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Review

Natural Deep Eutectic Solvents for Agro-Industrial By-Product Valorization: Emerging Strategies for the Development of Functional Foods Targeting Diabetes

by
Maria Bairaktari
1,
Stavroula Maria Konstantopoulou
1,
Olga Malisova
2,
Aristea Gioxari
1,
Alexandros Ch. Stratakos
3,
Georgios I. Panoutsopoulos
1 and
Konstantina Argyri
1,*
1
Department of Nutritional Science and Dietetics, School of Health Sciences, University of the Peloponnese, Antikalamos, 24100 Kalamata, Greece
2
Department of Food Science and Technology, University of Patras, G Seferi 2, 30100 Agrinio, Greece
3
Centre for Research in Sustainable Agri-Food and Environment, School of Applied Sciences, College for Health, Science and Society, University of the West of England, Coldharbour Ln, Bristol BS16 1QY, UK
*
Author to whom correspondence should be addressed.
Appl. Sci. 2025, 15(21), 11596; https://doi.org/10.3390/app152111596
Submission received: 7 October 2025 / Revised: 24 October 2025 / Accepted: 24 October 2025 / Published: 30 October 2025
(This article belongs to the Special Issue The Development of Novel Functional Foods: Trends, Prospectives, and Possible Bioactivity)
Browse Figure
Versions Notes

Abstract

Natural deep eutectic solvents (NaDESs) have emerged as green and sustainable alternative solvents for extracting valuable bioactive compounds from agro-industrial by-products. NaDESs are stable, soluble, and biodegradable with low melting points and a wide range of applications. These characteristics align closely with the principles of green chemistry, making NaDESs promising for use in the food industry. Recent studies demonstrate that NaDESs can effectively extract proteins, polysaccharides, polyphenols, carotenoids, alkaloids, and other bioactives from sources such as vegetable waste, cereal by-products, and fruit pomace, often performing better than traditional solvents such as methanol and ethanol. The bioactive components of these extracts may exhibit antioxidant, anti-inflammatory, antihypertensive, anticancer, or antimicrobial activity and can be used as functional ingredients, nutraceuticals, or preservatives. Furthermore, NaDES-derived extracts have been shown to have hypoglycemic effects by inhibiting enzymes involved in the metabolism of carbohydrates and reducing oxidative stress. As a result, they may find use as functional food ingredients in diabetes management. This review presents the recent research on the extraction of bioactive compounds from agro-industrial by-products using NaDESs and an evaluation of their antidiabetic potential.

1. Introduction

The food and agricultural industries generate substantial amounts of by-products throughout the entire supply chain. According to the Food and Agriculture Organization (FAO), approximately 1.3 billion tons of food is lost or wasted globally each year. Managing these agro-industrial by-products can be costly and environmentally challenging; they represent abundant, low-cost, and renewable sources of valuable compounds that can be transformed into high-value products. Efficient utilization of agro-industrial by-products aligns with the United Nation’s Sustainable Development Goal (SDG) 12, which emphasizes responsible consumption and production [1,2].
Agro-industrial by-products contain diverse chemical compounds with unique structures and biological activities, contributing to their health-promoting potential [3]. Owing to their potential therapeutic effects, the sustainable extraction of bioactive compounds from these materials is at the forefront of research in the food, nutraceutical, agriculture, and pharmaceutical industries. To meet this demand, novel extraction methods and solvent systems are being developed for improved efficiency and to maintain compound stability [4,5].
Traditional solvents, such as methanol, ethanol, and water (sometimes acidified), have been widely used for this purpose. However, their applicability is limited by their volatility, flammability, and toxicity. In addition, factors such as the pH, temperature, enzymatic activity, and oxidation can affect the stability of the extracts [5]. These challenges have driven research towards innovative, green solvents that enhance the extraction efficiency and preserve the integrity of bioactive compounds.
In this context, ionic liquids (ILs) and deep eutectic solvents (DESs) have emerged as promising alternatives. ILs are organic salts that remain liquid below 100 °C and possess favorable characteristics, being non-flammable and reusable with low vapor pressure and having high thermal stability [6]. DESs, introduced in the early 2000s, are simpler to make, less expensive, and potentially biodegradable. Among them, NaDESs, composed of naturally occurring metabolites, are fully compatible with green chemistry principles and have attracted scientific attention for eco-friendly extraction and food applications [7,8]. Produced from abundant, low-toxicity natural components [9,10], NaDESs have been successfully applied to recover bioactive compounds from lignocellulosic biomass [11,12] and agro-industrial residues from the vegetable, oil, dairy, and beverage industries [13]. Additionally, NaDESs have been employed for extracting phenolic compounds from natural sources [14,15]. Their effectiveness has been demonstrated with diverse materials such as blueberry leaves [16], coffee husk waste [17], olive oil by-products [18], cocoa residues [19], and grape pomace [20,21]. The extraction process is usually combined with pretreatment and innovative extraction techniques, such as microwave-assisted extraction (MAE) [22,23], ultrasound-assisted extraction (UAE) [24,25], supercritical CO2 extraction (SCE) [26], and pressurized liquid extraction (PLE) [27], which further enhance the recovery yields. Beyond extraction, NaDESs may also find applications in energy processes, pharmaceuticals, biomedicine, catalysis, and nanomaterial development [28].
The health benefits of bioactive extracts are particularly relevant in chronic diseases such as type 2 diabetes mellitus (T2DM). Over recent decades, T2DM has become a global epidemic and is expected to affect 4.4% of the global population by 2030. It is characterized by hyperglycemia due to defects in insulin secretion or action [29]. Chronic hyperglycemia induces oxidative stress via reactive oxygen species (ROS) production, contributing to the micro- and macrovascular complications of diabetes. Bioactive extracts rich in antioxidant compounds can potentially help mitigate these effects. Additionally, phenolics extracted from agricultural by-products may exhibit antidiabetic potential through alternative pathways. NaDESs, therefore, can contribute to diabetes control by extracting natural antidiabetic compounds from plant sources and enhancing their solubility and stability [30].
This review provides a comprehensive and up-to-date overview of NaDESs as sustainable, green extraction systems for the valorization of agro-industrial by-products. An extensive literature research was conducted in PubMed, Scopus, Semantic Scholar, Google Scholar, and Science.gov, using a combination of keywords (“natural deep eutectic solvents (NaDES)”, “green extraction”, “functional foods”, “sustainable valorization”, “bioactive compounds”, “food waste”, “agro-food by-products”, “diabetes mellitus (DM)”, “diabetes prevention”). References from the extracted articles were also used. We focused primarily on articles published in English between 2015 and 2025. Studies were selected based on their relevance, methodological rigor, and contribution to advancing the understanding of how NADESs can efficiently recover bioactive compounds from agro-industrial by-products, with particular emphasis on the antidiabetic potential of the obtained extracts. Accordingly, this review aims to critically evaluate the efficiency of NaDESs in extracting bioactive compounds from these by-products and to discuss their potential application in T2DM management by investigating the underlying mechanisms.

