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

• Published in: Nature communications Vol. 10; no. 1; pp. 548 - 10
• Main Authors: Perry, Rachel J., Rabin-Court, Aviva, Song, Joongyu D., Cardone, Rebecca L., Wang, Yongliang, Kibbey, Richard G., Shulman, Gerald I.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.02.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 59; 631/443/319; 631/443/319/1642; 631/443/319/2723; 692/163/2743; Adipose tissue; Animals; Antidiabetics; Benzhydryl Compounds - adverse effects; Catecholamine; Catecholamines; Corticosterone; Dehydration; Dehydration - complications; Dehydration - pathology; Depletion; Diabetes; Diabetes mellitus; Diabetes Mellitus, Type 2 - complications; Diabetes Mellitus, Type 2 - pathology; Diabetic ketoacidosis; Disease Models, Animal; Furosemide; Glucagon; Glucocorticoids - metabolism; Glucose; Glucose - metabolism; Glucose transport; Glucosides - adverse effects; Humanities and Social Sciences; Humans; Inhibitors; Insulin - metabolism; Ketoacidosis; Ketogenesis; Ketosis - chemically induced; Ketosis - etiology; Ketosis - pathology; Lipolysis; Lipolysis - drug effects; Liver - drug effects; Liver - metabolism; Male; multidisciplinary; Protein transport; Proteins; Rats, Sprague-Dawley; Receptors, Adrenergic, beta-1 - metabolism; Rodents; Science; Science (multidisciplinary); Secretion; Sodium; Sodium-glucose cotransporter; Sodium-Glucose Transporter 2 Inhibitors - adverse effects
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-08466-w

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. The use of sodium-glucose transport protein 2 (SGLT2) inhibitors for the treatment of diabetes has been associated with euglycemic ketoacidosis and increased glucose production and glucagon secretion. Here Perry et al. show that these effects rely on both insulinopenia and dehydration, and thus suggest ways to manage the side effects associated with the use of SGLT2 inhibitors.