Dehydration and insulinopenia are necessary and sufficient for euglycemic ketoacidosis in SGLT2 inhibitor-treated rats

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.

Empagliflozin Effectively Lowers Liver Fat Content in Well-Controlled Type 2 Diabetes: A Randomized, Double-Blind, Phase 4, Placebo-Controlled Trial

“…However, a recent clinical trial showed that canagliflozin still increases EGP when liraglutide prevents the changes in plasma insulin and glucagon levels (33). Similarly, hyperglucagonemia per se does not mediate the SGLT2i-induced increase in EGP (34). Of note, glycemia per se may regulate EGP in that a decrease in plasma glucose concentration can stimulate EGP independent of changes in plasma insulin and glucagon (35).…”

Sodium–glucose cotransporter 2 inhibitor and sarcopenia in a lean elderly adult with type 2 diabetes: A case report

“…Both dehydration and insulinopenia are shown to play a role in the development of euglycemic ketoacidosis. The present patient had insulinopenia, dehydration due to BP and consistent ketosis.…”

Basal insulin secretion capacity predicts the initial response and maximum levels of beta‐hydroxybutyrate during therapy with the sodium‐glucose co‐transporter‐2 inhibitor tofogliflozin, in relation to weight loss

“…Recently, both dehydration and insulinopaenia were reported to be associated with euglycaemic ketoacidosis in SGLT2 inhibitor-treated rats. 30 That report showed that volume loss early after SGLT2 inhibitor treatment was associated with increases in plasma epinephrine and corticosterone to enhance lipolysis. In the top quartile, a greater reduction in body weight at week 4 was observed, which might include not only loss of fat mass but also of lean mass, as well as fluid loss.…”

“…In particular, in the top quartile, the increases in BHB levels from week 4 to week 24 were attenuated. Recently, both dehydration and insulinopaenia were reported to be associated with euglycaemic ketoacidosis in SGLT2 inhibitor‐treated rats . That report showed that volume loss early after SGLT2 inhibitor treatment was associated with increases in plasma epinephrine and corticosterone to enhance lipolysis.…”