Exploring β-cell NADPH production and glucose-stimulated insulin secretion in proinflammatory cytokine induced stress
Bibliographic record
Abstract
The role of inflammation in the pathophysiology of Type I (T1D) and Type II diabetes (T2D) has prompted research into targeting inflammation to improve disease prevention and management. Pancreatic β cells respond to elevated blood glucose levels by releasing insulin hormone in a rapid first-phase burst followed by a sustained second phase. Loss of first-phase insulin secretion is both a predictor of the onset of T1D and a marker of early stages of T2D, highlighting the importance of the metabolic flux of first-phase response to the disease. Additionally, during inflammatory stress, the need for antioxidant defense through nicotinamide adenine dinucleotide phosphate (NADPH) is high, however it is unclear how the β cell responds to these needs. This thesis focuses on studying glucose-stimulated metabolism in a model of β-cell inflammation and investigates the dynamics of NADPH/NADP+ for antioxidant defense and the impact on glucose-stimulated insulin secretion. To investigate NADPH/NADP+ redox dynamics in stressed β cells, we used live-cell imaging of the Apollo-NADP+ sensor in mouse pancreatic β cells treated with pro-inflammatory cytokines (hereby referred to as PIC; Tumour Necrosis Factor alpha (TNF-α), Interferon‐gamma (IFN-γ), Interleukin-1beta (IL-1β)) and showed a diminishment in NADP+ reduction. We show a loss or muted glucose-stimulated insulin secretion (GSIS) in PIC-treated islets using our insulin secretion chip (InsC-Chip), suggesting a loss of glycolytic flux. This response was recovered with an inducible nitric oxide synthase (iNOS) inhibitor, N(G)-Nitro-L-arginine methyl ester (L-NAME) suggesting a role for iNOS induction in the loss of β-cell function. β-cells normally reduce NADP+ via mitochondrial pyruvate cycling. However, inhibitor studies in PIC-treated β-cells showed that NADP+ reduction mainly occurs through the pentose phosphate pathway (PPP) and citrate cycling (supplied by glutamate). Our data also suggested lower NADP+ pools in PIC-stressed β cells, which may be a limiting factor in NADP+ reduction. Lower NADP+ pools suggested diminished nicotinamide adenine dinucleotide (NAD+) in PIC, which we confirmed in PIC-treated INS1 cells. NADP+ pools were recovered with L-NAME (an iNOS inhibitor) and N-acetylcysteine (NAC; NF-κB inhibitor and reactive oxygen species (ROS) scavenger), suggesting their activation in cytokine-induced stress. Based on our findings, β-cells metabolically adapt to pro-inflammatory cytokines with reduced NADP+ availability, diminished redox factors NAD+ and NADP+, and impaired insulin secretion. We propose that this metabolic adaptation to NADP+ reduction could limit glycolytic flux to limit insulin secretion.
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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 | 0.000 | 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".