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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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Detalles Bibliográficos
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
Descripción
Sumario: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.