SGLT2 Inhibition by Dapagliflozin Attenuates Diabetic Ketoacidosis in Mice with Type-1 Diabetes

Background SGLT2 inhibitors increase plasma ketone concentrations. It has been suggested that insulinopenia, along with an increase in the counter-regulatory hormones epinephrine, corticosterone, glucagon and growth hormone, can induce ketoacidosis, especially in type-1 diabetes (T1DM). Dehydration precipitates SGLT2 inhibitor-induced ketoacidosis in type-2 diabetes. We studied the effects of dapagliflozin and water deprivation on the development of ketoacidosis and the associated signaling pathways in T1DM mice. Methods C57BL/6 mice were fed a high-fat diet. After 7 days, some mice received intraperitoneal injection of streptozocin + alloxan (STZ/ALX). The treatment groups were control + water at lib; control + dapagloflozin + water at lib; control + dapagloflozin + water deprivation; STZ/ALX + water at lib; STZ/ALX + water deprivation; STZ/ALX + dapagloflozin + water at lib; STZ/ALX + dapagloflozin + water deprivation. Dapagliflozin was given for 7 days. In the morning of day 18, food was removed, and water was removed in the water deprivation groups. ELISA, rt-PCR, and immunoblotting were used to assess blood, heart, liver, white and brown adipose tissues. Results The T1DM mice had ketoacidosis even without water deprivation. Water deprivation increased plasma levels of beta-hydroxybutyrate, acetoacetate, corticosterone, and epinephrine and reduced the levels of adiponectin in T1DM mice. Interleukin (IL) 1 beta, IL-6, IL-8, and TNF alpha were also increased in the T1DM mice with water deprivation. Dapagliflozin attenuated the changes in the T1DM mice without and with water deprivation. Likewise, water deprivation increased the activation of the inflammasome in the heart, liver, and white fat of the T1DM mice and dapagliflozin attenuated these changes. Dapagliflozin reduced the mRNA levels of glucagon receptors in the liver and the increase in GPR109a in white and brown fat. In the liver, dapagliflozin increased AMPK phosphorylation, and attenuated the phosphorylation of TBK1 and the activation of NF kappa B. Conclusions Dapagliflozin reduced ketone body levels and attenuated the activation of NF kappa B and the activation of the inflammasome in T1DM mice with ketoacidosis.

Automated summary

SGLT2 inhibitors increase plasma ketone concentrations and may induce ketoacidosis in diabetes patients. Dehydration can precipitate SGLT2 inhibitor-induced ketoacidosis in type-2 diabetes. Dapagliflozin attenuated the development of ketoacidosis and associated signaling pathways in T1DM mice.