1. Introduction
Since functional foods are very rich in health-promoting bioactive compounds, particularly antioxidants that actively participate in modulating disease development by inhibiting ROS-mediated reactions in the body, they may help control diseases such as cancer, coronary heart disease, and diabetes
[1][2]. Increasing clinical evidence shows that the regular consumption of foods that affect glycaemic control
[3], blood pressure regulation
[4], activation of antioxidant enzymes
[5], and gut microbiota
[6] and suppress the excessive production of pro-inflammatory cytokines during diabetes
[7] can prevent or delay T2D and its associated complications in high-risk individuals
[8]. The use of functional foods as complementary therapy for disease prevention and management has progressively increased over the past few decades, as a strategy to enhance health and psychological well-being. Additionally, this approach has increasingly been adopted by patients aiming to alleviate the adverse effects of traditional medicine and manage the symptoms associated with chronic illnesses
[9].
Fruits and vegetables are crucial components of a healthy diet, since they have a low-calorie density and help provide nutrients like vitamins, minerals, dietary fibre, and bioactive substances. They possess attractive colours and flavours and are very hydrating and filling. Their consumption can help replace diets high in salt, sugar, or saturated fats, prevent chronic NCDs like heart disease, cancer, diabetes, and obesity, and address micronutrient deficiencies. At all ages, they promote bodily functioning, development, and physical, mental, and social well-being. In addition to reducing the risk of NCDs
[10][11], they can prevent various forms of malnutrition including undernutrition, micronutrient deficiencies, overweightness, and obesity. Along with malnutrition, unhealthy diets are among the top ten global risk factors for disease
[12][13].
Li et al. found that an increase in the consumption of fruits and green leafy vegetables, according to previous studies, is linked to a reduced risk of developing T2D
[14]. According to Anderson et al., fruits and vegetables have a preventive impact on diabetes because of antioxidants such as polyphenols
[15]. The majority of secondary metabolites in plants are phenolic compounds, which are a diverse category of substances that includes simple flavonoids, phenolic acids, complex flavonoids, and coloured anthocyanins
[16][17]. According to Survay et al., fruits and vegetables have a hypoglycaemic effect that is attributed to their insulin-like activity
[18]. Jayaprakasam et al. and Wedick et al. suggest that this activity may also be due to the increase of insulin secretion by bioactive compounds—anthocyanins and anthocyanidins (insulin secretagogues)
[19][20]. The phenolic antioxidants found in berries, in particular, have a significant potential to manage T2D by controlling hyperglycaemia and the microvascular problems associated with cellular oxidative damage as well as macrovascular complications such as hypertension
[17].
2. In Vitro Studies with Functional Beverages and Diabetes
2.1. α-Glucosidase and α-Amylase Inhibition
According to several authors, functional beverages could represent an innovative strategy for managing diabetes. Natural functional beverages exhibit an inhibitory effect on
α-glucosidase and/or
α-amylase enzymes, which break down polysaccharides into glucose
[21]. The inhibition values of
α-glucosidase and
α-amylase were reported in the range from 6.12 to 98.6% and 20.03 to 60.14%, respectively
[21][22][23]. The ranges for the IC
50 are 1 to 40.68 and 0.25 to 71.28 mg/mL, respectively
[24][25][26]. These results vary depending on the concentration and administered amounts of the studied functional beverage. The small intestine’s
α-amylase enzyme is crucial in the breakdown of starch into glucose and maltose, consequently increasing the postprandial glucose levels. According to Ujiroghene et al., inhibiting or reducing this enzyme’s ability to digest starch may contribute to the management of diabetes
[25]. However, excessive inhibition of
α-amylase is not advised as it may lead to an accumulation of undigested carbohydrates in the colon, which could promote unfavourable bacterial fermentation and cause flatulence and diarrhoea
[27].
