Format

Send to

Choose Destination
Nat Commun. 2019 Feb 1;10(1):548. doi: 10.1038/s41467-019-08466-w.

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

Author information

1
Departments of Internal Medicine, Yale University School of Medicine, P.O. Box 208020, TAC S269, New Haven, CT, 06519, USA.
2
Departments of Cellular and Molecular Physiology, Yale University School of Medicine, P.O. Box 208020, TAC S269, New Haven, CT, 06519, USA.
3
Departments of Internal Medicine, Yale University School of Medicine, P.O. Box 208020, TAC S269, New Haven, CT, 06519, USA. gerald.shulman@yale.edu.
4
Departments of Cellular and Molecular Physiology, Yale University School of Medicine, P.O. Box 208020, TAC S269, New Haven, CT, 06519, USA. gerald.shulman@yale.edu.

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.

PMID:
30710078
PMCID:
PMC6358621
DOI:
10.1038/s41467-019-08466-w
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center