2. Natural Deep Eutectic Solvents: Characteristics and Properties

Deep eutectic solvents (DESs) are mixtures of two or more components that are able to form liquids upon mixing with melting points far below those of the individual constituents [7,31]. The name comes from the Greek words “εύ” (eu = well) and “τήξις” (tēxis = melting) [32]. Characterized by their efficiency, low toxicity, and biodegradability, DESs find applications in the extraction of bioactive compounds (flavonoids, alkaloids, phenolics) [33], metal recovery, catalysis, electrochemistry, biomass processing, and pharmaceutical formulations [28]. Their adjustable viscosity and solubility make it possible to design extraction methods specific for each substrate that increase yields while reducing the environmental impact.
DESs are inexpensive, easy to prepare, highly available, and in most cases biodegradable and non-toxic. They also exhibit fire resistance, negligible vapor pressure, and miscibility with water and remain in a liquid state over a wide temperature range. In contrast, organic solvents, such as ethanol, methanol, and acetone, usually used for the extraction of phenolic compounds, are generally flammable liquids with relatively high vapor pressures and low viscosity, often showing significant toxicity toward living organisms and posing negative environmental impacts [34,35]. To mitigate the adverse effects caused by organic volatile solvents, innovative techniques have been developed. For instance, supercritical and pressurized fluids offer high extraction efficiency and shorter extraction times compared to conventional solvents. On the other hand, when used for extraction, they may cause thermal degradation or undesirable oxidation of phenolic compounds at elevated temperatures. Furthermore, extraction with supercritical and pressurized fluids is carried out under high pressures and requires significant energy consumption [36].
Natural deep eutectic solvents (NaDESs) are biocompatible DESs composed of natural occurring metabolites such as amino acids, organic acids, and sugars [33]. Unlike synthetic DESs, NaDESs are often present in living organisms, making them attractive for sustainable and environmentally friendly applications compared to ionic liquids (ILs) and conventional DESs [37,38]. NaDESs are formed via interactions between hydrogen bond donors (HBDs) and acceptors (HBAs) in specific molar ratios [33].
These interactions result in the formation of strong intermolecular hydrogen bonds that significantly lower the melting point, allowing NaDESs to remain liquid under mild conditions. This property makes them suitable for biological and industrial applications that require non-toxic, biodegradable, and sustainable solvents [33,39].
NADESs also play a natural role in cellular metabolism, particularly in plants, where they facilitate the solubilization and transport of hydrophobic metabolites [40,41,42]. By acting as natural solvents, NaDESs enhance the bioavailability of compounds that are poorly soluble in water. For instance, during freezing conditions, plants produce NaDESs that stabilize critical biomolecules such as cell membranes, enzymes, and metabolites, preventing cellular damage [40,43].
Due to their biological significance and environmental safety, NaDESs are increasingly used in pharmaceuticals, food technology, and natural product extraction [44]. Their physicochemical properties (viscosity, polarity, conductivity, and solubility) closely resemble those of conventional DESs, enabling similar applications with enhanced biocompatibility [45,46].

2.1. Solubility and Stability Considerations of Plant-Derived Bioactive Compounds

Solubility, defined as the concentration of a solute in equilibrium with its undissolved form at a given temperature and pressure, is critical for efficient extraction [47]. Many phytochemicals have low water solubility and limited stability, which restricts their bioavailability and functional use [48,49]. Biocompatible solvents such as NaDESs can enhance both the solubility and stability, increasing the bioavailability of plant metabolites [6].
The composition of NaDESs, namely the choice of HBD and HBA, affects physicochemical properties (such as the polarity, viscosity, and dissolution capability) that influence extraction efficiency. For example, choline chloride (ChCl)-based NaDESs are usually employed to dissolve polyphenols and alkaloids, while sugar- or organic-acid-based NaDESs improve the solubility of antioxidants and pigments. Understanding these interactions allows for the optimization of NaDES selection in order to maximize the extraction efficiency and bioavailability of target compounds [50].
Several studies highlight this potential, including the study by Popovic et al. [51], in which flavonoids such as catechin, naringenin, and quercetin exhibited significantly higher solubility in ChCl-based NaDESs compared to water, methanol, or ethanol. Systems with Brønsted acids (e.g., citric or lactic acid) show enhanced flavonoid solubility via protonation, with ChCl–citric acid showing the highest efficiency [51]. Jeliński et al. [48] demonstrated that curcumin’s solubility increased dramatically in a NaDES, reaching 7.25 mg/g (12,000× higher than in water) using a ChCl/glycerol 1:1 system. In the study by Torres-Vega et al. [52], alkaloid extraction from Peumus boldus leaves was most efficient using an L-proline/oxalic acid 1:1 NaDES with 20% water, yielding eight times more alkaloids than methanol. An alcohol-based NaDES with similar polarity to ethanol was less effective, highlighting the role of molecular interactions in extraction efficiency.
NaDESs also demonstrate excellent thermal stability, often maintaining properties above 200 °C, which aids in preserving bioactive compounds during storage. This stabilization is particularly valuable for plant pigments in food, cosmetic, and pharmaceutical applications [25,48].

2.2. The Role of the Water Content in Natural Deep Eutectic Solvents

Water is often combined with DESs and NaDESs, influencing their physicochemical properties and extraction efficiency, depending on the specific components [10]. ChCl-based DESs are typically high viscous, limiting their mass transfer, although adding water can reduce their viscosity and lead to improved solute mobility [53,54]. Moderate water addition can enhance the polarity, favoring the extraction of polar compounds; however, excessive water (>15%) may reduce yields of less polar metabolites, as observed for curcuminoids from Curcuma longa L. [53,54].
A high water content can also disrupt the hydrogen bond network of NaDESs, weakening their eutectic properties and reducing their extraction efficiency. In some cases, aggregates may form that suspend DES particles, which in turn further diminishes the solvent’s performance, despite having intact HBD–HBA interactions. The optimal water content is, therefore, critical for balanced viscosity reduction and solvent integrity for maximal bioactive compound extraction [10,53].

3. Extraction of Bioactive Compounds from Food and Agro-Industrial Waste Using Natural Deep Eutectic Solvents

NaDESs have demonstrated potential in extracting bioactive compounds from food waste and agro-industrial by-products [32]. Compared to conventional extraction methods, these solvents have shown higher yields and purity of the obtained bioactive-rich extracts. DESs can be categorized into binary, ternary, and natural deep eutectic solvents (NaDESs), all of which are applied to recover bioactive molecules from food and agricultural residues [3,5].
One of the main advantages of NaDESs is their tunability. Adding water reduces the viscosity, enhancing mass transfer and improving the extraction efficiency. Water also adjusts the solvent’s polarity, making it more suitable for specific target compounds. However, excessive water (>50%) can lead to disruption of the hydrogen bonding network and reduce the extraction efficiency [37,55].
The recovery of bioactive compounds from non-edible food waste contributes to sustainability by minimizing waste generation and supporting circular economy principles [56,57]. Food waste contains numerous valuable bioactive compounds, including flavonoids, anthocyanins, tannins, polysaccharides, and essential fatty acids. These compounds have antioxidant, anti-inflammatory, and antimicrobial properties, making them highly beneficial for the food, pharmaceutical, and cosmetic industries. Additionally, dairy industry by-products, such as whey and colostrum, provide bioactive peptides with potential health benefits. The marine sector also contributes to bioactive extraction through the recovery of compounds with functional properties from shellfish, fish processing waste, and seaweed [58,59].
By transforming non-edible by-products into high-value functional ingredients, DES- and NaDES-based extraction promotes waste reduction and contributes to a sustainable circular economy. As the research continues to optimize formulations and scale-up processes, these green solvents are expected to play a central role in sustainable bioactive compound recovery [60].

3.1. Phytochemicals

The use of NaDESs for phytochemical extraction has recently attracted considerable attention, particularly for the recovery of polyphenols from agro-industrial by-products such as grape pomace [20]; olive leaves [61]; tomato pomace [58]; and fruit peels [59,62] from pears, oranges [63], and lemons [64]. Factors such as temperature and viscosity, as well as the phenolic profile of the substrate, may influence the extraction efficiency. Furthermore, the selection of the NaDES is critical, since the solvent properties, such as the solubility, diffusion rate, viscosity, polarity, and intermolecular interactions, also determine the effectiveness of the extraction [29,38].

