FFA1/Gq - Gi interaction determines glucose-induced insulin secretion of neonatal beta cells
Bibliographic record
Abstract
Background and aims: Adequate functional maturation of neonatal beta cells determines the efficacy of glucose metabolism during adult life. Insulin secretion of newborn islets relies on aminoacids and fatty acids metabolism, while glucose-responsive insulin secretion progressively arises days to weeks later after birth. Long chain fatty acids (LCFA) are major components of breastmilk and insulin secretagogues. LCFA are endogenous ligands of FFA1, a Gq/PLC coupled receptor acting on Ca2+ mobilization and actin network in beta cells. Whether FFA1 recruits Gα12/13 and impact on GSIS via downstream RhoA/ROCK-mediated actin remodelling is unknown. We assessed the role of FFA1 in postnatal maturation of neonatal beta cells in regard to the regulation of insulin secretion and beta cell mass. Materials and methods: WT and Ffar1 KO BL6NCrl mice harboring a RIP-Cre driven EGFP expression were bred and 1, 6, 11 and 26d old offspring (P1, P6, P11, P26) were used for analysis. Pancreatic insulin content was measured in P1-P26 pancreata. Beta cell proliferation and mass were determined in P1-P26 pancreatic sections by estimating the number of Ki67-stained/EGFP-positive islet cells and the EGFP-positive islet area, respectively. Insulin secretion was performed in static incubations with WT and Ffar1 KO P6 islets using palmitate (600 and 60 μM), TUG469 (FFA1 agonist, 10 μM), exendin-4 (GLP-1R agonist, 100 nM), FR900359 (Gq inhibitor, 1 μM), pertussis toxin (PTX, Go/Gi inhibitor, 100 ng/ml), CT3 toxin (RhoA inhibitor, 2 μg/ml) and H1152 (ROCK inhibitor, 1μM). Results: WT islets displayed glucose (12 mM) stimulated insulin secretion (GSIS, 6-fold change (FC) over 2.8G) mirroring the ongoing functional maturation. WT islets showed also a robust secretion in response to palmitate (600 μM) and exendin-4 (5-FC over 12G). In KO islets both glucose- and palmitate- stimulated insulin secretion were impaired, indicating that FFA1 signalling is critical for both secretagogues. As expected, palmitate (60 μM)- and TUG469-stimulated (2.25- and 3.4-FC over 12G, respectively) insulin secretion was inhibited by FR900359 (0.34- and 0.13-FC over 12G, respectively) in WT islets. Surprisingly, Gq inhibitor canceled also GSIS (from 10.6- to 1.7-FC over 2.8G) of WT islets. When the inhibitory Go/Gi signalling was blocked with PTX, GSIS was massively increased (100-FC over 2.8G), an effect that was up to 90% inhibited by FR900359 in WT islets. Noteworthy, PTX rescued GSIS in KO islets (from 1.6- to 11-FC over 2.8G). In addition, inhibition of RhoA and ROCK improved GSIS in KO islets. The secretory defects of KO islets do not originate in insufficient insulin production, since pancreatic insulin content increased with offspring’s age irrespective of Ffar1 genotype. Deletion of Ffar1 augmented beta cell proliferation in P6 offspring. Nevertheless, we found no genotype-driven differences in beta cell mass of P1-P26 offspring. Conclusion: These findings indicate that (i) glucose responsiveness of the neonatal islets fully depends on active Gq and (ii) FFA1/Gq inactivation unlocks Go/Gi- and G12/13/RhoA/ROCK-mediated signals with negative impact on GSIS. Thus, FFA1/Gq signaling is essential for the gain of function of neonatal beta cells.
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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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 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".