Adjunctive effects of intermittent fasting and exercise with glibenclamide on diabetic nephropathy in rats: a potential role of the polyol pathway

Abstract

Background: Diabetic nephropathy (DN) is a major complication of type 2 diabetes, often driven by hyperglycemia-induced activation of the polyol pathway. Exercise and intermittent fasting (IF) are non-pharmacological strategies known to improve glucose homeostasis, yet their renal protective roles remain underexplored. Aim: To explore how exercise and IF with glibenclamide therapy can have a therapeutic potential in diabetic nephropathy as adjuncts or alternatives to conventional pharmacological treatment by focusing on the polyol pathway as a mechanistic target. Methods: Type 2 diabetes was induced in rats using an 8-week high-fat diet followed by a single low dose of streptozotocin (STZ). Animals were treated for 4 weeks with glibenclamide (1 mg/kg/day), exercise, IF, or combined triple therapy. Biochemical, molecular, and histopathological analyses were performed to evaluate renal function, oxidative stress, inflammatory mediators, polyol pathway activity, apoptotic markers, and tissue architecture. Results: Untreated diabetic rats developed hyperglycemia, renal impairment, oxidative stress, and inflammation with marked polyol pathway activation. Triple therapy significantly improved glycemic control, restored antioxidant defenses, reduced pro-inflammatory and apoptotic markers, downregulated transforming growth factor-β (TGF-β) expression, and preserved renal histology. Conclusion: The combination of glibenclamide, exercise, and IF provides synergistic protection against diabetes-induced nephropathy, primarily through modulation of the polyol pathway, antioxidant enhancement, and suppression of inflammation and fibrosis.