<p>Dual SGLT1/SGLT2 Inhibitor Phlorizin Ameliorates Non-Alcoholic Fatty Liver Disease and Hepatic Glucose Production in Type 2 Diabetic Mice</p>

Abstract

Purpose: NAFLD is a hepatic component of type 2 diabetes mellitus (T2D), in which impaired hepatic glucose production plays an important role. Inhibitors of sodium glucose transporter 2 (SGLT2) reduce glycemia and exert beneficial effects on diabetic complications. Recently, dual SGLT1/2 inhibition has been proposed to be more effective in reducing glycemia. We hypothesized that improving hepatic glucose metabolism induced by SGLT1/2 inhibition could be accompanied by beneficial effects on NAFLD progression. Methods: Glycemic homeostasis, hepatic glucose production and NAFLD features were investigated in obese T2D mice, treated with SGLT1/2 inhibitor phlorizin for 1 week. Results: T2D increased glycemia; insulinemia; hepatic expression of phosphoenolpyruvate carboxykinase (PEPCK), glucose-6-phosphatase (G6Pase) and glucose transporter 2 (Slc2a2 gene); hepatocyte nuclear factors 1A/4A/3B-binding activity in Slc2a2; endogenous glucose production; liver weight, plasma transaminase concentration as well as hepatic inflammation markers, and induced histological signals of non-alcoholic steatohepatitis (NASH, according to NASH-CRN Pathology Committee System). Phlorizin treatment restored all these parameters (mean NASH score reduced from 5.25 to 2.75 P<0.001); however, plasma transaminase concentration was partially reverted and some hepatic inflammation markers remained unaltered. Conclusion: NAFLD accompanies altered hepatic glucose metabolism in T2D mice and that greatly ameliorated through short-term treatment with the dual SGLT1/2 inhibitor. This suggests that altered hepatic glucose metabolism participates in T2D-related NAFLD and highlights the pharmacological inhibition of SGLTs as a useful approach not only for controlling glycemia but also for mitigating development and/or progression of NAFLD.

Empagliflozin Attenuates Non-Alcoholic Fatty Liver Disease (NAFLD) in High Fat Diet Fed ApoE(-/-) Mice by Activating Autophagy and Reducing ER Stress and Apoptosis

“…More interestingly, SGLT-1 was expressed in the total of the liver tissues (both control and intervention group) suggesting its possible role in the attenuation of NAFLD in our model. Of note, empagliflozin can also bind to SGLT-1, albeit with a lower affinity than SGLT-2; strengthening the suggestion that empagliflozin could act, among others, through SGLT-1, dual SGLT-1/SGLT-2 inhibitor phlorizin recently found to ameliorate NAFLD in Type 2 diabetic mice [68]. Nevertheless, the existence of other, unknown yet, protein(s) which could be a direct target of empagliflozin in hepatocytes cannot be excluded.…”

The Bioavailability, Extraction, Biosynthesis and Distribution of Natural Dihydrochalcone: Phloridzin

“…Wang et al [ 85 ] demonstrated that apple phloridzin increased cell viability, relieved deoxyribonucleic acid (DNA) damage, oxidative stress and apoptosis in H 2 O 2 -induced HepG2 cells by the nuclear factor E2-related factor 2 (Nrf2) signaling pathway and anti-apoptosis genes. David-Silva et al [ 86 ] found that phloridzin restored glycemic control and hepatic glucose metabolism, inhibited hepatic glucose production and ameliorated non-alcoholic fatty liver disease in type 2 diabetic mice.…”

The Association between Hepatic Encephalopathy and Diabetic Encephalopathy: The Brain-Liver Axis

“…Previous study highlighted that patients with liver disease have similar insulin resistance to type 2 diabetes patients [ 24 ]. Also, type 2 diabetic mice share the same features in chronic liver disease, NAFLD, such as insulin resistance and altered glycaemic homeostasis, which are also main characteristics in type 2 diabetes [ 133 ]. Moreover, diabetes worsens the progression of liver fibrosis [ 134 ] and elevates the risk of HE in patients with cirrhosis [ 25 ], indicating a close link between HE and diabetes.…”

“…Also, the inhibition of SGLT1 or SGLT2 displays glucose lowering effect and improves glucose homeostasis in diabetes [ 139 ]. Also, SGLT1/SGLT2 inhibition prevents NAFLD progression and reduces glucose production in hepatocyte of type 2 diabetic animals [ 133 ]. In addition, patients with cirrhosis showed impaired brain glucose metabolism, even though they had no overt HE [ 140 ].…”