Hyper-variability in Circulating Insulin and Physiological Outcomes in Male High Fat-fed Ins1-/-:Ins2+/- Mice in a Conventional Facility
Bibliographic record
Abstract
Insulin is an ancient, multi-functional hormone with essential roles in glucose homeostasis and energy storage. Recently, our group has taken advantage of the ability to limit insulin secretion in vivo by reducing insulin gene dosage to demonstrate that insulin hypersecretion is a requirement for diet-induced obesity. Our previous studies employed male Ins1+/-:Ins2-/- mice that exhibit a complete inhibition of diet-induced hyperinsulinemia relative to Ins1+/+:Ins2-/- littermate controls, as well as female Ins1-/-:Ins2+/- mice with transient, partial reduction in circulating insulin relative to Ins1-/-:Ins2+/+ littermates. In the present study, we sought to extend these studies to male Ins1-/-:Ins2+/- mice on the same chow and high fat diets. Surprisingly, while reduced Ins2 gene dosage appeared capable of reducing Ins2 mRNA, insulin protein levels in these mice were not significantly reduced. Moreover, there was a marked hyper-variability in circulating insulin levels within and between two independent cohorts of mice that persisted over at least the first year of life. In Cohort 1, we observed a paradoxical increase in body weight in some high fat-fed male Ins1-/-:Ins2+/- mice relative to Ins1-/-:Ins2+/+ littermate controls. This phenomenon is consistent with the known satiety effects of insulin and our previous observations with Ins2 can be expressed in the brain. Collectively, our data reveal unexpected complexity associated with the Ins2 gene in male mice, and establish the Ins2 gene as a candidate for studying the effects of modifier genes and/or environmental influences on gene-to-phenotype variability. Further studies are required to define the molecular mechanisms of this phenotypic hyper-variability and to define the role of reduced Ins2 gene dosage in the brain.
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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 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.002 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.003 |
| Insufficient payload (model declined to judge) | 0.003 | 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".