AJP - Endo Email Content Delivery
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH
QUICK SEARCH:   [advanced]


     

Am J Physiol Endocrinol Metab (May 15, 2007). doi:10.1152/ajpendo.00070.2007
This Article
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
293/2/E538    most recent
00070.2007v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Zhou, J.
Right arrow Articles by Egan, J. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Zhou, J.
Right arrow Articles by Egan, J. M.
Submitted on January 29, 2007
Accepted on May 12, 2007

Ubiquitination is involved in glucose-mediated down-regulation of GIP receptors in islets

Jie Zhou1, Mauren F.A. Livak2, Michel Bernier2, Denis C Muller3, Olga D Carlson4, Dariush Elahi5, Stuart Maudsley6, and Josephine M. Egan7*

1 Diabetes Section/LCI/GRC, NIA/NIH, Baltimore, Maryland, United States
2 Diabetes Section/LCI/GRC, NIA/NIH, Baltimore, Maryland, United States; Baltimore, Maryland, United States
3 Clinical Research Branch, NIA/NIH, Baltimore, Maryland, United States
4 Clinical Research Branch, NIA/NIH, Baltimore, Maryland, United States; Baltimore, Maryland, United States
5 Dept of Surgery, Johns Hopkins Bayview Medical Center, Baltimore, Maryland, United States
6 Laboratory of Neuroscience, NIA/NIH, Baltimore, Maryland, United States
7 GRC / NIA, National Institutes of Health, Baltimore,, Maryland, United States

* To whom correspondence should be addressed. E-mail: eganj{at}vax.grc.nia.nih.gov.

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 ≥ 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 hours resulted in prevention of GIP-mediated intracellular cAMP increase compared to 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 we found that GIP R was targeted for ubiquitination in a glucose-and time-dependent manner. Down-regulation of GIP R was rescued by treating isolated islets with proteasomal inhibitors, lactacystin and MG132, 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.




This article has been cited by other articles:


Home page
 DiabetesHome page
C. W. Chia, O. D. Carlson, W. Kim, Y.-K. Shin, C. P. Charles, H. S. Kim, D. L. Melvin, and J. M. Egan
Exogenous Glucose-Dependent Insulinotropic Polypeptide Worsens Post prandial Hyperglycemia in T ype 2 Diabetes
Diabetes, June 1, 2009; 58(6): 1342 - 1349.
[Abstract] [Full Text] [PDF]

Home page
 Pharmacol. Rev.Home page
W. Kim and J. M. Egan
The Role of Incretins in Glucose Homeostasis and Diabetes Treatment
Pharmacol. Rev., December 1, 2008; 60(4): 470 - 512.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH
Visit Other APS Journals Online
Copyright © 2007 by the American Physiological Society.