A PHP Error was encountered

Severity: Warning

Message: file_get_contents(https://...@gmail.com&api_key=61f08fa0b96a73de8c900d749fcb997acc09): Failed to open stream: HTTP request failed! HTTP/1.1 429 Too Many Requests

Filename: helpers/my_audit_helper.php

Line Number: 143

Backtrace:

File: /var/www/html/application/helpers/my_audit_helper.php
Line: 143
Function: file_get_contents

File: /var/www/html/application/helpers/my_audit_helper.php
Line: 209
Function: simplexml_load_file_from_url

File: /var/www/html/application/helpers/my_audit_helper.php
Line: 994
Function: getPubMedXML

File: /var/www/html/application/helpers/my_audit_helper.php
Line: 3134
Function: GetPubMedArticleOutput_2016

File: /var/www/html/application/controllers/Detail.php
Line: 574
Function: pubMedSearch_Global

File: /var/www/html/application/controllers/Detail.php
Line: 488
Function: pubMedGetRelatedKeyword

File: /var/www/html/index.php
Line: 316
Function: require_once

Proinsulin misfolding and endoplasmic reticulum stress during the development and progression of diabetes. | LitMetric

Proinsulin misfolding and endoplasmic reticulum stress during the development and progression of diabetes.

Mol Aspects Med

Division of Metabolism, Endocrinology & Diabetes, University of Michigan, Ann Arbor, MI 48105, USA; Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, Tianjin 300052, China. Electronic address:

Published: April 2015

To maintain copious insulin granule stores in the face of ongoing metabolic demand, pancreatic beta cells must produce large quantities of proinsulin, the insulin precursor. Proinsulin biosynthesis can account for up to 30-50% of total cellular protein synthesis of beta cells. This puts pressure on the beta cell secretory pathway, especially the endoplasmic reticulum (ER), where proinsulin undergoes its initial folding, including the formation of three evolutionarily conserved disulfide bonds. In normal beta cells, up to 20% of newly synthesized proinsulin may fail to reach its native conformation, suggesting that proinsulin is a misfolding-prone protein. Misfolded proinsulin molecules can either be refolded to their native structure or degraded through ER associated degradation (ERAD) and autophagy. These degraded molecules decrease proinsulin yield but do not otherwise compromise beta cell function. However, under certain pathological conditions, proinsulin misfolding increases, exceeding the genetically determined threshold of beta cells to handle the misfolded protein load. This results in accumulation of misfolded proinsulin in the ER - a causal factor leading to beta cell failure and diabetes. In patients with Mutant INS-gene induced diabetes of Youth (MIDY), increased proinsulin misfolding due to insulin gene mutations is the primary defect operating as a "first hit" to beta cells. Additionally, increased proinsulin misfolding can be secondary to an unfavorable ER folding environment due to genetic and/or environmental factors. Under these conditions, increased wild-type proinsulin misfolding becomes a "second hit" to the ER and beta cells, aggravating beta cell failure and diabetes. In this article, we describe our current understanding of the normal proinsulin folding pathway in the ER, and then review existing links between proinsulin misfolding, ER dysfunction, and beta cell failure in the development and progression of type 2, type 1, and some monogenic forms of diabetes.

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4404191PMC
http://dx.doi.org/10.1016/j.mam.2015.01.001DOI Listing

Publication Analysis

Top Keywords

proinsulin misfolding
24
beta cells
24
beta cell
20
proinsulin
15
cell failure
12
beta
11
endoplasmic reticulum
8
development progression
8
misfolded proinsulin
8
failure diabetes
8

Similar Publications

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!