Evaluating the antidiabetic effects of R-verapamil in type 1 and type 2 diabetes mellitus mouse models.

The global incidence of diabetes mellitus (DM) is increasing. Types 1 and 2 DM are associated with declining β-cell function. Verapamil (50% S-verapamil and 50% R-verapamil) can treat DM by downregulating thioredoxin-interacting protein (TXNIP), which induces islet β-cell apoptosis. However, it may...

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Autores principales:	Yu-Syuan Chen, Shao-Ju Weng, Shu-Hsien Chang, Rou-Ying Li, Guang-Tzuu Shane, Jui-Pao Hsu, Sheng-Wen Yeh, Ai-Ching Chang, Meng-Ju Lee
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/76988b25082843899a3702c76d03fa40
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spelling	oai:doaj.org-article:76988b25082843899a3702c76d03fa402021-12-02T20:18:35ZEvaluating the antidiabetic effects of R-verapamil in type 1 and type 2 diabetes mellitus mouse models.1932-620310.1371/journal.pone.0255405https://doaj.org/article/76988b25082843899a3702c76d03fa402021-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0255405https://doaj.org/toc/1932-6203The global incidence of diabetes mellitus (DM) is increasing. Types 1 and 2 DM are associated with declining β-cell function. Verapamil (50% S-verapamil and 50% R-verapamil) can treat DM by downregulating thioredoxin-interacting protein (TXNIP), which induces islet β-cell apoptosis. However, it may also induce cardiovascular side effects as S-verapamil is negatively inotropic. In contrast, R-verapamil only weakly induces adverse cardiac effects. In this study, we aimed to determine the antidiabetic efficacy and cardiovascular safety of R-verapamil. We examined R- and S-verapamil binding through in vitro studies. Streptozotocin-induced type 1 and db/db type 2 DM mouse models were used to assess the antidiabetic efficacy of verapamil. IL-6, blood glucose (BG), Txnip expression, and β-cells were evaluated in streptozotocin-induced diabetic mice, while body weight, BG, and serum insulin were measured in the db/db mice. In the type 1 DM study, 100 mg/kg/day R-verapamil and racemic verapamil lowered BG, downregulated Txnip expression, and reduced β-cell apoptosis. In the type 2 DM study, the optimal R-verapamil dosage was 60 mg/kg/day and it lowered BG and raised serum insulin. However, efficacy did not increase with R-verapamil dosage. R-verapamil combined with metformin/acarbose improved BG and serum insulin more effectively than metformin/acarbose alone or verapamil combined with acarbose. R-verapamil had weaker cardiovascular side effects than S-verapamil. R-verapamil was 9.0× and 3.4× less effective than S-verapamil at inhibiting atrial inotropy and ileal contractility, respectively. It was also 8.7× weaker than S-verapamil as an agonist of somatostatin receptor type 2 (SSTR2), inhibiting ileal neurogenic contraction. Hence, R-verapamil may be an optimal DM treatment as it is safe, improves glycemic control, and preserves β-cell function both as monotherapy and in combination with metformin or acarbose. R-Verapamil has potential for delaying or arresting DM progression and improving patients' quality of life.Yu-Syuan ChenShao-Ju WengShu-Hsien ChangRou-Ying LiGuang-Tzuu ShaneJui-Pao HsuSheng-Wen YehAi-Ching ChangMeng-Ju LeePublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 8, p e0255405 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Yu-Syuan Chen Shao-Ju Weng Shu-Hsien Chang Rou-Ying Li Guang-Tzuu Shane Jui-Pao Hsu Sheng-Wen Yeh Ai-Ching Chang Meng-Ju Lee Evaluating the antidiabetic effects of R-verapamil in type 1 and type 2 diabetes mellitus mouse models.
description	The global incidence of diabetes mellitus (DM) is increasing. Types 1 and 2 DM are associated with declining β-cell function. Verapamil (50% S-verapamil and 50% R-verapamil) can treat DM by downregulating thioredoxin-interacting protein (TXNIP), which induces islet β-cell apoptosis. However, it may also induce cardiovascular side effects as S-verapamil is negatively inotropic. In contrast, R-verapamil only weakly induces adverse cardiac effects. In this study, we aimed to determine the antidiabetic efficacy and cardiovascular safety of R-verapamil. We examined R- and S-verapamil binding through in vitro studies. Streptozotocin-induced type 1 and db/db type 2 DM mouse models were used to assess the antidiabetic efficacy of verapamil. IL-6, blood glucose (BG), Txnip expression, and β-cells were evaluated in streptozotocin-induced diabetic mice, while body weight, BG, and serum insulin were measured in the db/db mice. In the type 1 DM study, 100 mg/kg/day R-verapamil and racemic verapamil lowered BG, downregulated Txnip expression, and reduced β-cell apoptosis. In the type 2 DM study, the optimal R-verapamil dosage was 60 mg/kg/day and it lowered BG and raised serum insulin. However, efficacy did not increase with R-verapamil dosage. R-verapamil combined with metformin/acarbose improved BG and serum insulin more effectively than metformin/acarbose alone or verapamil combined with acarbose. R-verapamil had weaker cardiovascular side effects than S-verapamil. R-verapamil was 9.0× and 3.4× less effective than S-verapamil at inhibiting atrial inotropy and ileal contractility, respectively. It was also 8.7× weaker than S-verapamil as an agonist of somatostatin receptor type 2 (SSTR2), inhibiting ileal neurogenic contraction. Hence, R-verapamil may be an optimal DM treatment as it is safe, improves glycemic control, and preserves β-cell function both as monotherapy and in combination with metformin or acarbose. R-Verapamil has potential for delaying or arresting DM progression and improving patients' quality of life.
format	article
author	Yu-Syuan Chen Shao-Ju Weng Shu-Hsien Chang Rou-Ying Li Guang-Tzuu Shane Jui-Pao Hsu Sheng-Wen Yeh Ai-Ching Chang Meng-Ju Lee
author_facet	Yu-Syuan Chen Shao-Ju Weng Shu-Hsien Chang Rou-Ying Li Guang-Tzuu Shane Jui-Pao Hsu Sheng-Wen Yeh Ai-Ching Chang Meng-Ju Lee
author_sort	Yu-Syuan Chen
title	Evaluating the antidiabetic effects of R-verapamil in type 1 and type 2 diabetes mellitus mouse models.
title_short	Evaluating the antidiabetic effects of R-verapamil in type 1 and type 2 diabetes mellitus mouse models.
title_full	Evaluating the antidiabetic effects of R-verapamil in type 1 and type 2 diabetes mellitus mouse models.
title_fullStr	Evaluating the antidiabetic effects of R-verapamil in type 1 and type 2 diabetes mellitus mouse models.
title_full_unstemmed	Evaluating the antidiabetic effects of R-verapamil in type 1 and type 2 diabetes mellitus mouse models.
title_sort	evaluating the antidiabetic effects of r-verapamil in type 1 and type 2 diabetes mellitus mouse models.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/76988b25082843899a3702c76d03fa40
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Evaluating the antidiabetic effects of R-verapamil in type 1 and type 2 diabetes mellitus mouse models.

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