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Predisposition to Proinsulin Misfolding as a Genetic Risk to Diet-Induced Diabetes

Throughout evolution, proinsulin has exhibited significant sequence variation in both C-peptide and insulin moieties. As the proinsulin coding sequence evolves, the gene product continues to be under selection pressure both for ultimate insulin bioactivity and for the ability of proinsulin to be fol...

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Autores principales: Alam, Maroof, Arunagiri, Anoop, Haataja, Leena, Torres, Mauricio, Larkin, Dennis, Kappler, John, Jin, Niyun, Arvan, Peter
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Diabetes Association 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8564407/
https://www.ncbi.nlm.nih.gov/pubmed/34462258
http://dx.doi.org/10.2337/db21-0422
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author Alam, Maroof
Arunagiri, Anoop
Haataja, Leena
Torres, Mauricio
Larkin, Dennis
Kappler, John
Jin, Niyun
Arvan, Peter
author_facet Alam, Maroof
Arunagiri, Anoop
Haataja, Leena
Torres, Mauricio
Larkin, Dennis
Kappler, John
Jin, Niyun
Arvan, Peter
author_sort Alam, Maroof
collection PubMed
description Throughout evolution, proinsulin has exhibited significant sequence variation in both C-peptide and insulin moieties. As the proinsulin coding sequence evolves, the gene product continues to be under selection pressure both for ultimate insulin bioactivity and for the ability of proinsulin to be folded for export through the secretory pathway of pancreatic β-cells. The substitution proinsulin-R(B22)E is known to yield a bioactive insulin, although R(B22)Q has been reported as a mutation that falls within the spectrum of mutant INS-gene–induced diabetes of youth. Here, we have studied mice expressing heterozygous (or homozygous) proinsulin-R(B22)E knocked into the Ins2 locus. Neither females nor males bearing the heterozygous mutation developed diabetes at any age examined, but subtle evidence of increased proinsulin misfolding in the endoplasmic reticulum is demonstrable in isolated islets from the heterozygotes. Moreover, males have indications of glucose intolerance, and within a few weeks of exposure to a high-fat diet, they developed frank diabetes. Diabetes was more severe in homozygotes, and the development of disease paralleled a progressive heterogeneity of β-cells with increasing fractions of proinsulin-rich/insulin-poor cells as well as glucagon-positive cells. Evidently, subthreshold predisposition to proinsulin misfolding can go undetected but provides genetic susceptibility to diet-induced β-cell failure.
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spelling pubmed-85644072022-11-01 Predisposition to Proinsulin Misfolding as a Genetic Risk to Diet-Induced Diabetes Alam, Maroof Arunagiri, Anoop Haataja, Leena Torres, Mauricio Larkin, Dennis Kappler, John Jin, Niyun Arvan, Peter Diabetes Islet Studies Throughout evolution, proinsulin has exhibited significant sequence variation in both C-peptide and insulin moieties. As the proinsulin coding sequence evolves, the gene product continues to be under selection pressure both for ultimate insulin bioactivity and for the ability of proinsulin to be folded for export through the secretory pathway of pancreatic β-cells. The substitution proinsulin-R(B22)E is known to yield a bioactive insulin, although R(B22)Q has been reported as a mutation that falls within the spectrum of mutant INS-gene–induced diabetes of youth. Here, we have studied mice expressing heterozygous (or homozygous) proinsulin-R(B22)E knocked into the Ins2 locus. Neither females nor males bearing the heterozygous mutation developed diabetes at any age examined, but subtle evidence of increased proinsulin misfolding in the endoplasmic reticulum is demonstrable in isolated islets from the heterozygotes. Moreover, males have indications of glucose intolerance, and within a few weeks of exposure to a high-fat diet, they developed frank diabetes. Diabetes was more severe in homozygotes, and the development of disease paralleled a progressive heterogeneity of β-cells with increasing fractions of proinsulin-rich/insulin-poor cells as well as glucagon-positive cells. Evidently, subthreshold predisposition to proinsulin misfolding can go undetected but provides genetic susceptibility to diet-induced β-cell failure. American Diabetes Association 2021-11 2021-08-30 /pmc/articles/PMC8564407/ /pubmed/34462258 http://dx.doi.org/10.2337/db21-0422 Text en © 2021 by the American Diabetes Association https://www.diabetesjournals.org/content/licenseReaders may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at https://www.diabetesjournals.org/content/license.
spellingShingle Islet Studies
Alam, Maroof
Arunagiri, Anoop
Haataja, Leena
Torres, Mauricio
Larkin, Dennis
Kappler, John
Jin, Niyun
Arvan, Peter
Predisposition to Proinsulin Misfolding as a Genetic Risk to Diet-Induced Diabetes
title Predisposition to Proinsulin Misfolding as a Genetic Risk to Diet-Induced Diabetes
title_full Predisposition to Proinsulin Misfolding as a Genetic Risk to Diet-Induced Diabetes
title_fullStr Predisposition to Proinsulin Misfolding as a Genetic Risk to Diet-Induced Diabetes
title_full_unstemmed Predisposition to Proinsulin Misfolding as a Genetic Risk to Diet-Induced Diabetes
title_short Predisposition to Proinsulin Misfolding as a Genetic Risk to Diet-Induced Diabetes
title_sort predisposition to proinsulin misfolding as a genetic risk to diet-induced diabetes
topic Islet Studies
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8564407/
https://www.ncbi.nlm.nih.gov/pubmed/34462258
http://dx.doi.org/10.2337/db21-0422
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