Effects of Roflumilast on Glycaemic Control, Insulin Secretion, Lipid Profile and Pancreatic Histology in Streptozotocin-Induced Diabetic Wistar Rats

Abstract

Background: Diabetes mellitus (DM) is a progressive metabolic disorder characterised by persistent hyperglycaemia, impaired β-cell function, chronic inflammation and oxidative stress. Current antidiabetic therapies improve glycaemic status but may not fully address inflammatory and oxidative processes involved in disease progression. Roflumilast, a selective phosphodiesterase-4 (PDE4) inhibitor, increases intracellular cyclic adenosine monophosphate (cAMP) and suppresses pro-inflammatory mediators; however, its effects in streptozotocin (STZ)-induced diabetic Wistar rats require further characterisation. Objective: This study evaluated the effects of roflumilast, alone and combined with metformin, on glycaemic control, plasma insulin, lipid profile and pancreatic histology in STZ-induced diabetic Wistar rats. Methods: Thirty adult male Wistar rats were assigned to five groups (n = 6): non-diabetic control (NDC), diabetic control (DC), metformin 100 mg/kg/day (MET), roflumilast 1 mg/kg/day (ROF) and ROF+MET. Diabetes was induced using a single intraperitoneal STZ injection (80 mg/kg). Treatments were administered orally for 21 days. Fasting blood glucose (FBG), plasma insulin and lipid profile were measured, and pancreatic tissue was examined using haematoxylin and eosin staining. Results: STZ induced sustained hyperglycaemia and markedly reduced plasma insulin. ROF monotherapy significantly reduced FBG and improved plasma insulin (p < 0.001). ROF+MET produced the greatest glycaemic improvement, with Day-21 FBG statistically comparable to NDC (p = 0.364 vs NDC). ROF also reduced total cholesterol, triglycerides and LDL cholesterol, whereas HDL-cholesterol was unchanged across groups. Histology showed severe islet degeneration in untreated diabetic controls, while ROF and ROF+MET showed near-normal islet morphology. Conclusion: Roflumilast improved glycaemic, insulin, lipid and pancreatic histological outcomes in STZ-induced diabetic rats, with the combination treatment showing the greatest overall effect.