Abstract
Background: Natural products of herbal medicines and their secondary metabolites have been suggested to treat T2DM and they may have the potential as DPP-4 inhibitors.
 Objective: This study was conducted to estimate the phytochemical content , radical scavenging activity (RSA) and DPP-4 (dipeptidyl peptidase-4) relative inhibition activity (RIA) of different extracts of Punica granatum peel. 
 Material and Methods: Fruit peel of pomegranate plant Punica granatum were subjected to extraction with four solvents (distilled water(AQ), 80% methanol(ME), 80% acetone(AC) and a mixed solvent(MX) that included methanol, ethanol, acetone and n-butanol at proportions (7:1:1:1), respectively. Yielded extracts were phytochemically analyzed for total polyphenols (TP) , flavonoids (TF) and HPLC analysis. The DPPH (2,2-diphenyl-1-picrylhydrazyl) radical scavenging activity (RSA) and DPP-4 (dipeptidyl peptidase-4) relative inhibition activity (RIA) were also assessed for each extract. 
 Results: The results showed that acetone solvent (AC) extract of fruit peel of Punica granatum recorded the highest content of TP and TF (159.9 ± 1.0 mg Gallic acid equivalent/g dry mass) and (7.6 ± 0.2 mg catechin equivalent/g dry mass, respectively) . Mixture extract (MX) was showed the highest antioxidant activity of (54.7 ± 0.9% RSA). While methanol extract (ME) recorded the highest DPP-4 RIA (47.1 ± 1.5%). HPLC analysis showed the presence of Gallic acid, Tannic acid, Ellagic acid and B carboxylic acid at concentrations of (94.61, 130.14, 528.46 and 159.64 ug/ml, respectively). Conclusion: The importance of natural products as radical scavengers and DPP-4 inhibitors is encouraged, and such biological effects were dependent on the plant species and the solvent of extraction. Punica granatum mixture extract was suggested to have a prominent RSA, while methanol extraction of Punica granatum peels are recommended to be a target for investigations involved in the development of anti-T2DM and anti-cancer therapies.
Highlights
Type 2 Diabetes mellitus (T2DM) is a global disease and recent estimates have revealed that around 10%of adults are diabetic, and 90% of whom are grouped under T2DM (1)
The results showed that acetone solvent (AC) extract of fruit peel of Punica granatum recorded the highest content of Total polyphenols (TP) and Total flavonoids (TF) (159.9 ± 1.0 mg Gallic acid equivalent/g dry mass) and (7.6 ± 0.2 mg catechin equivalent/g dry mass, respectively)
For TP, the acetone extract of P. granatum peels showed the highest content (159.9 ± 0.4 mg GE/g DM), while a lowest content was recorded in methanol (101.2 ± 1.0 mg GE/g DM)
Summary
Of adults are diabetic, and 90% of whom are grouped under T2DM (1) It is a progressive chronic metabolic syndrome that is hallmarked by hyperglycemia due to a defect in insulin secretion, insulin action, or betacell impairment (2). Hyperglycemia in T2DM is controlled by different oral hypoglycemic agents. They are classified as enhancers of insulin secretion (sulfonylureas and glinides) or insulin sensitivity (metformin and the thiazolidinediones). A further group includes inhibitors of intestinal carbohydrate absorption (alphaglucosidase inhibitors) (5). These agents have a complex mechanism of action, and they are associated with some adverse effects (hypoglycemia, weight gain, gastrointestinal disturbance, lactic acidosis and fluid retention) (6). Oral hypoglycemic agents that inhibit the enzyme dipeptidyl peptidase-4 (DPP-4) have emerged as an effective and promising therapeutic strategy for the management of T2DM (7)
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