α-glucosidase is another key enzyme that catalyses the final step in the digestive process of carbohydrates, and its inhibition could similarly delay the digestion of oligosaccharides and disaccharides into monosaccharides, thus reducing glucose absorption and consequently decreasing postprandial hyperglycaemia
[28].
According to Badejo et al., the phenolics and flavonoids present in these beverages may be responsible for the inhibitory effect on these enzymes. Polyphenolic compounds may bind covalently to
α-amylase and modify its activity by forming quinones or lactones that react with nucleophilic groups on the enzyme molecule
[23]. Therefore, a viable therapeutic strategy for the treatment of diabetes involves the controlled inhibition of the
α-amylase and
α-glucosidase enzymes by the compounds present in these natural functional beverages. The
Prunus fruit smoothies examined by Nowicka et al. are one of the most active beverages with low IC
50 values. The main compounds found in these fruits include chlorogenic acid, catechin, and rutin. Chlorogenic acid has been shown to inhibit
α-amylase and
α-glucosidase enzymes by binding to the
α-amylase-substrate complex and combining with
α-glucosidase
[29]. Catechin’s inhibitory effect on both enzymes has also been demonstrated
[30].
The sea buckthorn-based smoothies from Tkacz et al.’s study demonstrated inhibition of pancreatic lipase, primarily due to polymeric procyanidins found in the buckthorn fruit. This inhibition was in addition to that of
α-amylase and
α-glucosidase enzymes
[21]. Pancreatic lipase is an enzyme that breaks down triglycerides into bioavailable fatty acids and monoglyceride/glycerol molecules. Inhibiting this enzyme contributes to a reduction in energy intake, which can facilitate the control of diabetes
[31]. Quercetin and rutin, compounds present in this fruit, have been shown to be pancreatic lipase inhibitors
[32][33].
2.2. Glucose Uptake
To examine the antidiabetic potential of fruit juices, Mahmoud et al. and Zhong et al. tested glucose uptakes after the consumption of
Momordica charantia (bitter gourd) juice and probiotics-fermented blueberry juice, respectively
[26][34]. The glucose uptake assay was used to evaluate the antidiabetic activity of compounds that increase glucose uptake. The consequences of diabetes are caused by high blood glucose levels, which must be reduced to prevent them
[35]. The
M. charantia juice was able to stimulate glucose uptake in the diaphragms of diabetic rats, especially when combined with the administration of insulin. This may be related to the increase of the tissue’s sensitivity to insulin and the potentiation of its action, with charantin being the compound responsible for the diabetic potential of the fruit
[34]. Probiotics-fermented blueberry juices also promoted glucose consumption in HepG2 cell lines, highlighting the potential of phenolic compounds to prevent the progression of obesity and hyperglycaemia
[26]. A study revealed that the anthocyanin malvidin 3-
O-galactoside in blueberry improves glucose uptake in HepG2 cells, with malvidin-type anthocyanins exhibiting greater glucose uptake activity compared to delphinidin-type anthocyanins
[36]. Blueberry is rich in both types of anthocyanins. Castro-Acosta et al. found that apple and blackcurrant polyphenols decrease both sodium-dependent and -independent glucose uptake in Caco-2 cells, which are models for human enterocytes
[37]. The apple extract may have inhibited glucose transport in the small intestine since Caco-2 cells are a reliable in vitro model of the human enterocyte. The same extract dose-dependently decreased the total glucose absorption and sodium-independent glucose uptake. This suggests that the control of glucose uptake by polyphenols from natural sources can be a possible approach for the management of blood glucose levels in diabetes. Further research is needed in the development of novel beverages, fruits, and vegetables possessing anti-diabetic properties. Crucially, clinical trials are necessary to validate the above claims. The current in vivo research on this topic will be covered in the following section.
