Hyperinsulinemia and insulin receptor signaling in pancreatic cancer development
Bibliographic record
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the 3rd leading cause of cancer death in Canada and its incidence is increasing, largely driven by the expanding epidemics of PDAC risk factors including obesity and type 2 diabetes (T2D). Hyperinsulinemia is a cardinal feature of obesity and T2D, and is associated with increased PDAC incidence and mortality. Despite epidemiological data linking hyperinsulinemia to PDAC, there was no direct in vivo evidence of a causal role for endogenous insulin in any cancer type before this work. We studied how reduced insulin production or local insulin action affected the development of pancreatic intraepithelial neoplasia (PanIN) precursor lesions in Ptf1aCreER;KrasLSL-G12D mice. We first generated Ptf1aCreER;KrasLSL-G12D;Ins1+/+;Ins2-/- control and Ptf1aCreER;KrasLSL-G12D;Ins1+/-;Ins2-/- experimental mice. We found high fat diet (HFD)-induced hyperinsulinemia was modestly reduced in experimental mice without affecting glucose homeostasis. Genetically reduced insulin production resulted in ~50% suppression of PanIN. However, in this study, only female mice remained normoglycemic and only the gene dosage of rodent-specific Ins1 alleles was tested. Therefore, we then generated Ptf1aCreER;KrasLSL-G12D;Ins1-/-;Ins2+/+ control and Ptf1aCreER;KrasLSL-G12D;Ins1-/-;Ins2+/- experimental mice. Mice with reduced insulin production tended to develop fewer PanIN and acinar-to-ductal metaplasia (ADM) lesions. Using single-cell transcriptomics, we found hyperinsulinemia modulated pathways associated with protein translation, MAPK/ERK signaling and PI3K/AKT/mTOR signaling, which were changed in epithelial cells and subsets of immune cells. Finally, we examined whether hyperinsulinemia contributed to PDAC development directly through insulin receptor (INSR) signaling in KrasG12D carrying pancreatic acinar cells. We generated Ptf1aCreER;LSL-KrasG12D;nTnG mice with an Insrwt/wt, Insrwt/f, or Insrf/f genotype to reduce insulin receptor mRNA by 0%, 50%, or 100% in acinar cells. Loss of insulin receptors from acinar cells did not significantly influence body weight, fasting glucose, or insulin levels. Compared to mice with wild-type INSR expression in acinar cells, mice lacking INSR had a 2.7-fold and 5.3-fold significant reduction in PanIN plus tumor area in males and females, respectively. Collectively, these results indicate that hyperinsulinemia and INSR signaling in acinar cells are important for the early stages of pancreatic cancer. Insulin-lowering interventions such as lifestyle management and therapies targeting insulin receptor signaling may be beneficial in preventing and/or treating pancreatic cancer.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 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".