*2.4. Antidiabetic Activity*

Diabetes is the principal widespread metabolic disease in the world and its occurrence has a rising trend. According to the World Health Organization, it is the third most common disorder after cardiovascular and oncological diseases [93].

Diet allows for the control of diabetes mellitus, and pomegranate fruit and its derivatives are part of it [56].

Among antidiabetic molecules, polyphenols, contained in pomegranate, are able to lower glycemic values, including via the reduction of glucose absorption through the intestine or peripheral tissues, although the most likely mechanism is the decrease of the enzyme glucosidase [94].

Li et al. [95] have hypothesized that pomegranate flower extract improves post-prandial hyperglycemia in type 2 diabetes and obesity, at least partially, as a result of the suppression of intestinal α-glucosidase activity.

Huang et al. [96] instead reported a plausible mechanism of the antidiabetic activity of the PFE involving the activation of PPAR-γ. In addition, ca ffeic acid (17) or 3,4-dihydroxycinnamic acid another component of PE, increases the uptake of glucose by adipocytes in rats and myoblasts in mice [5].

Finally, McFarlin et al. [97] explored the impact of pomegranate seed oil on fat storage in mice noticing an enhancement of insulin sensitivity.

Parmar and Kar went into the potential e ffect of pomegranate peel extract on tissue lipid peroxidation (LPO), the concentration of thyroid hormones, insulin, and glucose in male rats starting from in vitro evaluations, which proved an inhibition of H2O2-induced LPO in red blood cells of rats by 0.25, 0.50, 1.0, and 2.0 μg/mL in a concentration-dependent manner. The maximum was achieved at 2.0 μg/mL. In vivo, *P. granatum* reduced LPO in hepatic, cardiac, and renal tissues and serum glucose concentration. These data suggested a potential regulatory role of this peel extract on thyroid function and glucose metabolism [98].

Another study assessed the ability of pomegranate fruit extract to decrease the serum resistin levels (adipocytokine, seen as a possible connection between obesity and type 2 diabetes) in ovariectomized mice, an animal pattern presenting exalted resistin levels in serum and upregulated resistin mRNA expression in white adipose tissue. Furthermore, PoMx was able to reduce the secretion and intracellular levels of resistin in di fferentiated murine 3T3-L1 adipocytes, without modifying resistin mRNA expression. Other findings suggested that PFE stimulated the degradation of resistin. All these activities could be mainly attributed to ellagic acid [99].

Several studies agree that oxidative stress triggered by diabetes mellitus gives rise to brain damage. Indeed, Cambay et al. indicated that the co-administration of pomegranate flower extract and antidiabetics resulted into improvements in learning and memory performances of diabetic rats. Moreover, in test subjects in which LPO was increased and glutathione (GSH) content was diminished in hippocampal tissue, the supplementation of pomegranate flower extract PGF was able to restore these levels. Besides, daily PGF intake decreased glial-fibrillar acidic protein contents induced by diabetes in the hippocampus [100].

On the contrary, in 2016, a research team questioned these findings, corroborating that daily consumption of pomegranate seed oil in patients su ffering from diabetes mellitus 2 did not substantially impact the levels of parameters such as fasting blood sugar (FBS), insulin, HbA1c, alanine transferase, and homeostasis model assessment-insulin resistance [101].

PFE has been, over the years, part of the Chinese diet as an ally against type 2 diabetes mellitus (T2DM). For this reason, Tang et al. tried to analyze the kind of activity implied in the antidiabetic e ffect. The rat model (male Sprague–Dawley (SD) rats) diet was implemented with PFE polyphenols extract at doses of 50 and 100 mg/kg for a period of 4 weeks. Several assays as oral glucose tolerance test (OGTT), insulin tolerance test (ITT) and homeostasis model assessment of insulin resistance (HOMA-IR) were performed, revealing an improvement of insulin sensitivity. Deeper molecular investigations established that insulin-signaling activity was enhanced with an elevation in insulin-stimulated phosphorylation of insulin receptor substrate (IRS-1), Akt, and GSK-3b. Additionally, they assessed a decrease, after the treatment, of endoplasmic reticulum (ER) stress signals including phosphorylation of inositol-requiring kinase1 (IRE1) and activation of X box-binding protein (XBP-1) splicing. In addition, regarding the blood lipid profile, liver glycogen content and antioxidant status were improved by PFE in the rats [102].

Similar results were found for pomegranate fruits aqueous extract as a conspicuous decrease in fasting blood glucose (FBG) by 28.1 and 67.9% in short-term and long-term treatment models (alloxan-diabetic male Wistar rats) and a raise in the mRNAs expression levels of IRS-1, Akt, Glut-2, and Glut-4, suggesting an improvement of glucose uptake and storage [103].

Recently, the potential combination of pomegranate juice and *Lactobacillus casei* NRRL-B-1922 (used as fermenting agent) to create a functional juice able to combat T2DM has been documented. The results highlighted that pomegranate could support the growth of *L. casei* even without nutrient supplementation. Further analysis demonstrated that the glucose and fructose contents were gradually lowered with consumption rates of 0.51 and 0.37 g/L/h, respectively, in the bioreactor. Moreover, the possible antidiabetic mechanism of action could be attributable to the dipeptidyl peptidase-4 (DPP-4) inhibition (with a rate of 80%). Indeed, DPP4 is a well-known target of many antidiabetic agents [104].

A recent clinical trial demonstrated that the assumption of pomegranate juice in patients with T2D can change and lower erythropoietin levels just after 3 h of ingestion whereas no modifications were observed in healthy patients [105]. However, further studies to assess the long-term antidiabetic effects of the pomegranate consumption are in progress.
