenesis of type 1 and type 2 diabetes, but therapies that interfere with this process are currently lacking. We recently discovered thioredoxin-interacting protein (TXNIP), a ubiquitously expressed cellular redox regulator, as an attractive novel target in this regard. We originally identified TXNIP as the top glucose-induced gene in a human islet microarray study and found that β-cell expression of TXNIP is increased in diabetes. Moreover, TXNIP overexpression induces β-cell apoptosis and is essential for glucotoxicity-induced β-cell death, whereas lack of TXNIP promotes endogenous β-cell survival and prevents type 1 and type 2 diabetes. In addition, TXNIP has recently been discovered to induce inflammasome activation and interleukin-1β production, a cytokine involved in type 1 diabetes. While together these findings have established TXNIP as an attractive therapeutic target, effective TXNIP inhibitors are currently missing. Of interest, we found that calcium channel blockers such as verapamil (commonly used as antihypertensive drugs) can reduce TXNIP expression as well as apoptosis in the heart.
The present studies were therefore aimed at determining whether calcium channel blockers may also decrease β-cell TXNIP expression, enhance β-cell survival, and protect against diabetes. Using INS-1 cells, primary human islets, and models of type 1 and type 2 diabetes, our results demonstrate that oral verapamil can indeed rescue from β-cell death and diabetes and shed light on the mechanisms involved.
Abstract and Introduction
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.
Introduction
Loss of pancreatic β-cell mass is a key factor in the pathogenesis of type 1 and type 2 diabetes, but therapies that interfere with this process are currently lacking. We recently discovered thioredoxin-interacting protein (TXNIP), a ubiquitously expressed cellular redox regulator, as an attractive novel target in this regard. We originally identified TXNIP as the top glucose-induced gene in a human islet microarray study and found that β-cell expression of TXNIP is increased in diabetes. Moreover, TXNIP overexpression induces β-cell apoptosis and is essential for glucotoxicity-induced β-cell death, whereas lack of TXNIP promotes endogenous β-cell survival and prevents type 1 and type 2 diabetes. In addition, TXNIP has recently been discovered to induce inflammasome activation and interleukin-1β production, a cytokine involved in type 1 diabetes. While together these findings have established TXNIP as an attractive therapeutic target, effective TXNIP inhibitors are currently missing. Of interest, we found that calcium channel blockers such as verapamil (commonly used as antihypertensive drugs) can reduce TXNIP expression as well as apoptosis in the heart.
The present studies were therefore aimed at determining whether calcium channel blockers may also decrease β-cell TXNIP expression, enhance β-cell survival, and protect against diabetes. Using INS-1 cells, primary human islets, and models of type 1 and type 2 diabetes, our results demonstrate that oral verapamil can indeed rescue from β-cell death and diabetes and shed light on the mechanisms involved.
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