Schiano, Elisabetta (2023) Thinned fruits as agro-food waste products with beneficial effects on the control of glucose homeostasis. [Tesi di dottorato]

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Control of glucose homeostasis represents the main goal in both the prevention and management of diabetes and prediabetes. Although a wide range of pharmacological approaches is currently available for the treatment of diabetes and its related morbidities, these are often associated with side effects, leading to poor adherence and treatment failure. Therefore, there is growing interest in natural products with beneficial potential in the management of diabetic condition. In this context, particular attention has recently been paid to the investigation of abscisic acid (ABA), an endogenous hormone with hypoglycemic potential in humans. Additionally, the role of ABA as a terpenoid phytohormone mainly responsible for regulating plant growth and differentiation is extensively described in the scientific literature. Due to its involvement in plant developmental processes, ABA reaches its maximum concentration in immature fruits that are often subjected to fruit thinning, an agronomic practice carried out to improve fruit size and quality. In this scenario, the large number of unripe fruits discarded every year due to this process turns out to represent innovative and high-value resources of ABA, in line with the concepts of food waste valorization and environmental sustainability. Based on these considerations, in the first part of this Ph.D. thesis, a screening of different extracts of unripe fruits derived from fruit thinning allowed us to identify thinned nectarines (Prunus persica L.) as the richest sources in terms of ABA content. In addition, the optimal extraction conditions to obtain the maximum ABA yield were explored, followed by the identification through HPLC-HESI-MS/MS analysis of three different ABA metabolites. Subsequently, we aimed to perform a qualitative and quantitative characterization of the polyphenolic profile of the thinned nectarine extract (TNE) through HPLC-HESI-MS/MS and HPLC-DAD-FLD analyses, which led to the detection of forty-eight polyphenolic compounds, nineteen of which were quantified. Overall, these results prompted us to test the clinical potential of a TN nutraceutical formulation (TNnf) on glucose homeostasis. Sixty-one patients with type 2 diabetes mellitus (T2DM) were enrolled in a three-month, three-arm, parallel-group, randomized controlled trial (RCT). Specifically, two different doses of the nutraceutical formulation, i.e. a low dose (500 mg 3 times/day) and a high dose (750 mg 3 times/day) of TNnf, were tested. Although a significant reduction of glycemic parameters was observed in both treatment groups compared to baseline, the supplementation with TNnf low dose showed a greater insulin-sparing effect (fasting plasma insulin, FPI: -29.2%, p < 0.05 vs baseline), compared to TNnf higher dose (FPI: -16.5%, p < 0.05 vs baseline). Moreover, the quantification of ABA serum levels by using a previously validated LC-MS/MS method, allowed us to observe a significant correlation between glycemia and ABA levels in both intervention groups. Finally, during my Ph.D. research period abroad, I had the opportunity to develop and optimize two nanoformulations (NF) containing a pure standard of ABA or TNE at the same ABA concentration, using ascorbyl palmitate/DSPE-PEG as nanocarrier delivery system. Overall, the results obtained demonstrated the high efficacy of the tested nanoformulated samples in terms of cell viability, antioxidant activity, and insulin secretion in a MIN6 pancreatic β-cell model. Moreover, the greater results obtained in cells treated with the NF-TNE sample compared to ABA alone, supported its additional potential to improve cellular antioxidant protection due to the synergistic combination of bioactive compounds contained in the TNE phytocomplex. Overall, the data obtained reasonably support TN as a source of innovative and promising nutraceutical products able to contribute to the management of glucose homeostasis. Undoubtedly, these data may pave the way for future in vitro and in vivo studies aimed at evaluating the beneficial potential of nutraceutical formulations based on TN in further experimental models.

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