3.1.1. Polyphenols

Polyphenols are a large family of secondary metabolites found in vegetables, fruits, whole grains, and other plant-based sources, including agro-industrial by-products from which they could be isolated; they have attracted researchers’ attention over the years due to their antioxidant, anti-inflammatory, and metabolic-regulating effects [63]. The extraction of these compounds has traditionally depended on organic solvents including ethanol, methanol, hexane and acetone. Recently, the application of DESs and NaDESs has emerged as a greener and often more efficient alternative [20,64,65]. Table 1 presents studies on the recovery of phenolic compounds from agro-industrial by-products using NaDESs as extraction solvents [66].
Apple pomace, the major by-product of apple juice production, contains up to 90% peel and flesh, with seeds and stems making up the remainder. It is particularly rich in polyphenols such as quercetin glycosides, kaempferol, catechin, and procyanidins, compounds associated with cardioprotective, anticancer, and antimicrobial effects. Han et al. [72] demonstrated that a betaine/urea NaDES (1:1) achieved a maximum polyphenol content of 5.2 ± 0.1 mg GAE/g pomace, surpassing conventional solvents. Bottu et al. [90] reported that a ChCl/ethylene glycol NaDES (1:4) provided higher antioxidant capacity compared with the conventional extraction procedure.
Citrus by-products represent a major global waste stream, generated from the industrial processing of citrus fruits, such as orange or lemon, for the production of juice, jellies, marmalade, and dehydrated products [91]. These by-products are rich in flavonoids (such as hesperidin and naringin) that show potential not only as antioxidants but also as food additives and nutraceuticals [76,92,93]. Vinas-Ospino et al. [74] reported that hydrophilic NaDESs such as proline/malic acid yielded 2.83 ± 0.073 mg/gfw, while the lactic acid/glucose and proline/malic acid NaDESs provided better capacity to stabilize polyphenols. Similarly, Ramírez-Sucre et al. [92] compared NaDESs with different ChCl/glucose ratios and demonstrated that Citrus aurantium peels extracted with 1:1 ChCl/Glu yielded the highest hesperidin content (20.03 ± 0.11 mg/g dry mass), whereas a 1:2 ratio yielded the highest neohesperidin content (10.46 ± 0.01 mg/g dry mass). Interestingly, this extract also exhibited the highest antioxidant capacity, achieving 100% inhibition, although the total phenolic content (TPC) was highest with a 1:0.5 molar ratio (0.96 ± 0.008 mg GAE/g dry mass) [92].
Carmona et al. [84] evaluated six NaDESs for olive mill waste (OMW) valorization and reported that citric acid–fructose (CF) made from food-grade and biodegradable substances was the most efficient system, yielding 3.99 mg polyphenols/g fresh OMW.
In a similar study, Maimulyanti et al. [85] demonstrated that a ChCl/proline NaDES (1:1) was particularly effective for coffee waste extraction, yielding 5.88 mg GAE/g and a polyphenol content of 294.02 mg/L in the NaDES.
From the above studies, it can be observed that in most cases the selected solvent is a choline chloride-based NaDES combined with organic acids, glycerol, or other substitutes at varying molar ratios. Despite differences in substrates, the extraction efficiency is largely determined by the physicochemical properties of the DES and the extraction method applied. High-energy techniques, particularly ultrasound-assisted extraction (UAE), have been shown to reduce the extraction time while substantially increasing the phenolic yields. Ojeda et al. [77] demonstrated that the combination of DES and UAE increased the phenolic extraction yield threefold (≈40% higher than conventional methods), highlighting the synergistic effect of solvent design and extraction optimization [75]. Similarly, Tzani et al. [86] compared UAE and microwave-assisted extraction (MAE) for recovering phenolics from coffee residues, reporting that UAE generated extracts higher in phenolics, whereas MAE was more effective for non-polar compounds due to its capacity to disrupt cell structures through elevated temperatures and release bioactive compounds into the extraction medium [86,94].

3.1.2. Flavonoids

Flavonoids represent a major class of approximately 8000 phenolic compounds and are recognized as biologically active secondary plant metabolites. They are widely known as natural pigment producers and exhibit a broad spectrum of bioactivities including antioxidant, anti-inflammatory, antibacterial, and antiviral effects [66,95]. Notably, several flavonoids, including apigenin, arbutin, catechins, and cyanidin, have demonstrated significant antidiabetic potential. Their clinical efficacy has been attributed to their capacity to lower blood glucose levels while enhancing insulin secretion [96]. Table 2 summarizes studies comparing the isolation of flavonoids from food by-products using NaDESs and conventional solvent extraction methods.
Chaves et al. (2024) [62] reported variations in the efficiency of different eutectic mixtures for flavonoid extraction. Once the optimal eutectic solvent was identified, subsequent research was conducted to determine the most effective and suitable methodology for extracting flavonoids from lemon peel. The most promising results emerged from the use of choline-based NaDESs, specifically ChCl/acetic acid (ChCL/AA). This system exhibited the highest performance compared to other eutectic mixtures, yielding approximately 5.60 mg hesperidin/g biomass and 0.30 mg narirutin/g biomass. The optimization of the operational parameters included ultrasound power of 320 W (UAE-probe), extraction time of 6 min, water content of 40%, total static time of 40 min, and solid-to-feed ratio of 30 (v/m). The ChCl/AA eutectic mixture exhibited the highest extraction efficiency, making it a promising option depending on the intended application, while also providing enhanced thermal stability of the extracted flavonoids.

3.1.3. Anthocyanins

Anthocyanins are water-soluble flavonoid compounds responsible for the red to purple coloration in various plant sources. They are widely used as natural colorants in the food, cosmetic, and pharmaceutical industries. In addition to their coloring properties, they offer numerous health benefits due to their antioxidant, anti-inflammatory, antidiabetic, neuroprotective, and anticancer effects, among others [99]. However, their recovery is often limited by their low stability and sensitivity to light, temperature, and pH. The application of DESs or NaDESs has been shown to significantly improve both the yield and stability of anthocyanins extracted from agro-industrial residues [98,100,101]. Table 3 presents studies on the recovery of anthocyanins from agro-industrial by-products using NaDESs as extraction solvents.
Benvenutti et al. [27] investigated the extraction of anthocyanins from Brazilian berry processing residues using DESs and pressurized liquid extraction (PLE). The extraction was carried out at 10 MPa for 12 min under optimized conditions using response surface methodology, with a 47% DES concentration at 90 °C and a flow rate of 5.3 mL/min. Compared with conventional solvents (water or acidified water), DESs achieved anthocyanin yields up to 50% higher. Notably, the ChCl/malic acid (1:1) system demonstrated the highest anthocyanin stability (E1a = 77.5 kJ/mol), making it a promising solvent for color retention and potential antidiabetic and antiobesity benefits [27].
In a related study, anthocyanins were recovered from black raspberry (Rubus occidentalis L.) pomace by employing a series of choline chloride-based NaDESs combined with different hydrogen bond acceptors. The extraction performance was compared with conventional solvents and further evaluated in the presence of hydroxypropyl-β-cyclodextrin (HP-β-CD). The impact of NaDESs on the anthocyanin storage stability at 4, 25, and 40 °C was also examined. The choline chloride/citric acid NaDES proved to be the most appropriate solvent for the extraction of black raspberry pomace anthocyanins, subsequently optimized through response surface methodology based on the Box–Behnken design and response surface methodology at 52.9 min., 65 °C, and 15.6% (w/w) water in a NaDES. Under these conditions, the yields of cyanidin-3-O-rutinoside and the total anthocyanin content reached 7.60 mg/g DW and 6.88 mg CGE/g DW, respectively [105].
Recently, Frontini et al. [20] applied NaDESs to valorize grape pomaces from different vinification processes. Τhree binary ChCl-based NaDESs combined with lactic acid (DES-Lac), tartaric acid (DES-Tar), and glycerol (DES-gly) were tested against ethanol. All NaDESs produced a substantially higher total phenolic yield than ethanol (up to 127.8 mg/g DW from Primitivo rosé grape pomace). DES-Lac and DES-Tar were more effective for anthocyanin extraction, with malvidin 3-O-glucoside being the most abundant compound, achieving its highest extraction yield (29.4 mg/g DW) with DES-Lac from Susumaniello pomace [20].

3.1.4. Carotenoids

Carotenoids are naturally occurring pigments, responsible for the yellow, orange, and red coloration in fruits, vegetables, and other plants. Carotenoids are subdivided into two types—carotenes, which consist only of hydrocarbons (e.g., carotenes and lycopene), and xanthophylls (e.g., lutein, zeaxanthin, and astaxanthin), which contain one or more oxygen atoms [106]. Beyond their role as natural colorants, they possess well-documented antioxidant properties. Carotenoids have been associated with health benefits such as promoting eye health, supporting the immune system, and potentially reducing the risk of chronic diseases such as cancer and cardiovascular disease. Among the most studied are beta-carotene, lutein, and zeaxanthin, which are widely used in the food, cosmetic, and pharmaceutical industries due to their dual bioactive and coloring properties [56,100,104].
A major challenge in the processing of carotenoids is their sensitivity to environmental factors such as heat, light, and oxygen, which may cause their degradation. In this context, DESs are an attractive alternative to conventional solvents, not only due to their greener profile but also because of their ability to allow for higher recovery efficiency and improved stability during storage [100,107]. Table 4 summarizes studies demonstrating the potential of DESs for carotenoid recovery from agro-industrial waste.
Vlachoudi et al. [108] investigated tomato industry waste using nine different hydrophobic DES (HDES) systems based on menthol and fatty acids. A menthol/hexanoic acid mixture (2:1) achieved the highest yield (94.5 ± 3.3 mg CtE/g dm). Similarly, Lazzarini et al. [56] explored tomato pomace valorization and found that a mixture of ethyl acetate and ethyl lactate combined with non-thermal air-drying achieved the highest recovery rates of lycopene and β-carotene (0.75 and 3.95 mg/g of dried sample, respectively). Hydrophobic NaDESs have also been applied to persimmon peels. The use of thymol/menthol (2:1) with ultrasound-assisted extraction (UAE) resulted in comparable results to conventional methods in terms of carotenoid yields but with enhanced antioxidant capacity [111]. Additionally, Viñas-Ospino et al. [74] compared hydrophilic and hydrophobic NaDESs for carotenoid recovery from orange peels. The results showed that the highest total carotenoid levels were achieved with hydrophobic DESs, specifically DL-menthol/camphor (1.64 ± 0.01 mg/g fw), DL-menthol/eucalyptol (1.69 ± 0.02 mg/g fw), and lauric acid/octanoic acid (1.53 ± 0.07 mg/gfw) [74].