3. In Vivo Studies with Functional Beverages and Diabetes
Some in vivo research has been conducted to explore the anti-diabetic properties of functional beverages. Rats are a suitable animal model used to understand the mechanisms of diabetes, with streptozotocin and alloxan being the most common chemical agents applied for the induction of diabetes in rats
[38]. Several studies have examined the efficacy of different functional beverages in preventing diabetes in streptozotocin- or alloxan-induced diabetic rats. Other studies have employed the induction of obesity in rats, via the administration of a high-fat diet, to assess the impact of vegetable and fruits on the development of diabetes in obese mice. Effects have been demonstrated on body weight, glucose and/or insulin metabolism, lipid profile, and antioxidant status.
3.1. Effects on Body Weight
Obesity, caused by the excessive accumulation of adipose tissue in the body, is a highly prevalent metabolic disorder, and its progression leads to T2D and associated health issues
[39]. As shown by several authors
[40][41][42][43], different functional beverages have helped obese rat models lose body weight. In a study by Seo et al., reduction in body weight, resulting from the consumption of a tomato and vinegar beverage, was attributed to increased fatty acid oxidation rather than inhibition of lipid biosynthesis
[41]. One of the main compounds of tomato is quercetin that has been previously associated with fatty acid oxidation resulting from lipophagy in hepatocytes, according to a study of Fukaya et al.
[44]. Another study showed that the
Emblica officinalis fruit juice reduced the body weight of mice. The effect of gallic acid from
E. officinalis was also tested in the same study and showed the same results. According to the authors, gallic acid is able to activate the PPAR-
α (peroxisome proliferator-activated receptor) and lipid metabolism of the high fat-induced obese rats
[43]. PPAR-
α is a key regulator of energy homeostasis and controls the expression of genes involved in fatty acid
β-oxidation
[45].
On the other hand, weight loss from the degeneration of adipocytes and muscular tissues to compensate for the body’s energy loss, which is caused by frequent urination and excessive glucose being transferred from glycogen, is an important aspect of managing diabetes. A few studies have indicated the control of body weight loss in diabetic rats through the consumption of different fruit/vegetable drinks
[46][47][48][49]. However, the specific mechanisms underlying this effect have not yet been discussed.
3.2. Effects on Glucose and Insulin Metabolism
Diabetes is characterized by increased fasting blood glucose, hyperinsulinemia, and insulin resistance
[50]. Diabetes is diagnosed when the fasting plasma glucose level exceeds 126 mg/dL, or the casual plasma glucose is >200 mg/dl
[51]. In these investigations, the ability of fruit juices to lower hyperglycaemia was frequently reported as causing a reduction in fasting blood, plasma, or serum glucose levels. For instance, Ariviani et al. showed the hypoglycaemic effect of a pigeon pea beverage on diabetic rats due to the antioxidant compounds that possess the ability to scavenge free radicals, which improves insulin secretion and as a result, decreases blood glucose levels
[46]. Pigeon pea’s main bioactive compounds include quercetin, quercetin 3-
O-glucoside, and quercetin 3-
O-methylether. The oral administration of quercetin in doses ranging from 15 to 100 mg/kg body weight for periods spanning 14 to 70 days demonstrated a reduction in blood glucose levels in diabetic rat models by increasing serum insulin levels, thus promoting the release of insulin and regenerating pancreatic islets
[52]. According to the literature, this flavonoid’s hypoglycaemic mechanisms may involve the following: promotion of the proliferation of pancreatic
β-cells, their protection against oxidative damage, and the increase of insulin secretion from these cells
[53][54]; enhancement of glucose uptake in organs and tissues
[55]; improvement of insulin resistance
[56]; and reduction of intestinal glucose absorption by the inhibition of the
α-glucosidase enzyme
[57].
The antidiabetic effect of Noni (
Morinda citrifolia)’s fruit juice was attributed to the regulation of the FoxO1 mRNA expression. The phosphorylation of the FoxO1 transcription factor inhibits gluconeogenic enzymes, improving glucose metabolism
[40]. This fruit contains damnacanthol, which has been found to have hypoglycaemic effects
[58].
