期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 112, 期 20, 页码 E2611-E2619出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1423849112
关键词
diabetes; apoCIII; insulin resistance; pancreatic islets
资金
- Swedish Diabetes Association
- Funds of Karolinska Institutet
- Swedish Research Council
- Novo Nordisk Foundation
- Family Erling-Persson Foundation
- Strategic Research Program in Diabetes at Karolinska Institutet
- The Family Knut and Alice Wallenberg Foundation
- Skandia Insurance Company
- Diabetes and Wellness Foundation
- The Bert von Kantzow Foundation
- Svenska Diabetesstiftelsen
- Lee Kong Chian School of Medicine, Nanyang Technological University Start-Up Grant
- The Stichting af Jochnick Foundation
- Diabetes Research Institute Foundation
- Agency for Science, Technology and Research, in Singapore
- Human islets were provided through Juvenile Diabetes Research Foundation (JDRF) Award [31-2008-416]
- [The ERC-2013-AdG 338936-BetaImage]
- Novo Nordisk Fonden [NNF12OC1016557] Funding Source: researchfish
Insulin resistance and beta-cell failure are the major defects in type 2 diabetes mellitus. However, the molecular mechanisms linking these two defects remain unknown. Elevated levels of apolipoprotein CIII (apoCIII) are associated not only with insulin resistance but also with cardiovascular disorders and inflammation. We now demonstrate that local apoCIII production is connected to pancreatic islet insulin resistance and beta-cell failure. An increase in islet apoCIII causes promotion of a local inflammatory milieu, increased mitochondrial metabolism, deranged regulation of beta-cell cytoplasmic free Ca2+ concentration ([Ca2+](i)) and apoptosis. Decreasing apoCIII in vivo results in improved glucose tolerance, and pancreatic apoCIII knockout islets transplanted into diabetic mice, with high systemic levels of the apolipoprotein, demonstrate a normal [Ca2+](i) response pattern and no hallmarks of inflammation. Hence, under conditions of islet insulin resistance, locally produced apoCIII is an important diabetogenic factor involved in impairment of beta-cell function and may thus constitute a novel target for the treatment of type 2 diabetes mellitus.
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