Manool restores glucose homeostasis by regulating JAK/STAT, mTOR, and antioxidant signaling in a type 2 diabetes rat model

Objective: To evaluate the antidiabetic effects of manool in streptozotocin-induced diabetic rats and HepG2 cells. Methods: Diabetes was induced in Wistar rats using streptozotocin and nicotinamide, and animals were treated with two doses of manool (1 and 2 mg/kg). Biochemical, oxidative stress, apoptotic, and inflammatory parameters were assessed, followed by histopathology of the pancreas. Expression of key marker genes in the liver and pancreas was analyzed via qRT-PCR. Catalase and superoxide dismutase activities, malondialdehyde level, and glucose consumption were examined in vitro . Results: Manool significantly reduced fasting glucose level, improved insulin levels, and restored glucokinase and Ki67 expression in rats with diabetes. It also enhanced antioxidant defense, upregulated insulin signaling, activated the mTOR pathway, and promoted β-cell regeneration via increased expression of Pdx1, MAFA, Ngn3 , and Ins1 in a dose-dependent manner. However, manool suppressed JAK/STAT pathway only at a higher dose of 2 mg/kg. Histopathological study showed near-normal islet architecture in manool-treated diabetic rats. Conclusions: Manool exerts antidiabetic effects by modulating oxidative stress, inflammation, β-cell regeneration, and insulin sensitivity in diabetic rats. However, further pharmacological and clinical investigations are required before confirming its therapeutic applicability.