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Title
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Ubiquitination is involved in glucose-mediated downregulation of GIP receptors in islets
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Author
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Abstract
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| Glucose-dependent insulinotropic polypeptide (GIP) is a gastrointestinal hormone that has a potent stimulatory effect on insulin release under conditions of normal glucose tolerance. However, its insulinotropic effect is reduced or even absent entirely in type 2 diabetic patients. In this study, we addressed the role of glucose concentration in the diabetic range of >= 11 mM, i.e., hyperglycemia per se, as a cause of the lack of response to GIP. Culturing rat and human pancreatic islets in >= 11 mM glucose for up to 24 h resulted in prevention of GIP-mediated intracellular cAMP increase compared with culturing in 5 mM glucose. Western blot analysis revealed a selective 67 +/- 2% (rat) and 60 +/- 8% ( =human) decrease of GIP-R expression in islets exposed to >= 11 mM glucose compared with 5 mM glucose (P < 0.001). We further immunoprecipitated GIP-R from islets and found that GIP-R was targeted for ubiquitination in a glucose- and time-dependent manner. Downregulation of GIP-R was rescued by treating isolated islets with proteasomal inhibitors lactacystin and MG-132, and the islets were once again capable of increasing intracellular cAMP levels in response to GIP. These results suggest that the GIP-R is ubiquitated, resulting in downregulation of the actions of GIP. |
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Language
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English
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Source (journal)
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American journal of physiology: endocrinology and metabolism / American Physiological Society. - Bethesda, Md
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Publication
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Bethesda, Md
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2007
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ISSN
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0193-1849
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DOI
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10.1152/AJPENDO.00070.2007
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Volume/pages
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293
:2
(2007)
, p. E538-E547
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ISI
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000248458100014
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Full text (Publisher's DOI)
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Full text (publisher's version - intranet only)
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