Ibiagbani M Max-Harry, Nida Ajmal, Palwasha Khan, Landen E Davis, Waleed J Hashmi, Noriko Kantake, Kathryn L Corbin, Thomas J Rosol, Craig S Nunemaker
{"title":"β细胞中PTHrP的过表达揭示了内质网应激的关键作用。","authors":"Ibiagbani M Max-Harry, Nida Ajmal, Palwasha Khan, Landen E Davis, Waleed J Hashmi, Noriko Kantake, Kathryn L Corbin, Thomas J Rosol, Craig S Nunemaker","doi":"10.1210/endocr/bqaf086","DOIUrl":null,"url":null,"abstract":"<p><p>Administration of parathyroid hormone-related protein (PTHrP) has been shown to increase insulin content and secretion in mice. PTHrP also increases β-cell mass and proliferation. However, the mechanisms for these effects are unknown, and investigations have yet to examine PTHrP in the transcriptome. In this study, we transiently transfected a mouse β-cell line (MIN6) with either full-length PTHrP or DSred vector. Insulin content and glucose-stimulated insulin secretion were measured, and RNA from the cells after incubating in 20 mM glucose was collected. The results showed that PTHrP overexpression increased insulin content and the ratio of insulin secretion between low and high glucose (stimulation index). RNA sequencing showed that PTHrP overexpression downregulated many genes associated with responses to endoplasmic reticulum (ER) stress such as Hspa40, Dnajc3, and Xbp1. Among enriched Kyoto Encyclopedia of Genes and Genomes pathways, the ER stress gene pathway was the most strongly downregulated by far, and the most upregulated pathway was for biosynthesis of amino acids required for protein synthesis. These pathways suggest increased rates of protein biosynthesis. Quantitative polymerase chain reaction supported RNA-sequencing results for several ER stress genes (Xbp1, Bax, Bip). MIN6 cells transfected with PTHrP also had lower proinsulin-to-insulin ratio, indicating that PTHrP enhanced insulin processing in the ER. Our working hypothesis is that PTHrP augments insulin production and ER efficiency, which is consistent with observations of increased insulin content, decreased proinsulin-to-insulin ratio and reduced ER stress markers in MIN6 cells. In conclusion, our findings suggest a previously unknown role for PTHrP in β-cell endoplasmic reticulum, which may have therapeutic implications for enhancing insulin production.</p>","PeriodicalId":11819,"journal":{"name":"Endocrinology","volume":" ","pages":""},"PeriodicalIF":3.3000,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Overexpression of PTHrP in β Cells Reveals Key Effects on Endoplasmic Reticulum Stress.\",\"authors\":\"Ibiagbani M Max-Harry, Nida Ajmal, Palwasha Khan, Landen E Davis, Waleed J Hashmi, Noriko Kantake, Kathryn L Corbin, Thomas J Rosol, Craig S Nunemaker\",\"doi\":\"10.1210/endocr/bqaf086\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Administration of parathyroid hormone-related protein (PTHrP) has been shown to increase insulin content and secretion in mice. PTHrP also increases β-cell mass and proliferation. However, the mechanisms for these effects are unknown, and investigations have yet to examine PTHrP in the transcriptome. In this study, we transiently transfected a mouse β-cell line (MIN6) with either full-length PTHrP or DSred vector. Insulin content and glucose-stimulated insulin secretion were measured, and RNA from the cells after incubating in 20 mM glucose was collected. The results showed that PTHrP overexpression increased insulin content and the ratio of insulin secretion between low and high glucose (stimulation index). RNA sequencing showed that PTHrP overexpression downregulated many genes associated with responses to endoplasmic reticulum (ER) stress such as Hspa40, Dnajc3, and Xbp1. Among enriched Kyoto Encyclopedia of Genes and Genomes pathways, the ER stress gene pathway was the most strongly downregulated by far, and the most upregulated pathway was for biosynthesis of amino acids required for protein synthesis. These pathways suggest increased rates of protein biosynthesis. Quantitative polymerase chain reaction supported RNA-sequencing results for several ER stress genes (Xbp1, Bax, Bip). MIN6 cells transfected with PTHrP also had lower proinsulin-to-insulin ratio, indicating that PTHrP enhanced insulin processing in the ER. Our working hypothesis is that PTHrP augments insulin production and ER efficiency, which is consistent with observations of increased insulin content, decreased proinsulin-to-insulin ratio and reduced ER stress markers in MIN6 cells. In conclusion, our findings suggest a previously unknown role for PTHrP in β-cell endoplasmic reticulum, which may have therapeutic implications for enhancing insulin production.</p>\",\"PeriodicalId\":11819,\"journal\":{\"name\":\"Endocrinology\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":3.3000,\"publicationDate\":\"2025-06-10\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Endocrinology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1210/endocr/bqaf086\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"ENDOCRINOLOGY & METABOLISM\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Endocrinology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1210/endocr/bqaf086","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"ENDOCRINOLOGY & METABOLISM","Score":null,"Total":0}
Overexpression of PTHrP in β Cells Reveals Key Effects on Endoplasmic Reticulum Stress.
Administration of parathyroid hormone-related protein (PTHrP) has been shown to increase insulin content and secretion in mice. PTHrP also increases β-cell mass and proliferation. However, the mechanisms for these effects are unknown, and investigations have yet to examine PTHrP in the transcriptome. In this study, we transiently transfected a mouse β-cell line (MIN6) with either full-length PTHrP or DSred vector. Insulin content and glucose-stimulated insulin secretion were measured, and RNA from the cells after incubating in 20 mM glucose was collected. The results showed that PTHrP overexpression increased insulin content and the ratio of insulin secretion between low and high glucose (stimulation index). RNA sequencing showed that PTHrP overexpression downregulated many genes associated with responses to endoplasmic reticulum (ER) stress such as Hspa40, Dnajc3, and Xbp1. Among enriched Kyoto Encyclopedia of Genes and Genomes pathways, the ER stress gene pathway was the most strongly downregulated by far, and the most upregulated pathway was for biosynthesis of amino acids required for protein synthesis. These pathways suggest increased rates of protein biosynthesis. Quantitative polymerase chain reaction supported RNA-sequencing results for several ER stress genes (Xbp1, Bax, Bip). MIN6 cells transfected with PTHrP also had lower proinsulin-to-insulin ratio, indicating that PTHrP enhanced insulin processing in the ER. Our working hypothesis is that PTHrP augments insulin production and ER efficiency, which is consistent with observations of increased insulin content, decreased proinsulin-to-insulin ratio and reduced ER stress markers in MIN6 cells. In conclusion, our findings suggest a previously unknown role for PTHrP in β-cell endoplasmic reticulum, which may have therapeutic implications for enhancing insulin production.
期刊介绍:
The mission of Endocrinology is to be the authoritative source of emerging hormone science and to disseminate that new knowledge to scientists, clinicians, and the public in a way that will enable "hormone science to health." Endocrinology welcomes the submission of original research investigating endocrine systems and diseases at all levels of biological organization, incorporating molecular mechanistic studies, such as hormone-receptor interactions, in all areas of endocrinology, as well as cross-disciplinary and integrative studies. The editors of Endocrinology encourage the submission of research in emerging areas not traditionally recognized as endocrinology or metabolism in addition to the following traditionally recognized fields: Adrenal; Bone Health and Osteoporosis; Cardiovascular Endocrinology; Diabetes; Endocrine-Disrupting Chemicals; Endocrine Neoplasia and Cancer; Growth; Neuroendocrinology; Nuclear Receptors and Their Ligands; Obesity; Reproductive Endocrinology; Signaling Pathways; and Thyroid.