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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...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Diabetes Association
2021
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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. |
format | Online Article Text |
id | pubmed-8564407 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | American Diabetes Association |
record_format | MEDLINE/PubMed |
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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