Insulin resistance is defined by compensatory hyperinsulinemia due to a decreased sensitivity of target tissues, such as skeletal muscles, the liver, and adipose tissue, to insulin
[59]. In an attempt to counteract hyperglycaemia, increased insulin production results in hyperinsulinemia
[43]. In diabetics, the body loses the ability to produce insulin, which is caused by pancreatic
β-cell apoptosis or insulin resistance
[60]. According to Mahmoud et al.’s hypothesis,
M. charantia in fruit juice has the ability to decrease blood glucose in diabetic rats by stimulating the surviving
β-cells to release more insulin
[34].
M. charantia is well known for its antidiabetic properties, mainly because it contains a compound named charantin, which has blood glucose-lowering properties similar to insulin
[61]. A tomato and vinegar beverage improved postprandial glucose levels with decreased plasma insulin levels, demonstrating the reduction of insulin resistance
[41]. This was attributed to the reduction of free fatty acid concentration in obese rats, which induces hepatic fat accumulation, leading to a decrease in insulin sensitivity and the production of glucose. In this study, an increase in the activity of the enzyme glucokinase (GCK) was observed. Reduced GCK activity has been associated with poor insulin production by pancreatic
β-cells and glucose tolerance
[40]. The main bioactive compound of tomato is lycopene, which has been found to increase the activity of pancreatic GCK in diabetic rat models
[62]. This is one of the possible routes that can be used to target hyperglycaemia in diabetes.
Variya et al.’s study on high fructose-induced diabetic rats demonstrated that gallic acid from
E. officinalis decreased insulin resistance by activating Akt. This is a protein that has a role in the transcriptional activation of PPAR-
γ. which is a receptor involved in the expression of the
GLUT-4 (glucose transporter type 4) gene
[43].
GLUT-4 mediates the circulation, glucose reduction, and body homeostasis, and its inappropriate translocation is caused by damaged insulin responders/signalling
[63][64]. This juice was able to decrease arterial blood pressure that had been increased by fructose. According to Iwansyah et al., drinking fruit juice from
P. angulata also increases the expression of the
GLUT-4 gene in diabetic rats. This resulted in the increased absorption of blood glucose into cells, thus decreasing glucose levels
[49].
Grapefruit juice has been shown to have an antiglycaemic effect as strong as that of metformin medication
[42]. This juice significantly lowered fasting serum insulin in diabetic rats. Naringin in the juice, one of the main compounds of grapes, had a lowering effect on blood glucose levels and insulin resistance. This compound’s antidiabetic effect has been attributed to the enhancement of insulin sensitivity by the activation of AMPK (AMP-activated protein kinase), which is involved in insulin signalling
[65].
Palm fruit juice has anti-hyperglycaemic effects on diabetic rats, which is explained by a decrease in insulin resistance, a reduction in glucose absorption, or an increase in insulin secretion. With a low intake of palm fruit phenolics, the rats showed low insulin levels, while with higher amounts, the plasma insulin increased, demonstrating a possible increase in insulin secretion
[47]. A later study tried to investigate the molecular mechanisms of the anti-diabetic effects of palm fruit juice
[66]. The treatment of T2D-induced rats with the juice led to the up-regulation of 71 hepatic genes, including apolipoproteins related to high-density lipoproteins and genes involved in hepatic detoxifications. The treatment down-regulated 108 genes related to insulin signalling and fibrosis. With these results, the authors concluded that the mechanism of action of palm fruit phenolics is not only related to increases in insulin secretion.
Numerous secondary disorders, such as obesity, cardiovascular problems, hypertension, hypertriglyceridemia, and atherosclerosis, are mostly attributed to insulin resistance
[67]. Treatments that can boost insulin sensitivity and reduce endogenous insulin levels are suitable approaches to manage diabetes and its metabolic complications
[68].
