Pre-clinical model of dysregulated FicD AMPylation causes diabetes by disrupting pancreatic endocrine homeostasis

IF 7 2区医学 Q1 ENDOCRINOLOGY & METABOLISM Molecular Metabolism Pub Date : 2025-03-10 DOI:10.1016/j.molmet.2025.102120

Amanda K. Casey , Nathan M. Stewart , Naqi Zaidi , Hillery F. Gray , Hazel A. Fields , Masahiro Sakurai , Carlos A. Pinzon-Arteaga , Bret M. Evers , Jun Wu , Kim Orth

{"title":"Pre-clinical model of dysregulated FicD AMPylation causes diabetes by disrupting pancreatic endocrine homeostasis","authors":"Amanda K. Casey , Nathan M. Stewart , Naqi Zaidi , Hillery F. Gray , Hazel A. Fields , Masahiro Sakurai , Carlos A. Pinzon-Arteaga , Bret M. Evers , Jun Wu , Kim Orth","doi":"10.1016/j.molmet.2025.102120","DOIUrl":null,"url":null,"abstract":"<div><div>The bi-functional enzyme FicD catalyzes AMPylation and deAMPylation of the endoplasmic reticulum chaperone BiP to modulate ER homeostasis and the unfolded protein response (UPR). Human hFicD with an arginine-to-serine mutation disrupts FicD deAMPylation activity resulting in severe neonatal diabetes. We generated the mFicDR371S mutation in mice to create a pre-clinical murine model for neonatal diabetes. We observed elevated BiP AMPylation levels across multiple tissues and signature markers for diabetes including glucose intolerance and reduced serum insulin levels. While the pancreas of mFicDR371S mice appeared normal at birth, adult mFicDR371S mice displayed disturbed pancreatic islet organization that progressed with age. mFicDR371S mice provide a preclinical mouse model for the study of UPR associated diabetes and demonstrate the essentiality of FicD for tissue resilience.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"95 ","pages":"Article 102120"},"PeriodicalIF":7.0000,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Metabolism","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2212877825000274","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ENDOCRINOLOGY & METABOLISM","Score":null,"Total":0}

引用次数: 0

Abstract

The bi-functional enzyme FicD catalyzes AMPylation and deAMPylation of the endoplasmic reticulum chaperone BiP to modulate ER homeostasis and the unfolded protein response (UPR). Human hFicD with an arginine-to-serine mutation disrupts FicD deAMPylation activity resulting in severe neonatal diabetes. We generated the mFicD^R371S mutation in mice to create a pre-clinical murine model for neonatal diabetes. We observed elevated BiP AMPylation levels across multiple tissues and signature markers for diabetes including glucose intolerance and reduced serum insulin levels. While the pancreas of mFicD^R371S mice appeared normal at birth, adult mFicD^R371S mice displayed disturbed pancreatic islet organization that progressed with age. mFicD^R371S mice provide a preclinical mouse model for the study of UPR associated diabetes and demonstrate the essentiality of FicD for tissue resilience.

Abstract Image

查看原文

微信好友朋友圈 QQ好友复制链接

本刊更多论文

求助全文

约1分钟内获得全文去求助

来源期刊

Molecular Metabolism ENDOCRINOLOGY & METABOLISM-

CiteScore

14.50

自引率

2.50%

发文量

219

审稿时长

43 days

期刊介绍： Molecular Metabolism is a leading journal dedicated to sharing groundbreaking discoveries in the field of energy homeostasis and the underlying factors of metabolic disorders. These disorders include obesity, diabetes, cardiovascular disease, and cancer. Our journal focuses on publishing research driven by hypotheses and conducted to the highest standards, aiming to provide a mechanistic understanding of energy homeostasis-related behavior, physiology, and dysfunction. We promote interdisciplinary science, covering a broad range of approaches from molecules to humans throughout the lifespan. Our goal is to contribute to transformative research in metabolism, which has the potential to revolutionize the field. By enabling progress in the prognosis, prevention, and ultimately the cure of metabolic disorders and their long-term complications, our journal seeks to better the future of health and well-being.