9171 Microbial D-lactate Contributes To Hyperglycemia During Obesity And Is A Potential Therapeutic Target
Notice bibliographique
Résumé
Abstract Disclosure: D. Kukje Zada: None. H. Fang: None. C. Gagnon: None. A. Tchernof: None. A. Marette: None. J. Schertzer: None. Metabolic disorders including obesity, type 2 diabetes, and metabolic dysfunction associated fatty liver disease (MAFLD), are associated with changes in the intestinal microbiome. The microbiome affects host energy balance by producing metabolites that are substrates for host metabolism. D-lactate, the enantiomer of L-lactate, is one microbial metabolite of interest. In the 1920s, Cori and Cori showed that L-lactate is used as a substrate for glucose production in the liver. It is less well known that they also showed that D-lactate is a more effective substrate for hepatic glycogen deposition relative to L-lactate. Our group previously showed that D-lactate is a key bacterial-derived substrate contributing to liver glycogen and liver fat. Therefore, since D-lactate contributes to host metabolism, we aimed to understand the role of D-lactate in metabolic diseases. First, we characterized the levels of D- versus L-lactate in mouse models of obesity and diabetes. We show that D-lactate levels in portal serum are significantly higher in hyperglycemic and normoglycemic obese mice (n=6-12/group; p<0.0001) relative to their healthy controls. However, there was no difference in diabetic mice. In systemic serum, D-lactate levels are also significantly higher in hyperglycemic and normoglycemic obese mice (n=7-10/group; p<0.0001) as well as in diabetic mice (n=7-10/group; p<0.01). In lean and obese individuals, we also show that there is significantly higher serum D-lactate in obese individuals (n=55; p<0.01). We then aimed to understand if microbial D-lactate is involved in hyperglycemia during obesity. We tested this through oral lactate tolerance tests (oLTT) in chow-fed lean mice versus high fat diet (HFD)-fed obese mice. Administration of 1g/kg of L- or D-lactate resulted in significantly higher blood-glucose in HFD mice relative to chow controls (n=9-10/group; p<0.05 L-lactate; p<0.01 D-lactate). Importantly, oral gavage of D-lactate resulted in significantly higher blood-glucose relative to L-lactate in HFD (n=10/group; p<0.01) but not in chow mice. This suggests that like L-lactate, D-lactate can be converted to glucose and contribute to hyperglycemia, and that D-lactate is a more efficient substrate for glucose production in HFD-fed obese mice. With these results, we can add microbial D-lactate to the Cori cycle which contributes to hyperglycemia in obesity. Considering the role of D-lactate, a bacterial metabolite, in obesity, gut-substrate trap therapies can be used to selectively restrict its absorption by the host to mitigate disease. Our group has validated the optimal dose and length of a poly-L-lactide polymer for use as a D-lactate trap in a diet-induced obesity model and showed that it is effective at lowering blood-glucose in these mice. Currently, we are investigating the role of D-lactate in MAFLD and testing the efficacy of the same polymer at preventing MAFLD in mice. Presentation: 6/3/2024
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Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,001 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».