3.3. Effects on the Lipid Profile
In diabetes mellitus, hyperglycaemia and dyslipidaemia coexist. Insulin resistance leads to a more atherogenic lipid profile
[69], and diabetics can benefit from medication that also regulates abnormal lipid levels
[70]. The high consumption of fruits and vegetables has been linked to decreased plasma lipid levels
[71]. Some studies on fruit/vegetable juices have demonstrated improvements in the lipid profiles of diabetic rats. The beverage administration of pigeon pea was able to significantly lower the cholesterol levels of rats with hypercholesteremia. The authors of the study attribute this to dietary fibre, which regulates the HMG-CoA reductase expression that is responsible for the production of cholesterol, and to the antioxidant capacity of the beverage with antioxidants inhibiting the oxidation of LDL cholesterol and suppressing its uptake in macrophages
[46]. The gallic acid from
E. officinalis fruit juice led to decreases in cholesterol and triglycerides in fructose-induced diabetic rats
[43]. Methods to modify blood lipids are necessary to lessen the risk of problems caused by and the progression of diabetes, since high levels of the total cholesterol and triglycerides may lead to cardiovascular complications.
3.4. Antioxidant Status
Diabetes and its complications are thought to be caused by oxidative stress, which can be a mediator of insulin resistance and its progression to glucose intolerance
[72]. Malondialdehyde (MDA) is a biomarker for oxidative stress in diabetes mellitus and is linked to lipid peroxidation. A high plasma level in this marker indicates low antioxidant status
[46]. The
M. charantia fruit juices used by Mahmoud et al. and Gao et al. were able to mitigate oxidative stress, as shown by the reduction of MDA levels
[34][48]. Ariviani et al. found that administering a pigeon pea beverage to diabetic-hypercholesterolemic rats also reduced their MDA levels
[46].
M. charantia juice also led to an increase in the TAOC (total antioxidant capacity) and pancreatic GSH levels (pancreatic reduced glutathione)
[34]. They attribute this effect to the augmented synthesis of GSH and other antioxidant enzymes, a reduction of oxidative stress and consequent reduction in the degradation of those enzymes, or a combination of both.
Several different mechanisms have been proposed regarding the anti-diabetic activity of natural juices, and they are still being studied. The next step is to perform clinical trials to evaluate their effect on humans.
4. Clinical Trials with Functional Beverages and Diabetes
A few clinical studies have been performed to validate the antidiabetic effect of functional beverages on patients with diabetes. Banihani et al. reported a decrease in fasting serum glucose and insulin resistance in patients with T2D, 3 h after the consumption of fresh pomegranate juice, at 1.5 mL/kg of body weight. In addition, they reported an increase in the
β-cell function
[73]. Pomegranate is rich in compounds such as punicid acid and punicalagin, which have been reported to stimulate PPARs
[74] and insulin secretion
[75], respectively. In a clinical study performed by Devaki and Premavalli, 6 months of daily consumption of 45 mL of an
M. charantia-fermented beverage (equivalent to a dose of 18 mg of phenols, 129 mg of quinine, and small quantities of five different vitamins every day) in diabetic subjects led to an improvement of symptoms. There was a significant reduction of fasting blood glucose, postprandial blood glucose, and HbA1c (glycated haemoglobin) levels
[76]. HbA1c levels reflect the average blood glucose concentration over the past few weeks
[77]. The blood lipid profile remained the same. The authors claim that the effect of this drink is due to a lectin with activity similar to insulin contributing to its hypoglycaemic effect. It also contains polypeptide-P, which is an insulin-like substance that decreases blood sugar levels.
