Suppressing hyperinsulinemia prevents obesity but causes rapid onset of diabetes in leptin-deficient Lepob/ob mice
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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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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| 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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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 it