Regulation of glucose-dependent insulinotropic polypeptide (GIP) receptor expression in the pancreatic β-cell
Bibliographic record
Abstract
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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".