Release of Glutamate Decarboxylase-65 into the Circulation by Injured Pancreatic Islet β-Cells

Author:

Waldrop Megan A.1,Suckow Arthur T.12,Marcovina Santica M.3,Chessler Steven D.1

Affiliation:

1. Department of Medicine (M.A.W., A.T.S., S.D.C.), University of California, San Diego, La Jolla, California 92093-0726

2. Biomedical Sciences Graduate Program (A.T.S.), University of California, San Diego, La Jolla, California 92093-0726

3. Northwest Lipid Metabolism and Diabetes Research Laboratories (S.M.M.), University of Washington, Seattle, Washington 98109

Abstract

The enzyme glutamate decarboxylase-65 (GAD65) is a major autoantigen in autoimmune diabetes. The mechanism whereby autoreactivity to GAD65, an intracellular protein, is triggered is unknown, and it is possible that immunoreactive GAD65 is released by injured pancreatic islet β-cells. There is a great need for methods by which to detect and monitor ongoing islet injury. If GAD65 were released and, furthermore, were able to reach the circulation, it could function as a marker of β-cell injury. Here, a novel GAD65 plasma immunoassay is used to test the hypotheses that β-cell injury induces GAD65 discharge in vivo and that discharged GAD65 reaches the bloodstream. Plasma GAD65 levels were determined in rats treated with alloxan, and with diabetogenic and low, subdiabetogenic doses of streptozotocin. β-Cell injury resulted in GAD65 release into the circulation in a dose-dependent manner, and low-dose streptozotocin resulted in a more gradual increase in plasma GAD65 levels than did diabetogenic doses. Plasma GAD65 levels were reduced in rats that had undergone partial pancreatectomy and remained undetectable in mice. Together, these data demonstrate that GAD65 can be released into the circulation by injured β-cells. Autoantigen shedding may contribute to the pathogenesis of islet autoimmunity in the multiple low-dose streptozocin model and perhaps, more generally, in other forms of autoimmune diabetes. These results demonstrate that, as is true with other tissues, islet injury, at least in some circumstances, can be monitored by use of discharged, circulating proteins. GAD65 is the first such confirmed protein marker of islet injury.

Publisher

The Endocrine Society

Subject

Endocrinology

Cited by 19 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

1. Markers for beta-cell loss;Transplantation, Bioengineering, and Regeneration of the Endocrine Pancreas;2020

2. Combined Analysis of GAD65, miR-375, and Unmethylated Insulin DNA Following Islet Transplantation in Patients With T1D;The Journal of Clinical Endocrinology & Metabolism;2018-09-07

3. Biomarkers in Islet Cell Transplantation for Type 1 Diabetes;Current Diabetes Reports;2018-09-05

4. An analytical comparison of three immunoassay platforms for subpicomolar detection of protein biomarker GAD65;PLOS ONE;2018-03-08

5. Current issues in allogeneic islet transplantation;Current Opinion in Organ Transplantation;2017-10

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3