Branched-Chain Amino Acid Catabolism: Regulation and Effect on Insulin Resistance
Notice bibliographique
Résumé
Insulin resistance is the reduced responsiveness of a target tissue to insulin. Insulin resistance is an underlying cause of Type 2 diabetes mellitus (T2DM) and cardiovascular diseases, two debilitating diseases. Therefore, targeting insulin resistance can help prevent the development of T2DM and cardiovascular diseases. \n\nDietary protein, and in particular branched-chain amino acids (BCAAs; leucine, valine and isoleucine) stimulate muscle protein synthesis, and regulate body weight and glucose homeostasis. However, despite these benefits, circulating levels of BCAAs and BCAA metabolites, branched-chain a-ketoacids (BCKAs) are upregulated in insulin-resistant states like T2DM. This raises the question if upregulated levels of BCAAs and BCKAs cause insulin resistance or are a symptom of insulin resistance. Numerous studies have also shown how insulin resistant states can regulate the BCAA catabolic pathway and the enzymes involved, and how targeting this pathway can provide benefits in regards to insulin resistance and its sequalae. Thus, the purpose of this dissertation is to examine the link between BCAAs and their metabolism, and insulin resistance.\n\nPrevious in vitro studies have showed that depletion of branched-chain ketoacid dehydrogenase (BCKD), the enzyme responsible for the catabolism of BCKAs, suppressed insulin-stimulated glucose uptake in L6 myotubes and the metabolite of leucine, ketoisocaproic acid (KIC) worsens it. Thus, I demonstrated that interventions that increased BCKD activity improved insulin sensitivity and attenuated the suppressive effect of KIC on insulin sensitivity in L6 myotubes. \n\nWe have previously shown that KIC reduces insulin-stimulated glucose transport in muscle cells. However, contributions from other tissues aside from skeletal muscle in BCAA metabolism emphasize the importance of studying the effect of KIC gavage in vivo as well. Whereas KIC alters insulin signaling in the liver, it did not affect whole-body insulin tolerance. \n\nFinally, since BCAA catabolism is implicated in many chronic conditions like insulin resistance, and age is a major risk factor in insulin resistance, we assessed how aging affects BCAA catabolism in both sexes. There was an increase in plasma BCAAs of old male mice, but changes in BCAA levels in plasma/tissues were not largely consistent with any changes in metabolic enzyme abundance/activity and did not correlate with changes in insulin sensitivity with sex or aging. Taken together, this thesis shows that although KIC suppresses glucose transport in vitro and its effect is attenuated by increasing BCAA oxidation, it does not affect insulin sensitivity in vivo likely due to contributions of the liver to catabolize KIC. Also, increases in plasma BCAAs seen in older male mice does not correlate with increased insulin resistance, suggesting that greater BCAAs in plasma may only be present in disease states. Together these studies suggest that altered BCAA levels do not cause insulin resistance but are a result of insulin resistance.
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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 | 0,001 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,001 | 0,001 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,001 |
| Science ouverte | 0,001 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,001 |
| 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 ».