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Diabetes mellitus (DM), particularly type 2 diabetes (T2DM), represents a global health crisis characterized by persistent hyperglycemia due to insulin resistance and β-cell dysfunction. With projections estimating 783 million affected adults by 2045, current pharmacotherapies like metformin and sulfonylureas face limitations including side effects, high costs, and therapeutic inertia. This has spurred interest in medicinal plants as complementary therapies. Spondias mombin L. (hog plum), traditionally used in Nigeria for diabetes management, exhibits antioxidant, anti-inflammatory, and hypoglycemic properties, yet its molecular mechanisms remain underexplored. This study investigates the effects of ethanol extract of S. mombin on insulin signaling pathway genes (IR-Insulin Receptor, AKT-AKT serine/theorine kinase, PPAR γ- Peroxisome Proliferator activated receptor Gamma, DPP-4- Dipeptidyl peptidases 4) in high fat diet (HFD) and streptozotocin (STZ)-induced T2DM rats, aiming to validate its ethnomedicinal use and elucidate gene-modulating potential. Male Wistar rats (150-200 g) were acclimatized, then divided into five groups (n=6): Group 1: normal control, Group 2: positive control, Group 3: diabetic control, Group 4: 200mg/kg of extract and Group 5: 400mg/kg of extract. T2DM was induced via 2-week HFD followed by low-dose STZ (40 mg/kg i.p.). Treatments were administered orally for 2 weeks. Body weights and organ weights (pancreas, liver) were measured. Liver RNA was isolated for semi-quantitative RT-PCR analysis of IR, AKT, GLUT-4, PPAR-γ, DPP-4. Results revealed diabetes-induced body weight loss (147 ± 9.56 g vs. 184.17 ± 11.92 g in controls), reduction in the weight of the pancreas (0.19 ± 0.04 g vs. 0.59 ± 0.14 g), and increase in liver weight (8.56 ± 0.25 g vs. 7.33 ± 0.53 g). Extract treatments restored body weights dose-dependently (189.11 ± 15.99 g at 200 mg/kg; 209.28 ± 17.74 g at 400 mg/kg), surpassing glipizide (170.79 ± 31.55 g). Pancreas weights increased to 0.29 ± 0.04 g and 0.32 ± 0.05 g, while liver weights normalized, indicating protective effects. Gene expression analysis showed downregulation in diabetic controls for IR, AKT, GLUT-4, PPAR-γ, and DPP-4. Extract upregulated these genes dose-dependently, often exceeding glipizide, suggesting enhanced insulin sensitivity, glucose uptake, and metabolic regulation. These findings corroborate S. mombin's antioxidant and anti-inflammatory mechanisms, likely driven by flavonoids and saponins, addressing T2DM's multifactorial nature. The extract's superiority over glipizide highlights its potential as a safe, affordable adjunct therapy, overcoming conventional limitations. This study provides mechanistic evidence supporting phytotherapy in T2DM management, contributing to natural product-based drug discovery. The research aligns with T2DM pathophysiology, involving disruptions in insulin signaling (e.g., IR, AKT, GLUT-4, PPAR-γ, DPP-4) exacerbated by oxidative stress and inflammation. Literature highlights plants' multi-target actions, such as enhancing glucose uptake via PI3K/AKT activation and enzyme inhibition, positioning S. mombin as a candidate with validated antihyperglycemic effects in prior model
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