9171 Microbial D-lactate Contributes To Hyperglycemia During Obesity And Is A Potential Therapeutic Target
Bibliographic record
Abstract
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
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| 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) | 0.000 | 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 teacher head, 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".