👤 Nao Hasuzawa

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. 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. 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 insulin. No corresponding between-group differences were detected in plasma metabolites. In db/db mice, luseogliflozin attenuated glomerular mesangial expansion and tubular epithelial atrophy, and reduced Col1a1 mRNA and TGF-β1 protein, compared with glargine at comparable glycemic levels. Luseogliflozin decreased the phosphorylated (inactive) form of the BCKDH E1α subunit (p-BCKDHA/BCKDHA) and lowered BCKDK protein. mRNA expression of amino acid transporters and BCAT2 expression was unchanged. Across complementary human and mouse studies, SGLT2 inhibition was suggested to enhance renal BCAA catabolism compared with insulin at comparable glycemic levels. In humans, increases in urinary BCAA-derived downstream metabolites without corresponding changes in plasma support a kidney-localized metabolic effect. In mice, SGLT2 inhibitor improved renal histopathology, and reduced phosphorylation-mediated inactivation of BCKDH. These findings provide mechanistic, translational evidence that SGLT2i modulate BCAA flux independently of glucose lowering, suggesting BCAA catabolism as a therapeutic axis in diabetic kidney disease. https://rctportal.mhlw.go.jp/en/detail?trial_id=UMIN000052955, identifier UMIN000052955. Show less