Figure 3.

Effects of SGLT2 inhibitors on energy metabolism. SGLT2 inhibitor therapy leads to glycosuria and a net urinary energy loss, along with a decreased insulin level and increased glucagon level, as well as GLP-1. Despite the reduction in insulin secretion, β-cell function and the whole body/peripheral tissue insulin sensitivity improved. Increased glucagon levels and decreased insulin-to-glucagon ratio lead to the elevation of EPG, which may be partly derived from the increased gluconeogenesis in the liver and the kidney. Glucose utilisation is downregulated, while increased lipid responses, involving lipolysis, lipid oxidation, and ketogenesis, markedly increased after SGLT2 inhibitor treatment. The elevated levels of ketone bodies can serve as an additional energy substrate, thus improving the performance of the heart and the kidney. Catabolism of protein might also be involved in the metabolic adaptation process when treated with SGLT2 inhibitors. BCAAs comes from skeletal muscle or diet protein and will be further utilised in myocardial and renal cells to meet the needs of energy metabolism. Increased protein catabolism, as well as increased lipolysis, finally lead to the loss of body weight, including lean body mass and fat mass, contributing to the improvement of β-cell function and insulin sensitivity. Abbreviations: SGLT2: sodium-glucose co-transporter 2; GLP-1: glucagon-like peptide-1; TCA: tricarboxylic acid cycle; mTORC1: mechanistic target of rapamycin complex 1; FFA: free fatty acid; EPG: endogenous glucose production; LV: left ventricular; BCAA: branched-chain amino acid.