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Preventing β-Cell Loss and Diabetes With Calcium Channel Blockers

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, a...

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Detalles Bibliográficos
Autores principales: Xu, Guanlan, Chen, Junqin, Jing, Gu, Shalev, Anath
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Diabetes Association 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3314354/
https://www.ncbi.nlm.nih.gov/pubmed/22442301
http://dx.doi.org/10.2337/db11-0955
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author Xu, Guanlan
Chen, Junqin
Jing, Gu
Shalev, Anath
author_facet Xu, Guanlan
Chen, Junqin
Jing, Gu
Shalev, Anath
author_sort Xu, Guanlan
collection PubMed
description 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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spelling pubmed-33143542013-04-01 Preventing β-Cell Loss and Diabetes With Calcium Channel Blockers Xu, Guanlan Chen, Junqin Jing, Gu Shalev, Anath Diabetes Islet Studies 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. American Diabetes Association 2012-04 2012-03-14 /pmc/articles/PMC3314354/ /pubmed/22442301 http://dx.doi.org/10.2337/db11-0955 Text en © 2012 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
spellingShingle Islet Studies
Xu, Guanlan
Chen, Junqin
Jing, Gu
Shalev, Anath
Preventing β-Cell Loss and Diabetes With Calcium Channel Blockers
title Preventing β-Cell Loss and Diabetes With Calcium Channel Blockers
title_full Preventing β-Cell Loss and Diabetes With Calcium Channel Blockers
title_fullStr Preventing β-Cell Loss and Diabetes With Calcium Channel Blockers
title_full_unstemmed Preventing β-Cell Loss and Diabetes With Calcium Channel Blockers
title_short Preventing β-Cell Loss and Diabetes With Calcium Channel Blockers
title_sort preventing β-cell loss and diabetes with calcium channel blockers
topic Islet Studies
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3314354/
https://www.ncbi.nlm.nih.gov/pubmed/22442301
http://dx.doi.org/10.2337/db11-0955
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