3.2. Proteins

Proteins are essential biomolecules composed of amino acids, and their extraction from agro-industrial by-products has recently been explored using DESs as greener alternatives to conventional methods. Table 5 presents studies investigating protein recovery from agro-industrial by-products using NaDESs.
Karabulut et al. [112] investigated the recovery of fungi-based protein from mushroom stem waste using DESs composed of ChCl as HBA and glycerol (G) or lactic acid (LA) as HBD. Under optimized parameters using UAE, the extract obtained through alkaline extraction (A9) had the highest protein content (45.90%) and yield (12.21%). However, DESs demonstrated higher protein recovery rates relative to the initial content, at 22.04% for DES-ChCl/Glycerol and 21.47% for DES-ChCl/Lactic acid compared to 15.39% for A9 [112]. Similarly, Roy et al. [113] employed DESs to valorize brewery spent grain (BSG), a protein-rich by-product. Six DESs based on ChCl and different HBDs were tested for their ability to extract vegetable protein via the pretreatment of BSG with subcritical water hydrolysis (SWH). The protein extraction rates ranged from 167.61 ± 0.70 to 228.08 ± 5.52 mg BSA/g BSG, with the ChCl/tartaric acid (1:2) DES achieving the highest efficiency [113]. Hernández-Corroto et al. [114] investigated both BSG and malt rootlets (MR), using fourteen DESs (pH 1.3–10.2) combined with pressurized liquid extraction (PLE) and high-intensity focused ultrasound (HIFU). The guanidinium chloride/urea DES (1:2, pH 9.1) achieved the highest protein yield for both residues, recovering 0.13 ± 0.02 mg/g from BSG and 0.10 ± 0.06 mg/g from MR. Optimization of the extraction parameters via a Box–Behnken experimental design revealed that longer extraction times, higher ultrasound amplitudes, and lower residue amounts promoted protein extraction [114].

3.3. Polysaccharides

NaDESs have the potential to act as efficient green co-solvents for the extraction of polysaccharides from agro-industrial waste. These compounds, such as pectin, cellulose, starch, hemicellulose, carrageenan, fucoidan, chitosan, and alginate, are structurally diverse, consisting of monomeric sugar units connected by different types of glycosidic bonds (e.g., α-1,4 or β-1,4) and further stabilized by hydrogen bonds and van der Waals forces. Pectin, in particular, a water-soluble carbohydrate found in plant cell walls consisting of D-galacturonic acid units linked by α-(1,4)-glycosidic bonds, has attracted attention due to its abundance in fruit processing residues and its applications in the food industry as a gelling agent, thickener, and stabilizer [116].
Several recent studies have explored the role of NaDESs in pectin extraction (Table 6).
Pectin was extracted from orange peels using ChCl/formic acid (1:2, 8% v/v) under both conventional maceration and microwave-assisted DES (MW-DES) conditions. Although maceration yielded a slightly higher recovery rate (46%) compared to MW-DES (40%), the latter reduced the extraction time by 75% (15 min at 360 W) compared to the maceration method. Interestingly, while both approaches produced high-methoxyl pectins, the MW-DES pectin exhibited better water retention capacity and higher viscosity compared to maceration–DES pectin [22]. Similarly, Benvenutti et al. [26] investigated the extraction of pectin from Brazilian berry by-products employing subcritical water extraction (SWE) with DES modification. Using a Box–Behnken factorial approach, the authors optimized the conditions using the response surface methodology (RSM) at 122 °C, with 8% DES and a flow rate of 2 mL/min. The SWE-DES method resulted in yields that were 1.5–1.8 times higher than conventional extraction, while also enhancing the galacturonic acid content, antioxidant activity, and emulsion stability [26].

