Intra-islet glucagon signalling regulates pulsatile insulin secretion and glucose homeostasis
Bibliographic record
Abstract
ABSTRACT Background Type 2 diabetes (T2D) is characterised by the loss of pulsatile insulin secretion. We studied mice with β-cell specific loss of the glucagon receptor (Gcgr fl/fl X Ins-1 Cre ), to investigate the role of intra-islet glucagon receptor signalling on pan-islet calcium oscillations and insulin pulsatility. Methods Frequently sampled intravenous glucose tolerance tests were conducted on Gcgr β-cell-/- and littermate controls. Crossing with GCaMP6f (STOP flox) animals further allowed for β-cell specific expression of a fluorescent calcium indicator. These islets were functionally imaged in vitro and in vivo . Wild-type mice were transplanted with islets expressing GCaMP6f in β-cells into the anterior eye chamber and placed on a high fat diet. Part of the cohort received a glucagon analogue (GCG-analogue) for 40 days and the control group were fed to achieve weight matching. Calcium imaging was performed regularly during the development of hyperglycaemia and in response to GCG-analogue treatment. Results Gcgr β-cell-/- mice exhibited impaired glucose tolerance following intraperitoneal glucose challenge (control 12.7mmol/L ±0.6 vs. Gcgr β-cell-/- 15.4mmol/L ±0.0 at 15 min, p=0.002); fasting glycaemia was not different to controls. In vitro , Gcgr β-cell-/- islets showed profound loss of synchronised calcium waves in response to glucose which was only partially rescued in vivo . First-phase insulin pulsatility on peripheral blood sampling (n=5) was significantly disordered in Gcgr β-cell-/- mice (burst mass Gcgr β-cell-/- 0.30 ±0.03 versus 0.84 ±0.23 for controls p=0.04). Diet induced obesity and hyperglycaemia resulted in a loss of co-ordinated [Ca 2+ ] I waves in transplanted islets. This was reversed with GCG-analogue treatment, independently of weight-loss (n=8). Conclusion These data provide novel evidence for the role of intra-islet GCGR signalling in sustaining synchronised calcium oscillations and support a possible therapeutic role for glucagonergic agents to restore the insulin pulsatility lost in T2D.
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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) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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 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".