Protective role of human insulin against the cytotoxicity associated with human mutant S20G islet amyloid polypeptide
Version of Record online: 18 MAR 2013
© 2013 Asian Association for the Study of Diabetes and Wiley Publishing Asia Pty Ltd
Journal of Diabetes Investigation
Volume 4, Issue 5, pages 436–444, September 2013
How to Cite
(J Diabetes Invest, doi: 10.1111/jdi.12069, 2013)
- Issue online: 13 SEP 2013
- Version of Record online: 18 MAR 2013
- Manuscript Accepted: 28 JAN 2013
- Manuscript Revised: 26 JAN 2013
- Manuscript Received: 19 DEC 2012
- Diabetes Masters Conference and Japan Diabetes Society
- Wakayama Medical University
- Charitable Trust Laboratory Medicine Research Foundation of Japan
- Islet amyloid polypeptide;
- S20G mutation
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.
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.
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.