4. NADES-Based Extracts in the Management of Diabetes Mellitus (DM)

Diabetes mellitus (DM) is a serious public health issue, and according to the International Diabetes Federation, it is one of the fastest-growing global health crises of the 21st century. DM is a group of metabolic disorders of carbohydrate metabolism in which glucose is both underutilized as an energy source and overproduced, resulting in hyperglycemia. Chronic hyperglycemia in DM is associated with dysfunction and damage to multiple vital organs, elevating the risk of cardiovascular disease, neuropathy, nephropathy, retinopathy, blindness, and even premature mortality [122,123]. The global prevalence of type 2 diabetes mellitus (T2DM) has increased dramatically in recent decades across all age groups, affecting over 462 million individuals worldwide (6.28% of the global population), with the prevalence projected to rise by 2030 [124]. The economic burden associated with T2DM management has increased considerably, posing a substantial challenge to healthcare systems. Therefore, the development of nutritional strategies that may contribute to T2DM prevention and management and promote population health has become imperative. Within this framework, recent research attention has focused on the functional properties of bioactive compounds.
Plants are rich sources of secondary metabolites with demonstrated hypoglycemic activity, including polyphenols, alkaloids, flavonoids, tannins, and terpenoids [125]. These compounds may influence glycemic control through multiple mechanisms. Alkaloids may suppress alpha-glucosidase activity and reduce glucose transport across the intestinal epithelium. Flavonoids, on the other hand, can enhance insulin release from pancreatic islets and improve hepatic glucose metabolism [126]. Similarly, terpenoids and steroidal glycosides have been reported to stimulate insulin release and inhibit hepatic glucose production [127]. In addition to glycemic control, many phytochemicals also exhibit antioxidant properties that protect from oxidative stress, which plays a role in both the initiation and progression of diabetes. However, their low solubility, stability, and bioavailability limit their application when these bioactives are extracted with conventional solvents [125]. Unlike traditional organic solvents, NaDESs can dissolve both hydrophilic and lipophilic compounds, significantly improving their solubility, stability, and bioavailability [128]. This property is particularly important for bioactive compounds with low solubility, such as quercetin, catechins, and curcumin [48,129]. Moreover, NaDESs provide a protective environment that stabilizes compounds sensitive to heat, light or oxygen, enabling them to preserve their biological activity. Consequently, the use of NaDESs may constitute a promising approach for obtaining bioactive-rich extracts with enhanced stability and bioactivity that target T2DM [19,130]. Table 7 presents plant extracts obtained using DESs with antidiabetic activities.
NaDES-derived extracts have demonstrated inhibitory activity toward the carbohydrate-hydrolyzing enzymes α-amylase and α-glucosidase [29,142,143]. This potential was supported in the study by Zengin et al. [132], who investigated Cytinus hypocistis extracts obtained using a ChCl/urea (1:2) NaDES compared to conventional extracts. The authors reported that the NaDES extracts exhibited stronger inhibitory effects on both a-amylase and a-glucosidase activity compared to extracts obtained with conventional solvents [132]. Similarly, Tebbi et al. [126] demonstrated that Pistacia lentiscus L. black fruits extracts in a choline chloride/acetic acid (1:2) NaDES exhibited stronger antioxidant and α-amylase inhibitory activity relative to Clematis flammula L. leaf extracts [126]. Moreover, extracts from seaweed, such as Hypnea flagelliformis, obtained using a ChCl/lactic acid (1:2) NaDES, exhibited higher antioxidant activity and more significant inhibitory activity against α-amylase and α-glucosidase enzymes compared to extracts obtained with conventional solvents (water, 80% ethanol, and 80% methanol) [135]. NaDES extraction has proven effective in recovering bioactive compounds from date (Phoenix dactylifera L.) seeds and fruits with antidiabetic potential. Subhash et al. [136] extracted date seed polysaccharides using NaDES ultrasound-assisted extraction. The extract, rich in galactose, mannose, fructose, glucose, and galacturonic acid, exhibited strong α-glucosidase and α-amylase inhibition (up to 86%), and also displayed antioxidant and antimicrobial activities and favored beneficial gut microbiota growth [136]. Similarly, Djaoudene et al. [137] investigated the extraction of phytochemicals from Algerian date fruit cultivars using a lactic acid/sucrose-based NaDES with the ultrasound-assisted extraction method. The fruits of the Ourous cultivar displayed the highest contents of phenolics, flavonoids, proanthocyanidins, and triterpenoids and exhibited the best inhibitory activity against α-amylase (up to 45%) [137]. Further supporting these observations, walnut green husk extracts obtained using ChCl/ethylene glycol (1:1) have been reported to exhibit multiple activities including α-amylase and α-glucosidase inhibition, antiglycation properties, and antioxidant activity [142]. Ahmad et al. [140] investigated cinnamon bark and sappan wood for their antidiabetic potential using a ChCl/glycerol NaDES for the extraction. The study showed that sappan wood exhibited strong DPP-IV inhibition (1254 μg/mL), primarily due to brazilin, a result confirmed by molecular docking. On the contrary, none of the marker substances chosen for cinnamon bark were found to have significant DPP IV-inhibitory activity [140].
Recent studies published in 2025 have reported potential antidiabetic properties in extracts obtained from quinoa (Chenopodium quinoa Willd.) leaves [143,144], Morchella ssp. [145], Wedelia chinensis [133], and Curcuma longa [142]. However, many of these studies emphasize the need for further research to confirm the antidiabetic potential of NaDES-derived extracts [143,144].
Furthermore, several studies have demonstrated that NADES-extracted compounds may exhibit antidiabetic activity, addressing the underlying validated mechanisms. For example, quercetin extracted recently from various plant sources with the use of NaDESs [146,147] is involved in glucose homeostasis through the inhibition of intestinal glucose absorption, insulin-sensitizing activity, improved glucose utilization in peripheral tissues [148], and activation of the 5′adenosine monophosphate-activated protein kinase (AMPK) pathway [95]. Similarly, genistein, extracted with NaDESs from soybeans, has shown antihyperglycemic effects through the promotion of cAMP/PKA signaling pathways and preservation of β cell functions [95]. Furthermore, proanthocyanidins, recently extracted from walnut green husk using ChCl/ethylene glycol NADESs, inhibited the activity of carbohydrate-metabolizing enzymes (α-amylase and α-glucosidase) [139], while other studies highlight their structure-dependent role in blood glucose homeostasis through other mechanisms that include the inhibition of monosaccharide transporters (such as SGLT1), the improvement of insulin secretion by increasing the number of β-cells in the pancreas, increases in glycogen synthesis in insulin-resistant hepatocytes, and the promotion of beneficial bacteria in the gut [149]. Chlorogenic acid, a NADES-extracted phenolic compound, demonstrated potent inhibitory potential against α-amylase and α-glucosidase, and this effect was further elucidated by in silico studies that showed possible binding of chlorogenic acid with the respective carbohydrate-metabolizing enzymes. Its antihyperglycemic activity was also observed in an animal model [150].
Overall, NaDES-based extraction offers a sustainable and efficient approach to harness the therapeutic potential of plant- and agro-industrial waste-derived bioactive compounds. NaDES can improve the solubility, stability, and bioavailability of these extracts, enabling the preservation of their antidiabetic potential. Nevertheless, most of the current evidence derives from in vitro studies. Therefore, further in vivo and well-designed clinical trials are essential to confirm these findings.

5. Mechanistic Perspectives on Bioactive Compound Extraction

Although the mechanisms involved in phytochemical extraction using NaDESs are not fully elucidated, the research interest is rapidly increasing. Current evidence suggests that NaDESs can enhance the solubility and transport of bioactive compounds through strong intermolecular interactions, including hydrogen bonding, dipole–dipole interactions, and van der Waals forces [1]. Wu et al. [151] described the NaDES-mediated extraction of phenolic compounds, reporting that intact cell structures are initially preserved in dry plant tissues; however, under ultrasound-assisted extraction, the strong penetration and erosive action of NaDESs disrupts the cell wall, exposing intracellular components. This disruption generates asymmetric collapsing jets that facilitate greater solvent penetration into the cell interior, thereby releasing intracellular phenolic compounds [151]. During ultrasonic propagation, alternating compression and rarefaction cycles lead to the formation of cavitation bubbles; their subsequent implosion alters the solvent properties and enhances mass transfer, ultimately increasing the extraction efficiency. Similarly, Zhou et al. [1], using scanning electron microscopy (SEM) and field emission SEM (FE-SEM), demonstrated that DESs significantly disrupt the cell structure of agri-food by-products. For instance, orange peel cells treated with ChCl-based DESs exhibited a higher degree of disintegration compared to untreated material, confirming their efficiency in dissolving plant cell wall structures [1].
Beyond physical disruption, several studies highlight the role of NaDESs in forming asymmetric molecular voids (cavities). These are created as HBD and HBA components of NaDESs through hydrogen bonding, van der Waals forces, and dipolar interactions, lead to rearrangements of the molecular lattice. Such voids formed in DESs can act as tiny “cavities” that transiently accommodate phytochemical molecules, stabilizing them via hydrogen bonds and other intermolecular interactions. Studies using molecular dynamics (MD) simulations and density functional theory (DFT) support this view, showing that small phytochemicals can be temporarily encapsulated within NaDES cavities (Figure 1).
This explains their increased solubility and improved stability in NaDES-based extracts. Unlike crystalline inclusion complexes, this encapsulation is not permanent, yet it is sufficient to enhance their solubility, bioavailability, and bioactivity in vitro. The stabilizing role of NaDESs was confirmed by Zhou et al. [1], who demonstrated that a ChCl/glycerol NaDES stabilized catechins through hydrogen bond formation, improving their thermal and storage stability. This stabilization mechanism is further supported by observations that specific NaDES formulations, such as those incorporating glycerol/glycine/water (7:1:3) with 9% (w/v) methyl-β-cyclodextrin (m-β-CD), can significantly reduce the oxidation of polyphenols, even at elevated temperatures, as compared to conventional solvents such as ethanol [152]. The precise composition of the NaDES, including the molar ratios of hydrogen bond acceptor and hydrogen bond donor components, along with the presence of water, can be fine-tuned to optimize these interactions and tailor the physicochemical properties for specific phytochemical stabilization [153]. Despite the recognized importance of such interactions, establishing a clear relationship between solvatochromic parameters of NaDESs and the solubility of specific natural products remains complex, suggesting the interplay of various forces rather than a simple correlation [152]. Furthermore, the ability of NaDESs to form a network of hydrogen bonds suggests they can induce conformational changes in dissolved compounds, potentially impacting their biological activity and stability. This liquid–crystalline structure of NaDESs, formed through hydrogen bonding networks, can effectively encapsulate and stabilize membrane-associated compounds such as flavonoids and anthocyanins, protecting them from oxidative damage within biological systems [154]. Moreover, NaDESs have been shown to maintain the stability of bioactive compounds, such as salvianolic acid B (SAB), even at room temperature after 60 days, outperforming traditional solvents such as methanol and ethanol. These stabilizing properties are particularly enhanced by the presence of hydroxyl or carboxyl groups in the NaDES components, which facilitate stronger hydrogen bonding with the target metabolites [152].
Faggian et al. [155] demonstrated that an amino acid-based NADES consisting of proline/glutamic acid improved the bioavailability of polyphenol rutin compared to the water suspension due to an increase in its solubility, thereby rendering rutin more available for absorption by the gastrointestinal tract [155]. In another study, Da Silva et al. [156] investigated in a rat model the bioavailability of a blueberry extract obtained using NADES. Interestingly, they observed that compared to an organic solvent extract, the NADES-based extract of blueberry showed increased bioavailability of anthocyanins. This effect was attributed to increased intestinal stability of phenolic compounds by delayed neutralization of gastric chyme in the presence of NADES [156].

