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

Cardiovascular Drugs and Therapy Aims and scope Submit manuscript

Abstract

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 β-hydroxybutyrate, acetoacetate, corticosterone, and epinephrine and reduced the levels of adiponectin in T1DM mice. Interleukin (IL) 1β, IL-6, IL-8, and TNFα 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 NFκB.

Conclusions

Dapagliflozin reduced ketone body levels and attenuated the activation of NFκB and the activation of the inflammasome in T1DM mice with ketoacidosis.

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Data Availability

Original research data will be available upon request.

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Funding

The study was funded by an investigator-initiated grant from AstraZeneca and the John S. Dunn Chair in Cardiology Research and Education.

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All authors contributed to the study conception and design. Material preparation, experiments, and data collection were performed by Huan Chen and Yumei Ye. Data analysis was performed by Yumei Ye and Yochai Birnbaum. Figures were made by Yochai Birnbaum. The first draft of the manuscript was written by Yochai Birnbaum and all authors read and edited the manuscript. All authors read and approved the final manuscript.

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Correspondence to Yumei Ye.

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Ethical Statement

The experimental designs and animal care were conducted in accordance with the Guide for the Care and Use of Laboratory Animals, published by the National Institutes of Health (NIH Publication No. 85–23, revised 1996) and approved by the Institutional Animal Care and Use Committee of the University of Texas Medical Branch.

Conflict of Interest

Huan Chen, Regina Ye—none. Yochai Birnbaum and Yumei Ye—research grant from AstraZeneca. Mandeep Bajaj—research grants: Novo Nordisk and AstraZeneca; Advisory Board: AstraZeneca; consulting fees: Genentech. At the time of publication, Hsiu-Chiung Yang was previously an employee of AstraZeneca.

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Chen, H., Birnbaum, Y., Ye, R. et al. SGLT2 Inhibition by Dapagliflozin Attenuates Diabetic Ketoacidosis in Mice with Type-1 Diabetes. Cardiovasc Drugs Ther 36, 1091–1108 (2022). https://doi.org/10.1007/s10557-021-07243-6

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