SGLT2 INHIBITION AND STIMULATION OF ENDOGENOUS GLUCOSE PRODUCTION

Inhibition of the renal SGLT2 transporter has proven to be an effective therapeutic interventionto reduce plasma glucose levels and HbA1c in type 2 diabetic patients. The glycemic-loweringefficacy of the SGLT2 inhibitors results from two distinct mechanisms: (i) induction ofglucosuria, which amounts to ~70-90 grams per day and (ii) amelioration of glucotoxicity leadingto increased insulin sensitivity in muscle and improved beta cell function (JCI 124:509-514,2014). However, the clinical efficacy of the SGLT2 inhibitors is countered by an increase inendogenous glucose production (EGP) that offsets by ~50% the amount of glucose excreted inthe urine. The increase in EGP is associated with a rise in plasma glucagon concentration anddecline in plasma insulin concentration. In the present grant we will define: (1) the organ, liverand/or kidney, responsible for the increase in EGP (Protocol One); (2) the role of increasedplasma glucagon, decline in plasma insulin, fall in plasma glucose concentration (Protocol Two);and (3) the role of the renal nerves in the increase in EGP (Protocol Three) following inhibitionof the renal SGLT2 transporter with dapagliflozin. In Protocol Four, we will examine whether theGLP-1 receptor agonist, exenatide, which stimulates insulin and inhibits glucagon secretion, canblock the increase in EGP following SGLT2 inhibition with dapagliflozin.