Effects of Sodium-Glucose Cotransporter 2 Inhibition on Glucose Metabolism, Liver Function, Ascites, and Hemodynamics in a Mouse Model of Nonalcoholic Steatohepatitis and Type 2 Diabetes

Abstract

Many blood glucose-lowering drugs cannot be used once patients with type 2 diabetes (T2D) and nonalcoholic fatty liver disease develop nonalcoholic steatohepatitis (NASH). Therefore, such patients often require insulin treatment. We aimed to determine the effect of sodium-glucose cotransporter 2 inhibitor (SGLT2i) dapagliflozin monotherapy on glucose metabolism in a mouse model of NASH/T2D, with a focus on its diuretic effects. To imitate ascites and to determine its severity by imaging, meglumine sodium amidotrizoate (MSA) was infused into the abdominal cavities of mice. The reduction in ascites induced by dapagliflozin was compared with that induced by furosemide using microcomputed tomography. The effects of each drug on hemodynamics were also compared. A dapagliflozin-related improvement in glucose tolerance was achieved in mice fed a high-fat diet (HFD) or an HFD + methionine-and-choline-deficient diet (MCDD). In dapagliflozin-treated NASH mice, hypoglycemia was not identified during 24-hour casual blood glucose monitoring. In the dapagliflozin and furosemide-treated groups, the time taken for the resolution of artificial ascites was significantly shorter than in the untreated group, and there were no significant differences between these groups. Furosemide significantly reduced the blood pressure and significantly increased the heart rate of the mice. Dapagliflozin caused a mild decrease in systolic, but not diastolic blood pressure, and the heart rate and circulating catecholamine and renin-aldosterone concentrations were unaffected. Dapagliflozin treatment improved glycemic control in the NASH mice versus untreated mice. Thus, dapagliflozin had a prompt diuretic effect but did not adversely affect the hemodynamics of mice with NASH and T2D. Therefore, it may be useful for the treatment of patients with both T2D and liver cirrhosis.