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Protective role of human insulin against the cytotoxicity associated with human mutant S20G islet amyloid polypeptide
AIMS/INTRODUCTION: Islet amyloid polypeptide (IAPP) is a main component of islet amyloid in type 2 diabetes and cosecreted from β‐cell with insulin. Clinical evidence from the patients with S20G mutation of the IAPP gene, as well as experimental evidence that insulin could inhibit amyloid formation...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Wiley-Blackwell
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4025108/ https://www.ncbi.nlm.nih.gov/pubmed/24843692 http://dx.doi.org/10.1111/jdi.12069 |
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author | Morita, Shuhei Ueyama, Minoru Sakagashira, Setsuya Shimajiri, Yoshinori Yamana, Akiko Furuta, Machi Sanke, Tokio |
author_facet | Morita, Shuhei Ueyama, Minoru Sakagashira, Setsuya Shimajiri, Yoshinori Yamana, Akiko Furuta, Machi Sanke, Tokio |
author_sort | Morita, Shuhei |
collection | PubMed |
description | AIMS/INTRODUCTION: Islet amyloid polypeptide (IAPP) is a main component of islet amyloid in type 2 diabetes and cosecreted from β‐cell with insulin. Clinical evidence from the patients with S20G mutation of the IAPP gene, as well as experimental evidence that insulin could inhibit amyloid formation of IAPP, suggests that a gradual reduction of insulin could be related to the cytotoxicity associated with S20G‐IAPP through long‐term deterioration of β‐cells in type 2 diabetes. Our objective was to show an effect of human insulin on S20G‐IAPP associated cytotoxicity. MATERIALS AND METHODS: We analyzed the cytotoxicity associated with S20G‐IAPP by controlling human insulin expression using adenovirus vectors with micro ribonucleic acid specifically against human insulin in endocrine AtT‐20ins cells, which express human insulin permanently. Additionally, we carried out a follow‐up study of circulating IAPP and insulin in type 2 diabetic patients. RESULTS: S20G‐IAPP expression was associated with a decrease in viability and an increase in terminal deoxynucleotidyl transferase‐mediated deoxyuridine triphosphate‐biotin nick end labeling‐positive cells in AtT‐20ins cells. Furthermore, downregulation of human insulin enhanced the cytotoxicity associated with S20G‐IAPP, and induced the cytotoxicity associated with wild‐type (WT)‐IAPP. Reduction of ubiquitin carboxy‐terminal hydrolase L1 activity enhanced cytotoxicity under the downregulation of human insulin expression in both S20G‐ and WT‐IAPP transduced cells. A 5‐year follow up of type 2 diabetic patients showed a disproportionate increase of serum fasting IAPP‐to‐insulin ratio from baseline. CONCLUSIONS: Human insulin plays a protective role against the cytotoxicity associated with S20G‐IAPP, as well as WT‐IAPP. The findings could suggest long‐term deterioration of insulin secretion associates with IAPP linked cytotoxicity in type 2 diabetes. |
format | Online Article Text |
id | pubmed-4025108 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Wiley-Blackwell |
record_format | MEDLINE/PubMed |
spelling | pubmed-40251082014-05-19 Protective role of human insulin against the cytotoxicity associated with human mutant S20G islet amyloid polypeptide Morita, Shuhei Ueyama, Minoru Sakagashira, Setsuya Shimajiri, Yoshinori Yamana, Akiko Furuta, Machi Sanke, Tokio J Diabetes Investig Articles AIMS/INTRODUCTION: Islet amyloid polypeptide (IAPP) is a main component of islet amyloid in type 2 diabetes and cosecreted from β‐cell with insulin. Clinical evidence from the patients with S20G mutation of the IAPP gene, as well as experimental evidence that insulin could inhibit amyloid formation of IAPP, suggests that a gradual reduction of insulin could be related to the cytotoxicity associated with S20G‐IAPP through long‐term deterioration of β‐cells in type 2 diabetes. Our objective was to show an effect of human insulin on S20G‐IAPP associated cytotoxicity. MATERIALS AND METHODS: We analyzed the cytotoxicity associated with S20G‐IAPP by controlling human insulin expression using adenovirus vectors with micro ribonucleic acid specifically against human insulin in endocrine AtT‐20ins cells, which express human insulin permanently. Additionally, we carried out a follow‐up study of circulating IAPP and insulin in type 2 diabetic patients. RESULTS: S20G‐IAPP expression was associated with a decrease in viability and an increase in terminal deoxynucleotidyl transferase‐mediated deoxyuridine triphosphate‐biotin nick end labeling‐positive cells in AtT‐20ins cells. Furthermore, downregulation of human insulin enhanced the cytotoxicity associated with S20G‐IAPP, and induced the cytotoxicity associated with wild‐type (WT)‐IAPP. Reduction of ubiquitin carboxy‐terminal hydrolase L1 activity enhanced cytotoxicity under the downregulation of human insulin expression in both S20G‐ and WT‐IAPP transduced cells. A 5‐year follow up of type 2 diabetic patients showed a disproportionate increase of serum fasting IAPP‐to‐insulin ratio from baseline. CONCLUSIONS: Human insulin plays a protective role against the cytotoxicity associated with S20G‐IAPP, as well as WT‐IAPP. The findings could suggest long‐term deterioration of insulin secretion associates with IAPP linked cytotoxicity in type 2 diabetes. Wiley-Blackwell 2013-09-13 2013-03-18 /pmc/articles/PMC4025108/ /pubmed/24843692 http://dx.doi.org/10.1111/jdi.12069 Text en Copyright © 2013 Asian Association for the Study of Diabetes and Wiley Publishing Asia Pty Ltd |
spellingShingle | Articles Morita, Shuhei Ueyama, Minoru Sakagashira, Setsuya Shimajiri, Yoshinori Yamana, Akiko Furuta, Machi Sanke, Tokio Protective role of human insulin against the cytotoxicity associated with human mutant S20G islet amyloid polypeptide |
title | Protective role of human insulin against the cytotoxicity associated with human mutant S20G islet amyloid polypeptide |
title_full | Protective role of human insulin against the cytotoxicity associated with human mutant S20G islet amyloid polypeptide |
title_fullStr | Protective role of human insulin against the cytotoxicity associated with human mutant S20G islet amyloid polypeptide |
title_full_unstemmed | Protective role of human insulin against the cytotoxicity associated with human mutant S20G islet amyloid polypeptide |
title_short | Protective role of human insulin against the cytotoxicity associated with human mutant S20G islet amyloid polypeptide |
title_sort | protective role of human insulin against the cytotoxicity associated with human mutant s20g islet amyloid polypeptide |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4025108/ https://www.ncbi.nlm.nih.gov/pubmed/24843692 http://dx.doi.org/10.1111/jdi.12069 |
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