Sodium-glucose cotransporter 2 inhibitors-but not insulin-enhance renal branched-chain amino acid catabolism
Abstract
Aims/hypothesis: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) confer cardio-renal protection, and recent work implicates enhanced branched-chain amino acid (BCAA) catabolism as a potential mechanism in the heart. Whether SGLT2i also promotes renal BCAA catabolism is largely unknown. We hypothesized that SGLT2i enhances renal BCAA catabolism independently of glycemic effects.
Methods: We conducted a prospective, single-center, open-label, nonrandomized, controlled clinical study in patients with type 2 diabetes stably treated with insulin, who were assigned to dapagliflozin (5 mg/day with dose-reduced insulin; n=8/9 completed) or insulin dose-up (n=5/8 completed). At 12 weeks, changes in urinary and plasma metabolites and short-chain acylcarnitines related to BCAA catabolism were quantified. To explore mechanisms, 10-week-old db/db mice received luseogliflozin (10 mg/kg/day, p.o.) or insulin glargine (10 U/day, s.c.) for 4 weeks; renal histology, mRNA and protein expression of key enzymes involved in BCAA catabolism, including branched-chain aminotransferase 2 (BCAT2), branched-chain ketoacid dehydrogenase (BCKDH), and BCKD kinase (BCKDK), were assessed.
Results: Dapagliflozin treatment induced greater increases in urinary excretion of three BCAA-derived metabolites-3-hydroxypropionic acid, C5-OH carnitine, and 3-hydroxybutyric acid-compared with insulin at comparable glycemic levels. In contrast, C4 carnitine (an earlier metabolite in valine catabolism) rose more with…
How strong is the evidence?
Evidence Hub reads this as a clinical trial, done in people. Its evidence level is 3 of 5 (Moderate · trial / cohort / secondary analysis). Trials without a large randomized design, cohorts and secondary analyses give moderate evidence. Reported size: 8 participants or records.
Read the paper
Related studies
- The Role of AMPK Activation for Cardioprotection in Doxorubicin-Induced Cardiotoxicity
- Hypoglycemic medicines in the treatment of Alzheimer’s disease: Pathophysiological links between AD and glucose metabolism
- Isorhamnetin Reduces Glucose Level, Inflammation, and Oxidative Stress in High-Fat Diet/Streptozotocin Diabetic Mice Model
- Modulating Sirtuin Biology and Nicotinamide Adenine Diphosphate Metabolism in Cardiovascular Disease—From Bench to Bedside
- Characterization of the SGLT2 Interaction Network and Its Regulation by SGLT2 Inhibitors: A Bioinformatic Analysis
- Early Treatment with Empagliflozin and GABA Improves β-Cell Mass and Glucose Tolerance in Streptozotocin-Treated Mice
Go deeper in Evidence Hub
Evidence Hub adds a study data sheet (design, sample size, evidence level, key numbers), an AI summary and a chat grounded in the paper's text.