Sex-dependent additive effects of dorzagliatin and incretin on insulin secretion in a novel mouse model of <i>GCK</i> -MODY
Bibliographic record
Abstract
Abstract Glucokinase (GK) catalyses the key regulatory step in glucose-stimulated insulin secretion. Correspondingly, hetero– and homozygous mutations in human GCK cause maturity-onset diabetes of the young (GCK-MODY) and permanent neonatal diabetes (PNDM), respectively. To explore the possible utility of glucokinase activators (GKA) and of glucagon–like receptor-1 (GLP-1) agonists in these diseases, we have developed a novel hypomorphic Gck allele in mice encoding an aberrantly spliced mRNA deleted for exons 2 and 3. In islets from homozygous knock-in (Gck KI/KI ) mice, GK immunoreactivity was reduced by >85%, and glucose-stimulated insulin secretion eliminated. Homozygous Gck KI/KI mice were smaller than wildtype littermates and displayed frank diabetes (fasting blood glucose >18 mmol/L; HbA1c ∼12%), ketosis and nephropathy. Heterozygous Gck KI/+ mice were glucose intolerant (HbA1c ∼5.5%). Abnormal glucose-stimulated Ca 2+ dynamics and beta cell-beta cell connectivity in Gck KI/+ islets were completely reversed by the recently-developed GKA, dorzagliatin, which was largely inactive in homozygous Gck KI/KI mouse islets. The GLP-1 receptor agonist exendin-4 improved glucose tolerance in male Gck KI/+ mice, an action potentiated by dorzagliatin, in male but not female mice. Sex-dependent additive effects of these agents were also observed on insulin secretion in vitro . Combined treatment with GKA and incretin may thus be useful in GCK -MODY or GCK -PNDM. Article Highlights a. Glucokinase deficiency can drive maturity-onset diabetes of the young (GCK-MODY; heterozygotes ) and permanent neonatal diabetes (GCK-PNDM; homozygotes ) b. We describe a hypomorphic Gck allele where aberrant splicing in islets lowers GK activity to by ∼85%. We use these mice to explore the effects of the glucokinase activator, dorzagliatin, and incretin on insulin secretion c. Whereas heterozygous mutant mice are mildly hyperglycemic, homozygotes have frank diabetes but survive to adulthood. Dorzagliatin potentiates the effects of GLP-1 receptor activation sex-dependently in heterozygotes d. Combined use of these drugs may be useful in some forms of GCK diabetes
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.002 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.003 | 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".