Abstract 15747: The Sarcoplasmic Reticulum Calcium ATPase Pump Modulates Whole-body Glucose Homeostasis Through a Protein Disulfide Isomerase-dependent Pathway
Bibliographic record
Abstract
Introduction: The heart is a very active metabolic organ which exerts endocrine effects by secreting cardiokines. However, its role in regulating whole-body metabolism has received scarce attention. Hypothesis: We hypothesized that cardiac-specific overexpression of the sarcoplasmic reticulum calcium ATPase (SERCA) pump, which tightly regulates cytosolic calcium, modulates whole-body glucose homeostasis by secreting cardiokines during healthy and diabetic states. Methods: Diabetes was induced by streptozotocin in wild type (WT) and transgenic (TG) mice overexpressing the SERCA pump in the heart (n=6-10/group). Translocation of glucose transporters (GLUTs) to the cell surface was measured via a photolabeling biotinylation assay. Glucose and palmitate oxidation rates, cardiac work and ATP production were quantified in isolated working hearts. Results: Blood glucose levels were lower in diabetic TG mice compared to diabetic WT mice (P=0.023). Diabetes induced a downregulation of cell surface GLUT4 protein content in cardiac and skeletal muscle (by 56% and 79%, respectively, P<0.05), as well as in white and brown adipose tissue of WT mice (by 68% and 74%, respectively, P<0.05), which was rescued in TG diabetic mice. WT diabetic hearts had decreased cardiac glucose oxidation rates and cardiac efficiency, and increased palmitate oxidation rates (P<0.05), which were restored in TG diabetic hearts. Using quantitative mass spectrometry, we found protein disulfide isomerase (PDI) upregulated in the heart of TG mice (by 1822%, P<0.0001), which was confirmed in the serum of TG mice via an ELISA assay (by 243%, P=0.03). Inoculation with exogenous PDI reduced blood glucose in WT healthy mice and partially rescued hyperglycemia in WT diabetic mice compared to untreated counterparts (P=0.009 and P=0.044, respectively). Conclusions: These data suggest that cardiac-specific SERCA overexpression rescues hyperglycemia by improving glucose transport in striated muscle and adipose tissue of diabetic TG mice. Identification of the pathways by which the SERCA pump and cardiac secreted proteins (i.e. PDI) are involved in the regulation of whole-body glucose homeostasis could lead to the identification of novel pharmacological targets in diabetic patients.
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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) | 0.001 | 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.006 | 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".