Background. Podocarpus gracilis is an evergreen, dioecious tree found in Ethiopia and other African nations. It can reach a height of 60 meters. Without any scientifc validation, ethnobotanical studies conducted in Ethiopia revealed that the Podocarpus gracilis plant’s leaf is consumed orally to treat diabetes mellitus. Hence, this study aims to evaluate the in vivo blood glucose level lowering, lipid-lowering, and in vitro-free radical scavenging responses of Podocarpus gracilis leaf extract and fractions on experimental mice induced with diabetes. Methods. Te in vitro antioxidant activity of PGC (Podocarpus gracilis) leaf extract was assessed by using a diphenyl-2-picrylhydrazyl (DPPH) assay. Te oral glucose-loaded, normoglycemic, and streptozotocin- (STZ-) induced diabetic mouse models were employed. In the STZ-induced mice model, the leaf extract and solvent fractions activity on serum lipid and weight were also measured. Te extract and fractions were tested at 100, 200, and 400 mg/kg dosages. One-way ANOVA was used to determine the statistical signifcance of BGL (blood glucose level) changes within and between groups, and Tukey’s post hoc multiple comparisons were then performed. Results. In the acute toxicity study of Podocarpus gracilis leaf extract and fractions, there was no evidence of animal mortality at the maximum dose of 2 g/kg during the observation period. Te extracttreated group with normoglycemia revealed a signifcant lowering in BGL at the 4-hour mark of 27.4% (p < 0.001) and 25.2% (p < 0.01) at doses of 200 mg/kg and 400 mg/kg, respectively, compared to that in negative control. In the oral glucose tolerance test (OGTT) model, only 400 mg/kg treated groups at 120 min after exposure showed a BGL reduction of 31.17% which was statistically signifcant (p < 0.05) in comparison to the negative control. In the single-dose STZ-induced model, eighth-hour BGL measurements from CE 100, CE 200, CE 400, and GLC5 showed drops in BGL of 43.1%, 44.1%, 45%, and 47.3% from baseline fasting BGL values. In the repeated streptozotocin (STZ)-induced model, at all doses of leaf extract and fractions, the fasting BGL was signifcantly (p < 0.001) reduced. Moreover, the leaf extract and solvent fractions have shown a signifcant (p < 0.001) reduction of serum lipids such as LDL, TC, and VLDL, and at the same time, it increases HDL at 14 days with body weight gained. In the test for antioxidant activity, the half-maximal inhibitory concentrations (IC50) for leaf extract and the standard medication (ascorbic acid) were 8.2 μg/ml and 3.3 μg/ml, respectively. Te IC50 value denotes the concentration of the sample required to scavenge 50% DPPH radicals. Conclusion. Te 80% hydromethanolic leaf extract and fractions of Podocarpus gracilis exhibited blood glucose lowering, lipid-lowering activity in normoglycemic, oral glucose tolerance test (OGTT) mode, and STZ-induced diabetic mice with weight gains. Tere is scientifc support for the alleged traditional use as an antidiabetic, lipid-lowering, and antioxidant activity. Te results need to be confrmed by future studies.

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