Regulation of glucose kinetics during exercise by the glucagon‐like peptide‐1 receptor
Bibliographic record
Abstract
Key points Glucagon‐like peptide‐1 (Glp1) regulates hepatic glucose production (HGP) and muscle glucose uptake (MGU) via its ability to stimulate insulin secretion. Using exercise as a means to stimulate glucose flux independently of insulin secretion, we observed that Glp1 receptor (Glp1r) knockout (Glp1r−/−) mice become hyperglycaemic but display normal rates of MGU. Since euglycaemia during exercise is typically maintained by matching rates of HGP to rates of MGU, we hypothesize that exercise‐induced hyperglycaemia in Glp1r−/− mice is due to excessive HGP. Using innovative catheterization and isotope dilution techniques, we demonstrate that hyperglycaemia in exercising Glp1r−/− mice is associated with excessive HGP and glucagon secretion. These results suggest an essential and novel role for basal Glp1r signalling in the suppression of alpha cell secretion during exercise. Abstract In response to oral glucose, glucagon‐like peptide‐1 receptor (Glp1r) knockout (Glp1r−/−) mice become hyperglycaemic due to impaired insulin secretion. Exercise also induces hyperglycaemia in Glp1r−/− mice. In contrast to oral glucose, exercise decreases insulin secretion. This implies that exercise‐induced hyperglycaemia in Glp1r−/− mice results from the loss of a non‐insulinotropic effect mediated by the Glp1r. Muscle glucose uptake (MGU) is normal in exercising Glp1r−/− mice. Thus, we hypothesize that exercise‐induced hyperglycaemia in Glp1r−/− mice is due to excessive hepatic glucose production (HGP). Wild‐type (Glp1r+/+) and Glp1r−/− mice implanted with venous and arterial catheters underwent treadmill exercise or remained sedentary for 30 min. [3‐3H]glucose was used to estimate rates of glucose appearance (Ra), an index of HGP, and disappearance (Rd). 2[14C]deoxyglucose was used to assess MGU. Glp1r−/− mice displayed exercise‐induced hyperglycaemia due to an excessive increase in Ra but normal Rd and MGU. Exercise‐induced glucagon levels were ∼2‐fold higher in Glp1r−/− mice, resulting in a ∼2‐fold higher glucagon:insulin ratio. Since inhibition of the central Glp1r stimulates HGP, we tested whether intracerebroventricular (ICV) infusion of the Glp1r antagonist exendin(9–39) (Ex9) in Glp1r+/+ mice would result in exercise‐induced hyperglycaemia. ICV Ex9 did not enhance glucose levels or HGP during exercise, suggesting that glucoregulatory effects of Glp1 during exercise are mediated via the pancreatic Glp1r. In conclusion, functional disruption of the Glp1r results in exercise‐induced hyperglycaemia associated with an excessive increase in glucagon secretion and HGP. These results suggest an essential role for basal Glp1r signalling in the suppression of alpha cell secretion during exercise.
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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 | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 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".