6. Limitations and Challenges

Despite the great potential of NaDESs as green solvents for the extraction of bioactive compounds from agro-industrial by-products, several limitations must be addressed.
Toxicological aspects are a concern, since although many NaDESs consist of natural metabolites, generally recognized as safe, their combinations may exhibit different or even higher toxicity compared to the individual components. This is demonstrated in studies investigating cytotoxicity in cell lines such as MCF-7, RTG-2, HT-29, HCT-16, HeLa, and Ha-CaT, which report increased cytotoxicity for NaDES systems compared to their separate components [157]. Furthermore, Sanchez-Argüello & Martin-Esteban [158] observed that NaDESs containing organic acids were more toxic than those containing alcohols. Moreover, although NADESs in general seem to possess relatively less acute toxicity profiles than their DES parents [159], some in vivo and short-term oral studies have documented organ-level toxicity (notably hepatic effects) and even mortality at specific doses and formulations [160,161]. A major reason for the inconsistent conclusions is methodological heterogeneity (e.g., different component pairs, water content, viscosity, concentrations, assays). Taken together, these results highlight the need to adopt a standardized protocol to enable the comparison of the various parameters related to toxicity [162] and underline the necessity of comprehensive ecotoxicological assessments for the design of safe NaDES [158].
Physicochemical properties may also pose limitations. The high viscosity of many NaDESs reduces mass transfer, prolongs the extraction time, and often requires high-energy techniques such as ultrasound or microwaves to achieve efficient recovery. The addition of small amounts of water can reduce their viscosity and improve their performance but excessive dilution disrupts the intermolecular network between the solvent and the bioactive compounds, lowering their solubility and extraction efficiency [163].
Recovery presents another challenge, since separating NaDESs from their extracts is often difficult and may require costly purification methods. One proposed strategy is to design formulations in which NaDES can remain in the final product; however, this approach raises regulatory and food safety concerns.

7. Future Perspectives

Interestingly, NaDESs are increasingly being explored for their direct incorporation into food matrices. Panić et al. [164] employed NADES-based extracts from cocoa waste directly for chocolate milk fortification. They concluded that adding between 1% and 10% of these extracts was sensorily acceptable to consumers while significantly enhancing the antioxidant capacity of the product. Similarly, Salazar-Bermeo et al. [165] incorporated NaDES extracts derived from persimmon by-products into beverages, producing formulations high in fiber and phenolic content with improved functional properties. More recently, Gomez-Urios et al. [166] developed a novel orange juice with orange peel NaDES extracts. The findings of the study indicated that the integration of NaDES into orange juice enhanced the shelf-life and nutritional value of the product, without altering its organoleptic properties [166]. In addition to beverages and dairy systems, emerging studies have begun exploring the use of NaDES-based extracts in edible films and coatings, aiming for improved food preservation and extended shelf life [167,168].
At the same time, the NaDES research is advancing rapidly toward customized solvent design, with formulations tailored to selectively extract specific bioactive compounds. Various combinations of hydrogen bond donors (HBDs) and hydrogen bond acceptors (HBAs) can be engineered to selectively target compounds such as polyphenols, flavonoids, and carotenoids found in diverse agro-industrial by-products and food waste. This tailored approach not only boosts the extraction efficiency but also minimizes the degradation of sensitive bioactive compounds, thereby enhancing their potential application in functional foods. Future research studies may focus on broadening the array of NaDES formulations to better address the complex composition of food waste and to optimize their industrial performance.
Despite their promising potential, transitioning NaDES-based extraction processes ranging from laboratory-scale experiments to large-scale industrial applications presents significant challenges. Key issues include the availability and cost of NaDES components, the energy demands of large-scale extraction, and the development of effective solvent recovery systems. Moreover, robust protocols are needed to ensure that NaDESs consistently maintain their performance over repeated cycles of use and regeneration—an essential factor for achieving cost-effectiveness and environmental sustainability. Addressing these scalability challenges will require interdisciplinary collaboration, integrating advances in chemical engineering and industrial design to develop scalable and cost- efficient systems for NaDES applications.
Life cycle assessments (LCAs) are essential to quantify the environmental benefits of replacing traditional solvents with NaDESs during the extraction process. Metrics such as reductions in carbon footprint, decreased energy consumption, and minimized waste generation will provide valuable insights into the sustainability of this approach. Additionally, the long-term impacts of incorporating NaDES-extracted bioactive compounds into functional foods, particularly for diabetes management, remain a critical area for investigation. Comprehensive clinical studies are necessary to evaluate the efficacy, bioavailability, and safety of these compounds when consumed regularly. Long-term studies can also help identify any unforeseen consequences, such as bioaccumulation or interactions with other food components, ensuring that NaDES-based functional foods meet both health and environmental standards. By addressing these challenges, NaDESs could become innovative and environmentally sustainable tools for effective diabetes management.

8. Conclusions

This review highlights the valorization opportunities offered by various food by-products, as well as the advantages of using NaDESs as a sustainable approach. The surveyed literature demonstrates that NADESs represent viable alternatives for implementing the valorization process, and that extracts rich in polyphenols and other bioactive compounds may have valuable applications as functional food ingredients, nutraceuticals, or preservatives. However, the industrial application of these extracts still needs to be further explored. Furthermore, the valorization of such alternative extracts that exhibit antidiabetic activity is also emphasized in this review. Although NADESs have been used for extracting bioactive compounds from food by-products and their incorporation into foods with the aims of (a) developing high-value-added foods and (b) improving their nutritional value and health-promoting properties, their application in commercially available foods that may exhibit antidiabetic activity is still in its early stages, with only a few publications addressing this aspect in vitro. The NaDES research is advancing rapidly and pilot-scale applications are emerging. With progress being made in safety evaluations, regulatory pathways, and recovery–reuse strategies, food-grade commercial applications are plausible.

Author Contributions

Conceptualization, K.A. and M.B.; validation, M.B. and S.M.K.; investigation and analysis, M.B., S.M.K., O.M., A.G. and A.C.S.; writing—original draft preparation, K.A., M.B. and S.M.K.; writing—review and editing, K.A., M.B., S.M.K., O.M., A.G., A.C.S. and G.I.P.; supervision, K.A. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Data Availability Statement

All data and analysis are available within the manuscript or upon request to the corresponding author.

Conflicts of Interest

The authors declare no conflicts of interest.

