Role of Sodium-Glucose Co-Transporter 2 Inhibitors in the Regulation of Inflammatory Processes in Animal Models

Abstract

Sodium-glucose co-transporter 2 inhibitors, also known as gliflozins, were developed as a novel class of anti-diabetic agents that promote glycosuria through the prevention of glucose reabsorption in the proximal tubule by sodium-glucose co-transporter 2. Beyond the regulation of glucose homeostasis, they resulted as being effective in different clinical trials in patients with heart failure, showing a strong cardio-renal protective effect in diabetic, but also in non-diabetic patients, which highlights the possible existence of other mechanisms through which gliflozins could be exerting their action. So far, different gliflozins have been approved for their therapeutic use in T2DM, heart failure, and diabetic kidney disease in different countries, all of them being diseases that have in common a deregulation of the inflammatory process associated with the pathology, which perpetuates and worsens the disease. This inflammatory deregulation has been observed in many other diseases, which led the scientific community to have a growing interest in the understanding of the biological processes that lead to or control inflammation deregulation in order to be able to identify potential therapeutic targets that could revert this situation and contribute to the amelioration of the disease. In this line, recent studies showed that gliflozins also act as an anti-inflammatory drug, and have been proposed as a useful strategy to treat other diseases linked to inflammation in addition to cardio-renal diseases, such as diabetes, obesity, atherosclerosis, or non-alcoholic fatty liver disease. In this work, we will review recent studies regarding the role of the main sodium-glucose co-transporter 2 inhibitors in the control of inflammation.

Low-grade inflammation in type 2 diabetes: a cross-sectional study from a Danish diabetes outpatient clinic

“…The antidiabetic effects of SGLT2 inhibitors rely on the inhibition of renal reabsorption of glucose, but anti-inflammatory effects have also been reported including attenuation of IL-6 production37 and modulation of macrophage polarisation 38. The prospect of using the anti-inflammatory potential of SGLT2 inhibitors in various pathologies is currently receiving much attention 39…”

“…38 The prospect of using the anti-inflammatory potential of SGLT2 inhibitors in various pathologies is currently receiving much attention. 39 Additional subgroups Apart from obesity, hyperglycaemia and sex, other factors such as current smoking status and specific medical therapy may likewise influence the level of inflammation in type two diabetes. 40 41 In our cohort, only 5% were smokers, which is surprisingly low, giving the fact that smoking is a substantial risk factor for development of type 2 diabetes.…”

Cardiac Sodium/Hydrogen Exchanger (NHE11) as a Novel Potential Target for SGLT2i in Heart Failure: A Preliminary Study

“…In recent years, a hypothesis that has gained strength describes that beneficial action of SGLT2i on HF is due to a systemic effect [ 5 ]. SGLT2i could act as modulators of metabolic fuel used by the myocardium, specifically reducing glucose consumption and increasing the use of ketone bodies, which ameliorate adverse left ventricle remodeling [ 25 , 26 ]. Previously, we observed alterations in lipids metabolism in HF patients [ 27 ], as well as in animal models treated with empagliflozin [ 19 ].…”

Mouse Models with SGLT2 Mutations: Toward Understanding the Role of SGLT2 beyond Glucose Reabsorption

“…SGLT2 inhibitors are not completely selective for SGLT2 and inhibit SGLT1 to different degrees. However, they are commonly referred to as SGLT2 inhibitors because their affinity for SGLT2 is considerably higher than for SGLT1 [ 48 ]. Although SGLT2 inhibition raises concerns about the risk of hypoglycemia, previous studies reported that SGLT2 inhibition increased glucose loading to the late proximal tubules, enhanced the glucose transport capacity of SGLT1, and limited glucose excretion and the risk of hypoglycemia.…”