Irisin Upregulation As a Contributory Mechanism for the Therapeutic Benefits of SGLT-2 Inhibitors

Different pharmacological and non-pharmacological interventions have been suggested for the management of blood glucose, among which are sodium-glucose cotransporter-2 (SGLT-2) inhibitors and exercise. SGLT-2 inhibitors (-gliflozins) are a class of drugs that reduceglucose reabsorption from the proximal renal tubule, thereby decreasing its levels in the blood, while increasing its excretion in the urine. Several studies have demonstrated cardio-, neuro-, and renoprotective benefits of these drugs, including reduced cardiovascular deaths, hospitalizations due to heart failure, rate of progression of kidney disease, cognitive deficits, reactive oxygen species, and progression of amyloid beta (Aβ) formation. Several additional mechanisms of action have been proposed for the observed benefits of SGLT-2 inhibitors. Irisin is a myokine released by skeletal muscles in response to exercise that results in browning of adipose tissue, that has been shown to have similar benefits to SGLT-2 inhibitors. Recent studies have shown that SGLT-2 inhibitors upregulate fibronectin type III domain-containing protein 5 (FNDC5) expression, from which irisin is derived, presumably by activating upstream regulators, such as adenosine monophosphate-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α), thereby mimicking exercise-induced pathways, contributing to their protective benefits across various organ systems. We hypothesize that activation of the PGC-1α - FNDC5/irisin axis represents a previously unrecognized downstream mediator of the pleiotropic cardiorenal and neuroprotective effects of SGLT-2 inhibitors. While current evidence is largely preclinical and associative, this framework generates a testable mechanistic model in which circulating irisin could serve both as a mediator and biomarker of SGLT-2 inhibitor-induced tissue protection.