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.

Oviductal Glycoprotein 1 Promotes Hypertension by Inducing Vascular Remodeling Through an Interaction With MYH9

“…To further explore whether OVGP1-induced hypertension is mediated through pathologic alteration of vascular function, we used different antihypertensive drugs to reduce BP in transgenic and nontransgenic mice 26,27 ; the diuretic furosemide did not ameliorate the difference between transgenic and nontransgenic mice, whereas the vasodilator prazosin did (Figure S9). These results indicated that the effect of OVGP1 overexpression on BP is mediated by pathologic alteration of the blood vessels.…”

SGLT-2 Inhibitors in NAFLD: Expanding Their Role beyond Diabetes and Cardioprotection

“…Similar results were observed in HFD-fed C57BL/6J male mice after administration of canagliflozin ( Table 2 ) at 30 mg/kg dose for four weeks in parallel with improvement of liver function, liver TG content and NAS score [ 108 ]. Additionally, short term and low dose administration of dapagliflozin ( Table 3 ) reduced both ALT levels and body weight in both HFD and HFD+MCD diet fed C57BL/6J mice [ 109 ]. However, it should be noted that not all studies point towards a beneficial effect of SGLT-2i on body weight.…”

“…However, the protective role of SGLT-2i against NAFLD progression also seems to be mediated by effects beyond those on body weight. Indeed, it has been shown that SGLT-2i treatment improves IR and ameliorates the intracellular FFA, total cholesterol (TC) and TG accumulation through reducing the expression of genes involved in de novo lipogenesis, FA uptake and hepatic TG secretion, whilst it also promotes the expression of key regulatory genes of fatty acid β-oxidation [ 30 , 84 , 100 , 107 , 109 , 112 , 117 ]. Specifically, empagliflozin administration has been shown to reduce hepatic triacylglycerol (TAG) levels and improve IR through reduction of lipotoxic intermediates formation, such as diacylglycerols (DAG) [ 115 ], which at elevated levels contribute to IR by activating the protein kinase C (PKC)ε pathway [ 118 ].…”

Effect of sodium-glucose cotransporter type 2 inhibitors on non-alcoholic fatty liver disease

“…С целью имитации асцита в брюшную полость мышей вводили амидотризоат натрия меглюмина (MSA), было проведено сравнение регрессии асцита, индуцированной приемом дапаглифлозина, с таковой на фоне приема фуросемида с использованием микрокомпьютерной томографии. В ходе эксперимента было показано, что дапаглифлозин обладал более эффективным диуретическим эффектом без отрицательного влияния на гемодинамику, что предполагает возможное применение в терапии цирроза печени [47].…”