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 nave 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 nave with FPG <160 mg/dl) at baseline and at day 1 and 12 weeks after treatment with SGLT2 inhibitor
SGLT2 inhibitor is a novel class of drugs approved by the FDA for the treatment of type 2 diabetes (T2DM). In addition to lowering the plasma glucose concentration, members of this class cause increase in hepatic glucose production, increase in fat oxidation and ketone production, all of which have important clinical significance. In the present grant proposal we will study the mechanisms responsible for these metabolic actions of this class of drugs with emphasis on the role of autonomic nervous system.
