EFFECT OF SGLT2 INHIBITORS ON HEPATIC GLUCOSE METABOLISM: ROLE OF AUTONOMIC NERVOUS SYSTEM

Sodium-Glucose cotransport inhibitors (SGLT2i) are a novel class of antidiabetic agentswhich lower the plasma glucose concentration by inhibiting renal glucose reuptake andproducing glucosuria. In addition to lowering the plasma glucose concentration,members of this class exert multiple metabolic actions in T2DM all of which havesignificant clinical relevance and include: (1) stimulation of hepatic glucose production;(2) reduce fasting plasma insulin concentration and stimulate glucagon secretion, thesehormonal changes were suggested to cause the increase in HGP; (3) inhibition ofglucose oxidation; and (4) increase in fat oxidation and ketone production. Ourpreliminary data demonstrate that, in normal glucose tolerant individuals, SGLT2inhibitors, stimulate glucose production, and cause significant increase in fat oxidationwithout a change in plasma glucose, insulin, glucagon and ketone concentrations.Further, SGLT2 inhibitors inhibited pyruvate oxidation in hepatocytes in culture. Basedupon these novel findings, we hypothesize that, signals (likely neuronal) other thanchange in plasma insulin to glucagon ratio are activated by glucosuria and stimulate theincrease in HGP in non-diabetic and likely in diabetic individuals as well. Further, wehypothesize that the increase in fat oxidation by SGLT2 inhibitors will depletes liver fatcontent in IFG and T2DM patients, increase hepatic glucose uptake and decrease thefasting plasma glucose concentration. To test these hypotheses, we will (1) Measureautonomic 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 tracerinfusion), whole body fat oxidation (indirect calorimetry), plasma insulin, glucagon, FFA,ketone and lactate concentrations, and hepatic fat content (1H-MRS) in IFG, NGT andT2DM patients (drug nave with FPG <160 mg/dl) at baseline and at day 1 and 12 weeksafter treatment with SGLT2 inhibitor