Open AccessProtective role of human insulin against the cytotoxicity associated with human mutant S 20 G islet amyloid polypeptide
Author(s) -
Morita Shuhei,
Ueyama Minoru,
Sakagashira Setsuya,
Shimajiri Yoshinori,
Yamana Akiko,
Furuta Machi,
Sanke Tokio
Publication year - 2013
Publication title -
journal of diabetes investigation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.089
H-Index - 50
eISSN - 2040-1124
pISSN - 2040-1116
DOI - 10.1111/jdi.12069
Subject(s) - islet , cytotoxicity , medicine , amyloid (mycology) , mutant , diabetes mellitus , insulin , amyloid precursor protein , human insulin , endocrinology , biochemistry , gene , in vitro , disease , biology , alzheimer's disease , pathology
Abstract 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 S 20 G 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 S 20 G ‐ IAPP through long‐term deterioration of β‐cells in type 2 diabetes. Our objective was to show an effect of human insulin on S 20 G ‐ IAPP associated cytotoxicity. Materials and Methods We analyzed the cytotoxicity associated with S 20 G ‐ IAPP by controlling human insulin expression using adenovirus vectors with micro ribonucleic acid specifically against human insulin in endocrine A t T ‐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 S 20 G ‐ 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 A t T ‐20ins cells. Furthermore, downregulation of human insulin enhanced the cytotoxicity associated with S 20 G ‐ IAPP , and induced the cytotoxicity associated with wild‐type ( WT )‐ IAPP . Reduction of ubiquitin carboxy‐terminal hydrolase L 1 activity enhanced cytotoxicity under the downregulation of human insulin expression in both S 20 G ‐ 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 S 20 G ‐ 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.