Inhibition of the renal SGLT2 transporter has proven to be an effective therapeutic intervention to reduce plasma glucose levels and HbA1c in type 2 diabetic patients. The glycemic-lowering efficacy of the SGLT2 inhibitors results from two distinct mechanisms: (i) induction of glucosuria, which amounts to ~70-90 grams per day and (ii) amelioration of glucotoxicity leading to 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 in endogenous glucose production (EGP) that offsets by ~50% the amount of glucose excreted in the urine. The increase in EGP is associated with a rise in plasma glucagon concentration and decline in plasma insulin concentration. In the present grant we will define: (1) the organ, liver and/or kidney, responsible for the increase in EGP (Protocol One); (2) the role of increased plasma 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 inhibition of the renal SGLT2 transporter with dapagliflozin. In Protocol Four, we will examine whether the GLP-1 receptor agonist, exenatide, which stimulates insulin and inhibits glucagon secretion, can block the increase in EGP following SGLT2 inhibition with dapagliflozin.
SGLT2 inhibitors (SGLTi) are a recently approved class of oral antidiabetic agents for the treatment of patients with type 2 diabetes mellitus (T2DM). However, we have demonstrated that their efficacy is offset by a ?paradoxical? increase in endogenous glucose production (EGP) that negates by ~50% the amount of glucose excreted in the urine. These results demonstrate the presence of a previously undescribed ?reno-hepatic? axis in which glucosuria sends a signal to the liver (and possibly to the kidney) to increase glucose production. In the present grant we will define the organ (liver and/or kidney) responsible for the increase in EGP and the mechanism(s) (stimulation of glucagon secretion, inhibition of insulin secretion, activation of the renal nerves) responsible for the rise in EGP. We also will examine whether a GLP-1 receptor agonist, by inhibiting glucagon/increasing insulin secretion, can block the rise in EGP following SGLT2 inhibition. If so, this would establish combined therapy with SGLT2i/GLP-1 RA as an early and effective strategy for the treatment of patients with T2DM.
