Liver autophagy-induced valine and leucine in plasma reflect the metabolic effect of sodium glucose co-transporter 2 inhibitor dapagliflozin

BACKGROUND: Sodium glucose co-transporter 2 (SGLT2) inhibitors are anti-diabetic drugs for type 2 diabetes that lower blood glucose levels and body weight. It is of special interest that SGLT2 inhibitors also improve liver metabolism and fatty liver. Liver is an important organ in regulation of energy metabolism, but the metabolic action of SGLT inhibitors in liver remains unclear. METHODS: We investigated the factors associated with the beneficial effects of dapagliflozin, a SGLT2 inhibitor, in the liver after confirming its glucose-lowering and weight loss effects using an obesity and diabetes mouse model. We also performed clinical study of patients with type 2 diabetes to explore candidate biomarkers that reflect the beneficial action of dapagliflozin in the liver. FINDINGS: In animal study, dapagliflozin induced autophagy in the liver (LC3-II to LC3-I expression ratio: P < 0·05 vs. control), and valine and leucine levels were increased in plasma (P < 0·01 vs. control) as well as in liver (P < 0·05 vs. control). Thus, increased plasma valine and leucine levels are potential biomarkers for improved liver metabolism. Clinical study found that valine and leucine levels were markedly higher in patients treated with dapagliflozin (valine: P < 0·05 vs. control, leucine: P < 0·01 vs. control) than those not treated after one week intervention. INTERPRETATION: Dapagliflozin improves liver metabolism via hepatic autophagy, and plasma valine and leucine levels may reflect its metabolic effect. FUNDING: AstraZeneca K.K., Ono Pharmaceutical Co., Ltd., Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan Society for the Promotion of Science (JSPS), Japan Agency for Medical Research and Development (AMED), Novo Nordisk Pharma Ltd., and Japan Foundation for Applied Enzymology, and MSD Life Science Foundation International

Histopathology of the Posterolateral Myocardium in a Responder to Cardiac Resynchronization Therapy

We present a 72-year-old man with idiopathic dilated cardiomyopathy, who was in New York Heart Association class III and had left ventricular (LV) dyssynchrony on tissue Doppler imaging. Cardiac resynchronization therapy (CRT) was performed for his heart failure, which improved to class I. Two years later, ventricular arrhythmias recurred, resulting in death. The LV posterior vein containing a pacing lead showed half-circumferential fibrous thickening. The LV myocardium of this region was relatively well preserved, and interstitial fibrosis due to cardiomyopathy was mild. Absence of a massive fibrotic scar on the LV posterior wall and positioning of the pacing lead in the optimal coronary vein (a posterolateral vein) might have been positive factors determining this patient's response to CRT

Liver autophagy-induced valine and leucine in plasma reflect the metabolic effect of sodium glucose co-transporter 2 inhibitor dapagliflozin

BACKGROUND: Sodium glucose co-transporter 2 (SGLT2) inhibitors are anti-diabetic drugs for type 2 diabetes that lower blood glucose levels and body weight. It is of special interest that SGLT2 inhibitors also improve liver metabolism and fatty liver. Liver is an important organ in regulation of energy metabolism, but the metabolic action of SGLT inhibitors in liver remains unclear. METHODS: We investigated the factors associated with the beneficial effects of dapagliflozin, a SGLT2 inhibitor, in the liver after confirming its glucose-lowering and weight loss effects using an obesity and diabetes mouse model. We also performed clinical study of patients with type 2 diabetes to explore candidate biomarkers that reflect the beneficial action of dapagliflozin in the liver. FINDINGS: In animal study, dapagliflozin induced autophagy in the liver (LC3-II to LC3-I expression ratio: P<0·05 vs. control), and valine and leucine levels were increased in plasma (P<0·01 vs. control) as well as in liver (P<0·05 vs. control). Thus, increased plasma valine and leucine levels are potential biomarkers for improved liver metabolism. Clinical study found that valine and leucine levels were markedly higher in patients treated with dapagliflozin (valine: P<0·05 vs. control, leucine: P<0·01 vs. control) than those not treated after one week intervention. INTERPRETATION: Dapagliflozin improves liver metabolism via hepatic autophagy, and plasma valine and leucine levels may reflect its metabolic effect. FUNDING: AstraZeneca K.K., Ono Pharmaceutical Co., Ltd., Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan Society for the Promotion of Science (JSPS), Japan Agency for Medical Research and Development (AMED), Novo Nordisk Pharma Ltd., and Japan Foundation for Applied Enzymology, and MSD Life Science Foundation International