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...

Descripción completa

Guardado en:
Detalles Bibliográficos
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:
R
Q
Acceso en línea:https://doaj.org/article/76988b25082843899a3702c76d03fa40
Etiquetas: Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
id oai:doaj.org-article:76988b25082843899a3702c76d03fa40
record_format dspace
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
work_keys_str_mv AT yusyuanchen evaluatingtheantidiabeticeffectsofrverapamilintype1andtype2diabetesmellitusmousemodels
AT shaojuweng evaluatingtheantidiabeticeffectsofrverapamilintype1andtype2diabetesmellitusmousemodels
AT shuhsienchang evaluatingtheantidiabeticeffectsofrverapamilintype1andtype2diabetesmellitusmousemodels
AT rouyingli evaluatingtheantidiabeticeffectsofrverapamilintype1andtype2diabetesmellitusmousemodels
AT guangtzuushane evaluatingtheantidiabeticeffectsofrverapamilintype1andtype2diabetesmellitusmousemodels
AT juipaohsu evaluatingtheantidiabeticeffectsofrverapamilintype1andtype2diabetesmellitusmousemodels
AT shengwenyeh evaluatingtheantidiabeticeffectsofrverapamilintype1andtype2diabetesmellitusmousemodels
AT aichingchang evaluatingtheantidiabeticeffectsofrverapamilintype1andtype2diabetesmellitusmousemodels
AT mengjulee evaluatingtheantidiabeticeffectsofrverapamilintype1andtype2diabetesmellitusmousemodels
_version_ 1718374291326631936