Defects in pancreatic development and glucose metabolism in SMN-depleted mice independent of canonical spinal muscular atrophy neuromuscular pathology
Bibliographic record
Abstract
Spinal muscular atrophy (SMA) is characterized by motor neuron loss, caused by mutations or deletions in the ubiquitously expressed survival motor neuron 1 (SMN1) gene. We recently identified a novel role for Smn protein in glucose metabolism and pancreatic development in both an intermediate SMA mouse model (Smn(2B/-)) and type I SMA patients. In the present study, we sought to determine if the observed metabolic and pancreatic defects are SMA-dependent. We employed a line of heterozygous Smn-depleted mice (Smn(+/-)) that lack the hallmark SMA neuromuscular pathology and overt phenotype. At 1 month of age, pancreatic/metabolic function of Smn(+/-)mice is indistinguishable from wild type. However, when metabolically challenged with a high-fat diet, Smn(+/-)mice display abnormal localization of glucagon-producing α-cells within the pancreatic islets and increased hepatic insulin and glucagon sensitivity, through increased p-AKT and p-CREB, respectively. Further, aging results in weight gain, an increased number of insulin-producing β cells, hyperinsulinemia and increased hepatic glucagon sensitivity in Smn(+/-)mice. Our study uncovers and highlights an important function of Smn protein in pancreatic islet development and glucose metabolism, independent of canonical SMA pathology. These findings suggest that carriers of SMN1 mutations and/or deletions may be at an increased risk of developing pancreatic and glucose metabolism defects, as even small depletions in Smn protein may be a risk factor for diet- and age-dependent development of metabolic disorders.
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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 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| 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".