Abstract
Sodium-glucose transport protein 2 (SGLT2) inhibitors are a class of anti-diabetic agents; however, concerns have been raised about their potential to induce euglycemic ketoacidosis and to increase both glucose production and glucagon secretion. The mechanisms behind these alterations are unknown. Here we show that the SGLT2 inhibitor (SGLT2i) dapagliflozin promotes ketoacidosis in both healthy and type 2 diabetic rats in the setting of insulinopenia through increased plasma catecholamine and corticosterone concentrations secondary to volume depletion. These derangements increase white adipose tissue (WAT) lipolysis and hepatic acetyl-CoA content, rates of hepatic glucose production, and hepatic ketogenesis. Treatment with a loop diuretic, furosemide, under insulinopenic conditions replicates the effect of dapagliflozin and causes ketoacidosis. Furthermore, the effects of SGLT2 inhibition to promote ketoacidosis are independent from hyperglucagonemia. Taken together these data in rats identify the combination of insulinopenia and dehydration as a potential target to prevent euglycemic ketoacidosis associated with SGLT2i.
Highlights
Sodium-glucose transport protein 2 (SGLT2) inhibitors are a class of anti-diabetic agents; concerns have been raised about their potential to induce euglycemic ketoacidosis and to increase both glucose production and glucagon secretion
The previously available data on ketoacidosis associated with SGLT2i do not provide a unifying mechanism and leave open three key questions regarding SGLT2i effects on in vivo metabolism: (1) what is the mechanism by which SGLT2 inhibition causes hyperglucagonemia?, (2) does this hyperglucagonemia contribute to euglycemic ketoacidosis and/or increased hepatic glucose production, and (3) if hyperglucagonemia is not sufficient to promote euglycemic ketoacidosis and increased hepatic glucose production following treatment with SGLT2i, what is the mechanism by which SGLT2 inhibitors promote euglycemic ketoacidosis? To answer these questions, in this study we apply stable isotope tracer methods to assess in vivo rates of hepatic ketogenesis, white adipocyte (WAT) lipolysis, and hepatic glucose production following acute dapagliflozin treatment
We show that SGLT2iinduced euglycemic ketoacidosis requires both insulinopenia, as well as increases in plasma corticosterone and catecholamine concentrations secondary to volume depletion, which together lead to increased rates of white adipose tissue (WAT) lipolysis, hepatic acetyl-CoA content, and hepatic ketogenesis
Summary
Sodium-glucose transport protein 2 (SGLT2) inhibitors are a class of anti-diabetic agents; concerns have been raised about their potential to induce euglycemic ketoacidosis and to increase both glucose production and glucagon secretion The mechanisms behind these alterations are unknown. We show that the SGLT2 inhibitor (SGLT2i) dapagliflozin promotes ketoacidosis in both healthy and type 2 diabetic rats in the setting of insulinopenia through increased plasma catecholamine and corticosterone concentrations secondary to volume depletion. These derangements increase white adipose tissue (WAT) lipolysis and hepatic acetyl-CoA content, rates of hepatic glucose production, and hepatic ketogenesis. We go on to show that SGLTi-induced glucagon secretion may be mediated at least in part through an autonomic nervous system response, and that this effect is not sufficient to cause ketoacidosis or increased hepatic glucose production
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