RGD Reference Report - Ubiquitination is involved in glucose-mediated downregulation of GIP receptors in islets. - Rat Genome Database

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Ubiquitination is involved in glucose-mediated downregulation of GIP receptors in islets.

Authors: Zhou, J  Livak, MF  Bernier, M  Muller, DC  Carlson, OD  Elahi, D  Maudsley, S  Egan, JM 
Citation: Zhou J, etal., Am J Physiol Endocrinol Metab. 2007 Aug;293(2):E538-47. Epub 2007 May 15.
RGD ID: 2312603
Pubmed: PMID:17505054   (View Abstract at PubMed)
PMCID: PMC2640485   (View Article at PubMed Central)
DOI: DOI:10.1152/ajpendo.00070.2007   (Journal Full-text)

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 >or=11 mM, i.e., hyperglycemia per se, as a cause of the lack of response to GIP. Culturing rat and human pancreatic islets in >or=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 >or=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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
hyperglycemia  ISOGipr (Rattus norvegicus)2312603; 2312603protein:decreased expression:pancreatic islet (rat)RGD 
hyperglycemia  IEP 2312603protein:decreased expression:pancreatic islet (rat)RGD 

Objects Annotated

Genes (Rattus norvegicus)
Gipr  (gastric inhibitory polypeptide receptor)

Genes (Mus musculus)
Gipr  (gastric inhibitory polypeptide receptor)

Genes (Homo sapiens)
GIPR  (gastric inhibitory polypeptide receptor)


Additional Information