Novel Molecular Mechanisms Controlling Pancreatic β-cell Function and Hepatic Glucose Homeostasis
Bibliographic record
Abstract
The key defects characteristic of hyperglycemia in T2D include increased hepatic glucose production, a diminution of insulin secretion, and an absolute impairment in peripheral insulin action. The objective of my thesis was to investigate the molecular mechanisms leading to fatty acid induced β-cell dysfunction and determine the role of a novel transcriptional coregulator in the regulation of hepatic glucose homeostasis. The first part of my work focused on the chronic effects of fatty acids on human pancreatic β-cell function. Using microarray technology I established an important role for fatty acids in the pathogenesis of β-cell dysfunction. Accordingly chronic exposure of islets to oleate resulted in a significant reduction in glucose-stimulated insulin secretion and to an increase in the rate of reactive oxygen species generation. Additionally, pre-treatment of human islets with oleate led to a significant increase in the rate of oxidation of this fatty acid and to a significant decrease in glucose oxidation. My data indicate that chronic exposure of human islets to fatty acids activates inflammatory and metabolic pathways that lead to oxidative stress. \nIn addition, the first part of my work demonstrated that fatty acids induce oxidative stress in vitro an effect that is preventable to a large extent by the use of antioxidants. In this setting and recapitulating the human islet data, fatty acids are causally linked to impaired insulin secretion, and the induction of oxidative stress. Our report demonstrated that oxidative stress plays a key role in the decrease in β-cell function induced by chronic lipotoxicity. My work also demonstrated that fatty acids are causally linked to the induction of endoplasmic reticulum stress in human islets. Finally, in the second part of my work I provide novel evidence for the role of PHIP in the regulation of hepatic gluconeogenesis. My work is the first to demonstrate that PHIP suppresses hepatic gluconeogenesis in vitro and in vivo. PHIP is amongst the few proteins that have ever been reported to suppress gluconeogenesis to date. PHIP thus represents a novel target for pharmaceutical intervention of diabetes and the suppression of hepatic glucose production.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
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".