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Applsci 15 11596 g001
Figure 1. Mechanisms of phytochemical extraction with NaDESs and potential antidiabetic activity.
Figure 1. Mechanisms of phytochemical extraction with NaDESs and potential antidiabetic activity.
Applsci 15 11596 g001
Table 1. Selected examples of polyphenol recovery from agro-industrial by-products using NaDESs.
Table 1. Selected examples of polyphenol recovery from agro-industrial by-products using NaDESs.
Source/
By-Product		Bioactive CompoundDES
(Molar Ratio;
Water Content)		Extraction MethodYields mg GAE g−1YearRef.
broccoli leaf wastephenolic compoundsChCl/1,2-propylene glycerol (1:2)Ultrasound-assisted extractionTPC: 4.912023[67]
broccoli stemspolyphenols
trans-cinnamic acid (88.8%), sinapinic acid (5.32%), quercetin (3.06%), isochlorogenic acid (2.88%)		ChCl/urea (1:3; 60%)conventional heating5.10 ± 0.042025[68]
kale wastepolyphenolsBetaine/glycerol (1:3)conventional heatingTPC: 16.802023[69]
Psidium myrtoides
purple araçá		phenolic compoundsChCl/glycerol (1:2)ultrasound
-assisted extraction		59.29 ± 4.802024[70]
apple pomacepolyphenol compounds, quercetin, chlorogenic acid, gallic acid, phloretin, phloridizin, rutin, procyanidinChCl/glycerol (1:3)ultrasound
-assisted extraction		5.802023[71]
Betaine/urea (1:1)5.245 ± 0.1242024[72]
Betaine/malic Acid (1:1)5.157 ± 0.164
orange peelspolyphenolsChCl/malic acid (1:1)solid–liquid extraction and
hot solvent extraction		10.53
AA = 4.30		2022[73]
Proline/malic acid (1:1)conventional heating2.83 ± 0.072023[74]
lactic acid/glucose
citrus
pomace		naringin, narirutin, hesperidin, ellagic acid, naringenin, hesperitin, diosmetin, gallic acidBetaine/lactic acid (1:1)conventional heating6.15 ± 0.032022[75]
ChCl/glycerol (1:2)5.45 ± 0.02
citrus peel wasteneohesperidinChCl/glucose (1:1)ultrasound-assisted extraction10.45 ± 0.012024[76]
mango peel wastepolyphenolslactic acid/glucose (5:1, 20%)Ultrasound-assisted extraction69.852022[57]
mango by-productspolyphenols, mangiferinChCl/ethylene glycol (1:2)conventional extraction and ultrasound-assisted extraction60.01 ± 1.402023[77]
ChCl/glycerol
β-alanine/DL-malic acid: H2O (1:1:3)50.61 ± 2.51
β-alanine/DL-malic acid: H2O (1:1:3)
spirulinaphenolic compounds, caffeic acid, chlorogenic acid, salicylic acid, quinic acid, gallic acid, catechinBetaine/glucose (1:2, 30%)Freezing–thawing cycle extraction11.77 ± 0.122025[78]
Corylus avellana L. by productsD-(−)-quinic acid, gallic acid, protocatechuic acid, hydroxybenzoic acid, catechin, caffeic acid, vanillic acid, epicatechin gallate, ferulic acid, sinapic acid; 16: rutin, quercetin-3-O-glucoside, salicylic acid, quercetin-3-O-rhamnoside, quercetinChCl/1,2-propylene glycol (1:4)Microwave-assisted extraction5.602022[79]
Crocus sativus L. floral by-productspolyphenolsL-proline/glycerol (1:2)Ultrasound-assisted extraction35.15 ± 1.992023[80]
olive oil industry by-productshydroxytyrosolcitric acid/glycine:H2O (2:1:1)Ultrasound-assisted extraction-2020[81]
phenolic compounds oleuropeinChCl/acetic acid (1:2)solid–liquid equilibrium0.472021[82]
ChCl/malic acid (1:1)
ChCl/malonic acid (1:1)
olive pomacephenolic compoundsChCl/malonic acid (1:1)conventional extraction19.802022[83]
olive mill wastephenolic compoundscitric acid/fructose (1:1)conventional extraction3.992023[84]
coffee huskphenolic compoundsChCl/citric acid (1:1)conventional extraction5.882023[85]
ChCl/proline (1:1)
spent coffee groundsphenolic compounds, caffeineBetaine/glycerol (1:3)Ultrasound-assisted extraction, microwave-assisted extraction22.672023[86]
phenolic compoundsBetaine/triethylene glycol (1:2, 30–60%)conventional heating1.27 ± 0.132024[87]
gallic acid,
3-O-caffeoylquinic acid,
caffeic acid		ChCl/1,2-propanediol (1:2)agitation-assisted water138.5 ± 1.09
131.34 5 ± 0.75
63.17 ± 0.53		2023[88]
Wine-making by-productsCatechins,
tannins		ChCl/urea (1:2)subcritical water extraction118.77 ± 5.83
14.24 ± 0.86		2020[89]
grape pomacephenolic compoundsChCl/lactic acid (1:1, 50%)Solid–liquid extraction 2024[20]
ChCl/tartaric acid (1:1, 50%)127.8
ChCl/glycerol (1:1, 50%)
Graševina grape pomaceEpigallocatechin,
Catechin,
Epicatechin,
gallic acid		Betaine/glucose (1:1)Ultrasound-assisted extraction0.24 ± 0.01
0.74 ± 0.006
0.75 ± 0.005
0.55 ± 0.008		2024[21]
Table 2. Examples of flavonoid recovery from agro-industrial by-products using NaDESs.
Table 2. Examples of flavonoid recovery from agro-industrial by-products using NaDESs.
Source/
By-Product		Bioactive CompoundDES
(Molar Ratio;
Water Content)		Extraction MethodYields mg g−1YearRef.
orange peelsflavonoidsChCl/Malic Acid (1:1)SLE/HSETFC = 0.95 2022[78]
lemon peel wastehesperidin, narirutinChCl/Acetic Acid (1:2)ultrasound-assisted extraction5.60 2024[64]
Magnifera indica L.
by-products		flavonoidsChCl/Ethylene Glycolconventional extraction and ultrasound-assisted extraction7.60 ± 0.72 2023[80]
ChCl/Glycerol
β-alanine/D-Malic acid/H2O (1:1:3)
Arachis hypogaea L.
hulls		flavonoidsL-proline/acetic acid (1:4)ultrasound-assisted extraction2.51 2024[97]
peanut shellsluteolinChCl/ethylene glycol (1:2, 1:3, 1:4)microwave-assisted extraction2.90 ± 0.02 2025[23]
Crocus sativus
floral by-products		flavonols: kaempferol, quercetin, myricetin, and isorhamnetin glycosides L-proline/glycerol (1:2)ultrasound-assisted extraction8.04 ± 0.492023[83]
Camellia sinensis wasteepigallocatechin gallate (EGCG), epicatechin gallate (ECG)citric acid/polypropylene glycol (1:1)microwave-assisted extraction(EGCG, 15.58), (ECG, 12.85)2025[98]
spent tea leavesflavonoidsacetic acid/glycerol (2:1, 20%)ultrasound-assisted extraction20.42024[24]
spend coffee grounds flavonoidsbetaine/glycerol (1:3)ultrasound-assisted extraction, microwave-assisted extraction24.052023[89]
Table 3. Selected examples of anthocyanin recovery from agro-industrial by-products using NaDESs.
Table 3. Selected examples of anthocyanin recovery from agro-industrial by-products using NaDESs.
Source/
By-Product		Bioactive CompoundDES
(Molar Ratio;
Water Content)		Extraction MethodYields YearRef.
Myrciaria cauliflora
by-product		cyanidin-3-glucoside ChCl/malic acid (1:1)pressurized liquid extraction1.60 ± 0.09 mgCGE g−1 DW2022[27]
ChCl/propylene glycol (1:2)1.7 ± 0.06 mgCGE g−1 DW
Rubus occidentalis L.
pomace		cyanidin-3-Orutinosidecitric acid/H2O (1:1:3)ultrasound-assisted extraction7.60 mg g−1 DW and TAC 6.88 mg CGE g−1 DW2025[102]
Cichorium intybus
by-products		cyanidin-3-glucoside citric acid/ChCl (3:2,
25%) 		ultrasound-assisted extraction11.35 ± 0.06 mg CGE g−1 DW2025[103]
Primitivo
pomace		delphinidin 3-O-glucoside, cyanidin 3-O-glucoside, petunidin 3-O-glucosideChCl/lactic acid (1:1)
ChCl/tartaric acid (1:1)
ChCl/gycerol (1:1)		liquid–liquid extraction with 2-MeTHF>80%2025[104]
Table 4. Selected examples of carotenoid recovery from agro-industrial by-products using NaDESs.
Table 4. Selected examples of carotenoid recovery from agro-industrial by-products using NaDESs.
Source/
By-Product		Bioactive CompoundDES
(Molar Ratio;
Water Content)		Extraction MethodYields mg g−1YearRef.
tomato industry wastecarotenoidsmenthol/hexanoic acid (2:1)solid–liquid extraction94.5 2023[108]
tomato pomacelycopene, β-caroteneethyl acetate/ethyl lactateultrasound-assisted extraction lycopene = 0.07
β-carotene = 3.95		2022[56]
tomato skin wastelycopenethymol/menthol (1:1)ultrasound-assisted extraction358.7 ± 1.2 2024[109]
tomato processing by-productslycopeneChCL/lactic acid (1:2)ultrasound-assisted extraction 2024[110]
persimmon peelscarotenoidsthymol/menthol (2:1)ultrasound-assisted extraction3.12 ± 0.042025[111]
orange peelscarotenoidsDL-menthol/camphor (1:1)conventional extraction1.64 2023[74]
DL-menthol/eucalyptol (1:1)1.69
lauric acid/octanoic acid (1:3)1.53
Proline/malic acid (1:1)2.83
Table 5. Selected examples of protein recovery from agro-industrial by-products using NaDESs.
Table 5. Selected examples of protein recovery from agro-industrial by-products using NaDESs.
Source/
By-Product		Bioactive CompoundDES
(Molar Ratio;
Water Content)		Extraction MethodTotal Protein mg g−1YearRef.
mushroom agro-waste fungi-based proteinChCl/glycerol (1:2)ultrasound-assisted extraction22.04 ± 1.90
21.47 ± 1.05		2024[112]
ChCl/lactic acid (1:2)
brewery spent grainleucine, isoleucine, phenylalanine, and histidineChCl/tartaric acid (1:2)subcritical water hydrolysis-2024[113]
brewing wastesProteinGuanidium/chloride (1:2)high-intensity focused ultrasound0.13 ± 0.02 2023[114]
brewer’s spent grainProteinChCl/trehalose (3:1)conventional extraction 42 ± 0.72025[115]
olive pomaceProteinChCl/malonic acid (1:1)conventional extraction6.67 ± 0.312022[83]
Table 6. Selected examples of polysaccharide recovery from agro-industrial by-products using NaDESs.
Table 6. Selected examples of polysaccharide recovery from agro-industrial by-products using NaDESs.
Source/
By-Product		Bioactive CompoundDES
(Molar Ratio;
Water Content)		Extraction MethodYield mg g−1/%YearRef.
orange peelspectinChCl/formic acid (1:2)microwave-assisted extraction 40.00 ± 0.32024[22]
Brazilian berry by-productpectincitric acid/glucose/H2O (1:2:3)subcritical water extraction 15.9 ± 0.62022[26]
onion peel wastepectinChCl/tartaric acid (1:50)ultrasound-assisted extraction and microwave-assisted extraction36 ± 0.852024[117]
mango peelspectinBetaine/citric acid (2:1)
ChCl/malic acid (1:2)		conventional extraction36.76 ± 6.23
38.72 ± 5.61		2022[118]
mango peel wastespectinProline/malonic Acid (1:1)
ChCl/tartaric acid (1:1)		microwave-assisted extraction 88.8 ± 0 21
90.82 ± 0 11		2024[119]
Malus Domestica
(pulp and peel)		pectincitric acid/glucose/H2O (1:1:3)
lactic acid/glucose/H2O (5:1:3)		conventional extraction13–18 2025[120]
jackfruit wastepectinChCl/maleic acid (1:1)microwave-assisted extraction 33.182025[121]
Table 7. Plant extracts obtained using NADESs and their reported antidiabetic activity.
Table 7. Plant extracts obtained using NADESs and their reported antidiabetic activity.
Plant Source/
By-Product		DES
(Molar Ratio;
Water Content)		Bioactive
Compounds		Biological
Activity		Type of StudyRef.
Glycine maxcholine chloride/lactic acid (1:1)genisteindocking studies alphaglucosidase PBD ID: 5nn8 and SGLT-2 inhibitor PDB ID: 7vsiin silico[131]
Cytinus hypocistis L.choline chloride/urea (1:2)total phenolicsα-glucosidase (2.20 mmol ACAE/g)in vitro[132]
total flavonoidsα-amylase (2.54 mmol ACAE/g)
Wedelia chinensis leavescitric acid/argininetotal phenolicsα-amylase (IC50: 0.4 ± 0.1 mg/mL) and α-glucosidasein vitro
in silico		[133]
total flavonoids
Clematis flammula L. leaves
Pistacia lentiscus L. black fruits		choline chloride/acetic acid (1:2)antioxidants TBARS assay (72.80 ± 9.67%)α -amylase
(64.03 ± 1.21%)		in vitro[126]
choline chloride/acetic acid (1:2)antioxidants
TBARS assay
(81.32 ± 1.27%)		α-amylase
(44.08 ± 2.61%)
Geum japonicum Thunb. var. chinenseL-proline/lactic acid (1:2)total tanninsα-glucosidase (IC50: 1.401–4.801 μg/mL)in vitro
Caco-2 model system
in vivo (animal)		[134]
Hypnea flagelliformischoline chloride/lactic acid (1:2)total phenol contentα-amylase IC50 (1.21 ± 0.03 mg/mL)in vitro[135]
α -glucosidase IC50 (0.94 ± 0.04 mg/mL)
Phoenix dactylifera L.
seed		choline chloride/ethylene glycol (1:1)polysaccharidesα-amylase (1000 μg/mL, 82%)in vitro[136]
α-glycosidase (1000 μg/mL, 86%)
Phoenix dactylifera L. fruit lactic acid/sucrose (3:1)total phenolics (1.29 mg GAE/g)α-amylase (IC50: 45%)
acetylcholinesterase (IC50: 37%)		in vitro[137]
total flavonoids (53.8 mg QE/100 g)
proanthocyanidins (179.5 mg CE/g)
total triterpenoids (12.88 mg OAE/100 g)
Psidium myrtoides
by-product		choline chloride/glycerol (1:2)phenolic compoundsα-amylase (12.00 ± 0.62%)in vitro[70]
α-glycosidase (17.17 ± 1.75%)
Strychnos potatorum L. seedglycerol/sodium acetate (3:1)total phenolic contentα-amylase (46.95%)in vitro[138]
total flavonoid content
walnut green huskcholine chloride/ethylene glycol (1:1)proanthocyanidin (56.34 mg/g)
antioxidant activity		α-amylase (3.91 μg/mL, IC50: 60%)in vitro[139]
α-glucosidase (125 μg/mL, IC50: 75%)
anti-glycation capacity (IC50: 86.49 μg/mL)
Cinnamomum burmannii
Caesalpinia sappan		choline chloride/glycerol (2:1)trans-cinnamaldehyde, coumarin, and trans-cinnamic aciddipeptidyl peptidase IV, DPP IV (205.0 g/mL)
dipeptidyl peptidase IV, DPP IV (1254.0 g/mL)		in vitro
in silico		[140]
Zingiber officinale var. Rubrumcitric acid/sucrose (1:1)
NADES1		total phenolic content in vitro[141]
sucrose:glucose/fructose (1:1:1) NADES2total flavonoid contentα-amylase (19.62 ± 0.20 µg/mL) from NADES1
choline chloride/glycerol (1:2) NADES3α-glucosidase (IC50: 57.36 ± 6.08 µg/mL) from NADES1
Glycerol/urea (1:1) NADES4antioxidants (DPPH and FRAP methods)
Curcuma longa L.ChCl/lactic acid/water (1:2:5)total phenolic content
antioxidants (DPPH and ABTS methods)		α-amylase (90.0%)in vitro[142]
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MDPI and ACS Style

