| Constitutively active heat shock factor 1 enhances glucose-driven insulin secretion. | |
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MedLine Citation:
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PMID: 20817212 Owner: NLM Status: In-Data-Review |
Abstract/OtherAbstract:
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Weak pancreatic β-cell function is a cause of type 2 diabetes mellitus. Glucokinase regulates insulin secretion via phosphorylation of glucose. The present study focused on a system for the self-protection of pancreatic cell by expressing heat shock factor (HSF) and heat shock protein (HSP) to improve insulin secretion without inducing hypoglycemia. We previously generated a constitutively active form of human HSF1 (CA-hHSF1). An adenovirus expressing CA-hHSF1 using the cytomegalovirus promoter was generated to infect mouse insulinoma cells (MIN6 cells). An adenovirus expressing CA-hHSF1 using a human insulin promoter (Ins-CA-hHSF1) was also generated to infect rats. We investigated whether CA-hHSF1 induces insulin secretion in MIN6 cells and whether Ins-CA-hHSF1 can improve blood glucose and serum insulin levels in healthy Wister rats and type 2 diabetes mellitus model rats. CA-hHSF1 expression increased insulin secretion 1.27-fold compared with the overexpression of wild-type hHSF1 in MIN6 cells via induction of HSP90 expression and subsequent activation of glucokinase. This mechanism is associated with activation of both glucokinase and neuronal nitric oxide synthase. Ins-CA-hHSF1 improved blood glucose levels in neonatal streptozotocin-induced diabetic rats. Furthermore, Ins-CA-hHSF1 reduced oral glucose tolerance testing results in healthy Wister rats because of an insulin spike at 15 minutes; however, it did not induce hypoglycemia. CA-hHSF1 induced insulin secretion both in vitro and in vivo. These findings suggest that gene therapy with Ins-CA-hHSF1 will be able to be used to treat patients with type 2 diabetes mellitus and impaired glucose tolerance without causing hypoglycemia at fasting. |
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Authors:
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Tsuyoshi Uchiyama; Shoichi Tomono; Toshihiro Utsugi; Yoshio Ohyama; Tetsuya Nakamura; Hideaki Tomura; Shoji Kawazu; Fumikazu Okajima; Masahiko Kurabayashi |
Publication Detail:
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Type: Journal Article Date: 2010-09-03 |
Journal Detail:
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Title: Metabolism: clinical and experimental Volume: 60 ISSN: 1532-8600 ISO Abbreviation: Metab. Clin. Exp. Publication Date: 2011 Jun |
Date Detail:
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Created Date: 2011-05-17 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0375267 Medline TA: Metabolism Country: United States |
Other Details:
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Languages: eng Pagination: 789-98 Citation Subset: IM |
Copyright Information:
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Copyright © 2011 Elsevier Inc. All rights reserved. |
Affiliation:
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Laboratory of Signal Transduction and Department of Cell Biology, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Gunma 371-8512, Japan. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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