Suppressing hyperinsulinemia prevents obesity but causes rapid onset of diabetes in leptin-deficient Lepob/ob mice
Bibliographic record
Abstract
Objective Hyperinsulinemia is commonly associated with obesity. Mice deficient in the adipose-derived hormone leptin ( Lep ob/ob ) develop hyperinsulinemia prior to onset of obesity and glucose intolerance . Whether the excess of circulating insulin is a major contributor to obesity and impaired glucose homeostasis in Lep ob/ob mice is unclear. It has been reported previously that diet-induced obesity in mice can be prevented by reducing insulin gene dosage. In the present study, we examined the effects of genetic insulin reduction in Lep ob/ob mice on circulating insulin, body composition, and glucose homeostasis . Methods Leptin expressing ( Lep wt/wt ) mice lacking 3 insulin alleles were crossed with Lep ob/ob mice to generate Lep ob/ob and Lep wt/wt littermates lacking 1 ( Ins1 +/+ ; Ins2 +/− ), 2 ( Ins1 +/+ ; Ins2 −/− ) or 3 ( Ins1 +/− ; Ins2 −/− ) insulin alleles. Animals were assessed for body weight gain , body composition, glucose homeostasis, and islet morphology. Results We found that in young Lep ob/ob mice, loss of 2 or 3 insulin alleles reduced plasma insulin levels by 75–95% and attenuated body weight gain by 50–90% compared to Ins1 +/+ ; Ins2 +/− ; Lep ob/ob mice. This corresponded with ∼30% and ∼50% reduced total body fat in Ins1 +/+ ; Ins 2 −/− ; Lep ob/ob and Ins1 +/− ; Ins2 −/− ; Lep ob/ob mice, respectively. Loss of 2 or 3 insulin alleles in young Lep ob/ob mice resulted in onset of fasting hyperglycemia by 4 weeks of age, exacerbated glucose intolerance, and abnormal islet morphology. In contrast, loss of 1,2 or 3 insulin alleles in Lep wt/wt mice did not significantly alter plasma insulin levels, body weight , fat mass , fasting glycemia , or glucose tolerance . Conclusion Taken together, our findings indicate that hyperinsulinemia is required for excess adiposity in Lep ob/ob mice and sufficient insulin production is necessary to maintain euglycemia in the absence of leptin.
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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 | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.000 |
| 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".