Effect of SGLT2 Inhibitors on Hepatic Glucose Metabolism: Role of Autonomic Nervous System

钠-葡萄糖共转运抑制剂（SGLT2i）是一类新型的抗糖尿病药物

Sodium-Glucose cotransport inhibitors (SGLT2i) are a novel class of antidiabetic agents which lower the plasma glucose concentration by inhibiting renal glucose reuptake and producing glucosuria. In addition to lowering the plasma glucose concentration, members of this class exert multiple metabolic actions in T2DM all of which have significant clinical relevance and include: (1) stimulation of hepatic glucose production; (2) reduce fasting plasma insulin concentration and stimulate glucagon secretion, these hormonal changes were suggested to cause the increase in HGP; (3) inhibition of glucose oxidation; and (4) increase in fat oxidation and ketone production. Our preliminary data demonstrate that, in normal glucose tolerant individuals, SGLT2 inhibitors, stimulate glucose production, and cause significant increase in fat oxidation without a change in plasma glucose, insulin, glucagon and ketone concentrations. Further, SGLT2 inhibitors inhibited pyruvate oxidation in hepatocytes in culture. Based upon these novel findings, we hypothesize that, signals (likely neuronal) other than change in plasma insulin to glucagon ratio are activated by glucosuria and stimulate the increase in HGP in non-diabetic and likely in diabetic individuals as well. Further, we hypothesize that the increase in fat oxidation by SGLT2 inhibitors will depletes liver fat content in IFG and T2DM patients, increase hepatic glucose uptake and decrease the fasting plasma glucose concentration. To test these hypotheses, we will (1) Measure autonomic balance (with heart rate variability) and sympathetic nervous system activity (3H-norepinephrine turnover) in IFG, NGT and T2DM subjects (drug naïve with FPG <160 mg/dl) at baseline and at day 1 and 12 weeks of treatment with SGLT2 inhibitors, and (2) Measure FPG, bHGP (3H-glucose infusion), HGU (with Oral-IV double tracer infusion), whole body fat oxidation (indirect calorimetry), plasma insulin, glucagon, FFA, ketone and lactate concentrations, and hepatic fat content (1H-MRS) in IFG, NGT and T2DM patients (drug naïve with FPG <160 mg/dl) at baseline and at day 1 and 12 weeks after treatment with SGLT2 inhibitor