Regulation of glucose-dependent insulinotropic polypeptide (GIP) receptor expression in the pancreatic β-cell
Notice bibliographique
Résumé
Glucose-dependent insulinotropic polypeptide (GIP) is a peptide hormone that is released postprandially from the small intestine and acts to potentiate glucose induced insulin secretion from the pancreatic β-cell. In type 2 diabetes (T2D) there is a decreased responsiveness of the pancreas to GIP. The literature suggests that the ineffectiveness of GIP in T2D may be a result of chronic homologous desensitization of the GIP receptor (GIPR); however, there has been no conclusive evidence suggesting that GIP levels are elevated in diabetes. The first hypothesis of this thesis is that one cause of decreased responsiveness to GIP in T2D is an inappropriate expression of the GIPR on the pancreatic islet. This hypothesis was tested using the Vancouver Diabetic Fatty (VDF) strain of Zucker rats. The VDF rats were unresponsive to a GIP infusion during an intraperitoneal glucose tolerance test (IPGTT). GIP did not alter insulin secretion or cAMP production in isolated VDF islets, nor did it stimulate insulin secretion from perfused VDF pancreata. The expression of GIPR mRNA and protein in islets from VDF rats was significantly reduced. The second hypothesis is that hyperglycemia and hyperlipidemia are able to regulate β-cell expression of the GIP receptor. High glucose was able to significantly reduce GIPR mRNA levels in INS(832/13) cells after only 6 hours. Palmitic acid and the PPARα activator, WY 14643, produced an approximate doubling of GIPR expression in INS(832/13) cells under 5.5 mM but not 25 mM glucose conditions, suggesting that free fatty acids can regulate GIPR expression via PPARα in a glucose-dependent manner. A dominant negative form of PPARα transfected into INS(832/13) cells caused a significant reduction in GIPR expression in 5.5 but not 25 mM glucose. In hyperglycemic clamped rats, there were reductions in GIPR expression in the islets and in GIP-stimulated insulin secretion. Thus, evidence is presented that the GIPR is controlled at normoglycemia by the fatty acid load on the islet; however, when exposed to hyperglycemic conditions the GIPR is down-regulated. The final hypothesis of this thesis is that glycosylation of the GIPR is able to control receptor expression on the cell surface. Here we demonstrate that cell surface expression of the GIPR and GIPstimulated insulin secretion are dependent on glycosylation of the GIPR. Furthermore, the asparagine-linked glycosylation sites on the GIPR include Asn-59, Asn-69, and Asn- 200 and alteration of any of these sites decreased total cell surface GIPR expression. Overall, this thesis presents evidence that the GIPR is regulated negatively by glucose and positively by free fatty acids. Additionally, it is demonstrated that hyperglycemia leads to downregulation of the GIPR in models of T2D. This glucose-induced downregulation is a result of a decrease in transcription of the receptor as well as a glucose-induced defect in glycosylation of the receptor.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,001 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».