Maturation-stage effects of <i>Ziziphus spina-christi</i> fruits and leaves on digestive, inflammatory, antioxidant, and glucose metabolism enzymes in obese rats with type 2 diabetes

<i>Ethnopharmacological relevance</i>: <i>Ziziphus spina-christi</i> (Sidr/Nabag) is a medicinal fruit widely used in traditional Middle Eastern remedies. Rich in polyphenols, it offers potent therapeutic and nutritional benefits. <i>Aim of the study</i>: this study investigates the effects of <i>Ziziphus spina-christi</i> (ZSC) fruit and leaf extracts at different maturation stages in obese rats with type 2 diabetes (OB/T2D). <i>Materials and methods</i>: ZSC fruits (ZFU, ZFHR, ZFR) and leaves (ZL) were analyzed by DAD-HPLC. Their effects were evaluated in OB/T2D rats on digestive enzymes, insulin signaling, and metabolic pathways. <i>Results</i>: DAD-HPLC analysis of ZSC fruits and leaves identified 13 phenolic compounds. Phenolic acids decreased from 69% in unripe to 50.6% in ripe fruits, while polyphenolic content increased. In OB/T2D rats, administration of ZSC extracts restored pancreatic function by reducing pancreatic MPO activity. The extracts suppressed the activities of inflammatory enzymes and decreased oxidative stress markers, with the most remarkable effects observed in OB/T2D rats treated with ZFHR. Specifically, MPO activity was reduced by 58%, PLA2 by 46%, ELA by 62%, and PGS by 69%. Additionally, antioxidant defenses were strengthened, demonstrated by reductions in pancreatic H₂O₂ by 64%, TOS by 61%, and TBARS by 62%, along with an increase in TAS levels by 121%, compared to untreated OB/T2D rats. Ingestion of ZSC extracts inhibits intestinal α-amylase and lipase, slowing glucose and lipid absorption. The ZFHR showed the strongest inhibition, reducing α-amylase and lipase activities by 67 and 56%, respectively. This treatment also enhanced by a 68% increase in hepatic glycogen level. Additionally, administration of these extracts suppressed liver glucose anabolic enzymes G6PDH, G6P, FBP, and PEPCK; while stimulating glucose catabolic enzymes (HK, PK, LDH, PFK) and Krebs cycle enzymes (IDH, SDH, MDH). All extracts reduced BW and blood glucose levels, with the greatest effect in the ZFHR group, showing decreases of 30, 52, and 47% in BW, blood glucose, and HbA1c, respectively, followed by ZFU, ZFR, and ZL. These findings suggest that the semi-ripe fruit extract of ZSC may serve as a promising candidate for managing OB/T2D, due to its potent bioactivity and simultaneous richness in phenolic acids and polyphenolic compounds.