Bairaktari, M.; Konstantopoulou, S.M.; Malisova, O.; Gioxari, A.; Stratakos, A.C.; Panoutsopoulos, G.I.; Argyri, K. Natural Deep Eutectic Solvents for Agro-Industrial By-Product Valorization: Emerging Strategies for the Development of Functional Foods Targeting Diabetes. Appl. Sci. 2025, 15, 11596. https://doi.org/10.3390/app152111596

AMA Style

Bairaktari M, Konstantopoulou SM, Malisova O, Gioxari A, Stratakos AC, Panoutsopoulos GI, Argyri K. Natural Deep Eutectic Solvents for Agro-Industrial By-Product Valorization: Emerging Strategies for the Development of Functional Foods Targeting Diabetes. Applied Sciences. 2025; 15(21):11596. https://doi.org/10.3390/app152111596

Chicago/Turabian Style

Bairaktari, Maria, Stavroula Maria Konstantopoulou, Olga Malisova, Aristea Gioxari, Alexandros Ch. Stratakos, Georgios I. Panoutsopoulos, and Konstantina Argyri. 2025. "Natural Deep Eutectic Solvents for Agro-Industrial By-Product Valorization: Emerging Strategies for the Development of Functional Foods Targeting Diabetes" Applied Sciences 15, no. 21: 11596. https://doi.org/10.3390/app152111596

APA Style

Bairaktari, M., Konstantopoulou, S. M., Malisova, O., Gioxari, A., Stratakos, A. C., Panoutsopoulos, G. I., & Argyri, K. (2025). Natural Deep Eutectic Solvents for Agro-Industrial By-Product Valorization: Emerging Strategies for the Development of Functional Foods Targeting Diabetes. Applied Sciences, 15(21), 11596. https://doi.org/10.3390/app152111596

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