TY - JOUR
T1 - Monogenic and syndromic diabetes due to endoplasmic reticulum stress
AU - Stone, Stephen I.
AU - Abreu, Damien
AU - McGill, Janet B.
AU - Urano, Fumihiko
N1 - Funding Information:
This work was partly supported by the grants from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health ( DK112921 , DK113487 , DK020579 ), National Center for Advancing Translational Sciences (NCATS) of the NIH ( TR002065 , TR000448 ), JDRF ( 2-SRA-2016-233-S-N ) and philanthropic supports from the Unravel Wolfram Syndrome Fund, the Silberman Fund, the Stowe Fund, the Snow Foundation, the Eye Hope Foundation, the Ellie White Foundation for the Rare Genetic Disorders, Sindrome di Wolfram Italia, the Team Ian, the Team Alejandro, and the Feiock Fund to F. Urano. Additional assistance was provided by the Washington University Diabetes Research Center and the Washington University Institute of Clinical and Translational Sciences supported by the NCATS of the NIH (UL1TR002345). The authors thank all the members of the Washington University Wolfram Syndrome Study and Research Clinic for their support ( https://wolframsyndrome.dom.wustl.edu ) and all the participants in the Wolfram syndrome International Registry and Clinical Study, Research Clinic, and Clinical Trials for their time and efforts. S. Stone, J. McGill, and F. Urano are active investigators for the Rare and Atypical Diabetes Network ( https://www-uat.atypicaldiabetesnetwork.org/ ) supported by the NIDDK of the NIH (U54DK118612).
Funding Information:
F. Urano received research funding from Eli Lilly, Ono Pharmaceuticals, and Amarantus BioScience for the development of MANF-based regenerative therapy for Wolfram syndrome and diabetes. He also received chemical compounds from Amylyx Pharmaceuticals, Mitochon Pharmaceuticals, Aetas Pharma, and National Center for Advancing Translational Sciences for the development small molecule-based therapies for ERstress-related disorders, including Wolfram syndrome and diabetes. F. Urano is an inventor of two patents related to the treatment of Wolfram syndrome, US 9,891,231 B2 SOLUBLE MANF IN PANCREATIC BETA CELL DISORDERS and US 10,441,574, B2 TREATMENT FOR WOLFRAM SYNDROME AND OTHER ER STRESS DISORDERS. F. Urano and S. Stone assisted with the development of the diabetes genetic testing panels at Washington University, however they receive no direct financial benefits from testing performed at their institutions.
Funding Information:
This work was partly supported by the grants from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health(DK112921, DK113487, DK020579), National Center for Advancing Translational Sciences (NCATS) of the NIH(TR002065, TR000448), JDRF(2-SRA-2016-233-S-N) and philanthropic supports from the Unravel Wolfram Syndrome Fund, the Silberman Fund, the Stowe Fund, the Snow Foundation, the Eye Hope Foundation, the Ellie White Foundation for the Rare Genetic Disorders, Sindrome di Wolfram Italia, the Team Ian, the Team Alejandro, and the Feiock Fund to F. Urano. Additional assistance was provided by the Washington University Diabetes Research Center and the Washington University Institute of Clinical and Translational Sciences supported by the NCATS of the NIH (UL1TR002345). The authors thank all the members of the Washington University Wolfram Syndrome Study and Research Clinic for their support (https://wolframsyndrome.dom.wustl.edu) and all the participants in the Wolfram syndrome International Registry and Clinical Study, Research Clinic, and Clinical Trials for their time and efforts. S. Stone, J. McGill, and F. Urano are active investigators for the Rare and Atypical Diabetes Network (RADIANT; https://www.atypicaldiabetesnetwork.org/) supported by the NIDDK of the NIH.
Publisher Copyright:
© 2020 Elsevier Inc.
PY - 2021/1
Y1 - 2021/1
N2 - The endoplasmic reticulum (ER) lies at the crossroads of protein folding, calcium storage, lipid metabolism, and the regulation of autophagy and apoptosis. Accordingly, dysregulation of ER homeostasis leads to β-cell dysfunction in type 1 and type 2 diabetes that ultimately culminates in cell death. The ER is therefore an emerging target for understanding the mechanisms of diabetes mellitus that captures the complex etiologies of this multifactorial class of metabolic disorders. Our strategy for developing ER-targeted diagnostics and therapeutics is to focus on monogenic forms of diabetes related to ER dysregulation in an effort to understand the exact contribution of ER stress to β-cell death. In this manner, we can develop personalized genetic medicine for ERstress-related diabetic disorders, such as Wolfram syndrome. In this article, we describe the phenotypes and molecular pathogenesis of ERstress-related monogenic forms of diabetes.
AB - The endoplasmic reticulum (ER) lies at the crossroads of protein folding, calcium storage, lipid metabolism, and the regulation of autophagy and apoptosis. Accordingly, dysregulation of ER homeostasis leads to β-cell dysfunction in type 1 and type 2 diabetes that ultimately culminates in cell death. The ER is therefore an emerging target for understanding the mechanisms of diabetes mellitus that captures the complex etiologies of this multifactorial class of metabolic disorders. Our strategy for developing ER-targeted diagnostics and therapeutics is to focus on monogenic forms of diabetes related to ER dysregulation in an effort to understand the exact contribution of ER stress to β-cell death. In this manner, we can develop personalized genetic medicine for ERstress-related diabetic disorders, such as Wolfram syndrome. In this article, we describe the phenotypes and molecular pathogenesis of ERstress-related monogenic forms of diabetes.
KW - ER stress
KW - Endoplasmic reticulum
KW - Genetic medicine
KW - Genetic testing
KW - Personalized medicine
KW - Wolfram syndrome
UR - http://www.scopus.com/inward/record.url?scp=85086014729&partnerID=8YFLogxK
U2 - 10.1016/j.jdiacomp.2020.107618
DO - 10.1016/j.jdiacomp.2020.107618
M3 - Article
C2 - 32518033
AN - SCOPUS:85086014729
VL - 35
JO - Journal of Diabetes and its Complications
JF - Journal of Diabetes and its Complications
SN - 1056-8727
IS - 1
M1 - 107618
ER -