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Niacin exacerbates β cell lipotoxicity in diet-induced obesity mice through upregulation of GPR109A and PPARγ2: Inhibition by incretin drugs

The widely used lipid-lowering drug niacin was reported to increase blood glucose in diabetes. How does niacin regulate β Cell function in diabetic patients remains unclear. This study aimed to investigate the effect of niacin on β cell lipotoxicity in vitro and in vivo. Niacin treatment sensitized...

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Autores principales: Zhang, Xiaojing, Zhu, Baoyi, Lin, Peibin, Liu, Xiaoping, Gao, Jun, Yin, Dazhong, Zeng, Jianwen, Liao, Baojian, Kang, Zhanfang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9768175/
https://www.ncbi.nlm.nih.gov/pubmed/36568082
http://dx.doi.org/10.3389/fendo.2022.1057905
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author Zhang, Xiaojing
Zhu, Baoyi
Lin, Peibin
Liu, Xiaoping
Gao, Jun
Yin, Dazhong
Zeng, Jianwen
Liao, Baojian
Kang, Zhanfang
author_facet Zhang, Xiaojing
Zhu, Baoyi
Lin, Peibin
Liu, Xiaoping
Gao, Jun
Yin, Dazhong
Zeng, Jianwen
Liao, Baojian
Kang, Zhanfang
author_sort Zhang, Xiaojing
collection PubMed
description The widely used lipid-lowering drug niacin was reported to increase blood glucose in diabetes. How does niacin regulate β Cell function in diabetic patients remains unclear. This study aimed to investigate the effect of niacin on β cell lipotoxicity in vitro and in vivo. Niacin treatment sensitized the palmitate-induced cytotoxicity and apoptosis in INS-1 cells. In addition, palmitate significantly increased the niacin receptor GPR109A and PPARγ2 levels, which could be further boosted by niacin co-treatment, creating a vicious cycle. In contrast, knocking down of GPR109A could reverse both PPARγ2 expression and niacin toxicity in the INS-1 cells. Interestingly, we found that GLP-1 receptor agonist exendin-4 showed similar inhibitive effects on the GPR109A/PPARγ2 axis and was able to reverse niacin induced lipotoxicity in INS-1 cells. In diet-induced obesity (DIO) mouse model, niacin treatment resulted in elevated blood glucose, impaired glucose tolerance and insulin secretion, accompanied by the change of islets morphology and the decrease of β cell mass. The combination of niacin and DPP-4 inhibitor sitagliptin can improve glucose tolerance, insulin secretion and islet morphology and β cell mass, even better than sitagliptin alone. Our results show that niacin increased β cell lipotoxicity partially through upregulation of GPR109A and PPARγ2, which can be alleviated by incretin drugs. We provide a new mechanism of niacin toxicity, and suggest that the combination of niacin and incretin may have better blood glucose and lipid control effect in clinical practice.
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spelling pubmed-97681752022-12-22 Niacin exacerbates β cell lipotoxicity in diet-induced obesity mice through upregulation of GPR109A and PPARγ2: Inhibition by incretin drugs Zhang, Xiaojing Zhu, Baoyi Lin, Peibin Liu, Xiaoping Gao, Jun Yin, Dazhong Zeng, Jianwen Liao, Baojian Kang, Zhanfang Front Endocrinol (Lausanne) Endocrinology The widely used lipid-lowering drug niacin was reported to increase blood glucose in diabetes. How does niacin regulate β Cell function in diabetic patients remains unclear. This study aimed to investigate the effect of niacin on β cell lipotoxicity in vitro and in vivo. Niacin treatment sensitized the palmitate-induced cytotoxicity and apoptosis in INS-1 cells. In addition, palmitate significantly increased the niacin receptor GPR109A and PPARγ2 levels, which could be further boosted by niacin co-treatment, creating a vicious cycle. In contrast, knocking down of GPR109A could reverse both PPARγ2 expression and niacin toxicity in the INS-1 cells. Interestingly, we found that GLP-1 receptor agonist exendin-4 showed similar inhibitive effects on the GPR109A/PPARγ2 axis and was able to reverse niacin induced lipotoxicity in INS-1 cells. In diet-induced obesity (DIO) mouse model, niacin treatment resulted in elevated blood glucose, impaired glucose tolerance and insulin secretion, accompanied by the change of islets morphology and the decrease of β cell mass. The combination of niacin and DPP-4 inhibitor sitagliptin can improve glucose tolerance, insulin secretion and islet morphology and β cell mass, even better than sitagliptin alone. Our results show that niacin increased β cell lipotoxicity partially through upregulation of GPR109A and PPARγ2, which can be alleviated by incretin drugs. We provide a new mechanism of niacin toxicity, and suggest that the combination of niacin and incretin may have better blood glucose and lipid control effect in clinical practice. Frontiers Media S.A. 2022-12-07 /pmc/articles/PMC9768175/ /pubmed/36568082 http://dx.doi.org/10.3389/fendo.2022.1057905 Text en Copyright © 2022 Zhang, Zhu, Lin, Liu, Gao, Yin, Zeng, Liao and Kang https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Endocrinology
Zhang, Xiaojing
Zhu, Baoyi
Lin, Peibin
Liu, Xiaoping
Gao, Jun
Yin, Dazhong
Zeng, Jianwen
Liao, Baojian
Kang, Zhanfang
Niacin exacerbates β cell lipotoxicity in diet-induced obesity mice through upregulation of GPR109A and PPARγ2: Inhibition by incretin drugs
title Niacin exacerbates β cell lipotoxicity in diet-induced obesity mice through upregulation of GPR109A and PPARγ2: Inhibition by incretin drugs
title_full Niacin exacerbates β cell lipotoxicity in diet-induced obesity mice through upregulation of GPR109A and PPARγ2: Inhibition by incretin drugs
title_fullStr Niacin exacerbates β cell lipotoxicity in diet-induced obesity mice through upregulation of GPR109A and PPARγ2: Inhibition by incretin drugs
title_full_unstemmed Niacin exacerbates β cell lipotoxicity in diet-induced obesity mice through upregulation of GPR109A and PPARγ2: Inhibition by incretin drugs
title_short Niacin exacerbates β cell lipotoxicity in diet-induced obesity mice through upregulation of GPR109A and PPARγ2: Inhibition by incretin drugs
title_sort niacin exacerbates β cell lipotoxicity in diet-induced obesity mice through upregulation of gpr109a and pparγ2: inhibition by incretin drugs
topic Endocrinology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9768175/
https://www.ncbi.nlm.nih.gov/pubmed/36568082
http://dx.doi.org/10.3389/fendo.2022.1057905
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