ER calcium stores contribute to glucose-induced Ca2+ waves and intercellular connectivity in mouse pancreatic islets
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Bibliographic record
Abstract
Defective insulin secretion is a hallmark of diabetes mellitus. Glucose-induced Ca 2+ oscillations are critical for the stimulation of insulin secretion, though the mechanisms through which these propagate across the islet are poorly understood. Here, we use beta cell-targeted GCaMP6f to explore the role of endoplasmic reticulum (ER) Ca 2+ mobilization in response to submaximal (11mM) or hyperglycemic (25mM) glucose, mimicking diabetes. Inhibition of inositol 1,4,5-trisphosphate (IP 3 ) receptors, and other ion channels, with 2-aminoethoxydiphenyl borate (2-APB), had minimal effects on the initial peak or intercellular connectivity provoked by 11mM glucose. However, 2-APB lowered subsequent glucose-induced cytosolic Ca 2+ increases and connectivity at both 11 and 25mM glucose. Unexpectedly, the activation of IP 3 receptors with the muscarinic acetylcholine receptor agonist carbachol had minimal impact on the initial peak elicited by 11 mM glucose, but Ca 2+ waves at 11 and 25 mM glucose were more poorly coordinated. To determine whether ER calcium mobilization was sufficient to initiate Ca 2+ waves we next blocked sarco(endo)plasmic Ca 2+ ATPase (SERCA) pumps with thapsigargin, whilst preventing plasma membrane depolarization with the K ATP -channel opener, diazoxide. Under these conditions, an initial cytosolic Ca 2+ increase was followed by secondary Ca 2+ waves that subsided slowly. The application of carbachol alongside diazoxide still enhanced Ca 2+ dynamics, though activity was uncoordinated. After genetic deletion of SERCA2 in beta cells, Ca 2+ wave frequency, but not connectivity, were lowered. Our results show that ER Ca 2+ mobilization plays a relatively minor role in the initiation and propagation of Ca 2+ waves in response to glucose but is needed for sustained Ca 2+ waves.
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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) | 0.001 | 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 | 0.000 |
| 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