A clinical trial involving the daily consumption of a beverage enriched with 333 mg of polyphenols from cranberry and strawberry for 6 weeks on 116 insulin-resistant individuals revealed an improvement in insulin sensitivity. However, the beverage did not affect the total LDL and HDL cholesterol or triglycerides or the markers for oxidative stress and inflammation (pro-inflammatory cytokines, C-reactive protein, HMW adiponectin, PAI-1, and oxidised-LDL, RANTES, or total antioxidant capacity of plasma)
[78]. According to the author’s results and research, doses of polyphenols lower than 800 mg have metabolic benefits. Kim et al. tested the modulation of the lipid and glucose metabolism and of oxidative stress and inflammation by a beverage made with açaí, which is rich in anthocyanins like cyanidin 3-
O-rutinoside and cyanidin 3-
O-glucoside. Here, 37 individuals with metabolic syndrome were randomized and drank 325 mL of the beverage with 1.139 mg/L gallic acid equivalents of total polyphenolics (or a placebo control) twice a day for 12 weeks. At the end of the study, the plasma level of interferon-gamma (IFN-
γ) and urinary level of 8-isoprostane (inflammatory response and oxidative stress biomarkers, respectively) were significantly decreased, which contribute to reducing the risk of developing chronic diseases. However, the glucose and lipid metabolism biomarkers were not affected
[79]. According to a case report by Aktan et al., the daily consumption of
Vaccinium corymbosum juice for 2 years by a 75-year-old pre-diabetic patient induced profound hypoglycaemia. The serum glucose values were at the level of 30 mg/dl after the episode, and the patient had drunk up to 500 mL of the juice 1–2 h prior. After discontinuing the consumption of the beverage for 6 months, the levels increased to 105 mg/dl
[80]. This suggests the important role of
V. corymbosum juice in lowering serum glucose levels. This fruit (blueberry) is rich in anthocyanins such as delphinidin 3-galactoside, malvidin-3-galactoside, and malvidin 3-glucoside. Hasniyati et al. reported that functional yogurt containing
bengkuang was able to decrease the MDA levels of T2D patients, after 2 weeks of daily consumption by a group of 46 people, but had no impact on fasting blood glucose levels
[81]. Lastly, drinks rich in apple and blackcurrant polyphenols had a diabetes-preventing effect, by lowering postprandial plasma glucose levels, C-peptide, GIP, and insulin in 25 healthy men and women, 30 min after the daily dose of 1200 mg apple polyphenols or 600 mg apple polyphenols + 600 mg blackcurrant anthocyanins drinks. The triglyceride levels stayed the same
[37].
As of now, enough clinical trials have not been conducted to determine the specific dose of a compound necessary to induce a specific anti-diabetic effect. Moreover, complex polyphenol combinations found in fruit extracts might be responsible for these effects, which are potentially due to additive or synergistic actions
[37]. Due to the complexity of these foods, their effects might not be solely attributed to one or two specific compounds, and the outcomes may differ from one beverage to another even if they contain the same fruit.
Regarding safety, the consumption of natural polyphenols is relatively high in a typical human diet, and they have an excellent safety profile
[82]. For example, a study demonstrated that a daily dose of 320 mg of anthocyanins has positive effects on dyslipidaemia and insulin resistance in diabetic patients
[83]. Polyphenols from blueberries have been found to be safe for consumption up to 1000 mg/kg body weight in rats for 90 days
[84]. Currently, there is little evidence to suggest toxicity from polyphenols at higher dosages, since most of the polyphenol research has been focused on determining the lowest amount required to show a positive health impact. Although the dose of individual polyphenols can be investigated using traditional toxicological or pharmacological models, alternative methods are needed to study the complex mixes that consumers are exposed to
[85].
An interesting aspect of this research is the positive effects observed in certain fermented beverages that were studied. Research has indicated a protective effect of alcoholic beverages against diabetes, particularly with light to moderate consumption
[86]. Conigrave and Rimm suggested that the consumption of a small amount of alcohol might even be beneficial in managing cardiac complications of diabetes, as long as it is done in low doses to prevent hypoglycaemia or poor glycaemic control
[87]. This highlights the potential of functional beverages to exert beneficial health effects even if they contain alcohol in their composition and provided the consumption levels are controlled.
The carbohydrate content of different fruit and vegetable juices may significantly impact the effects of their consumption. Fruit juice composition varies depending on the species or variety of fruit, maturity, and the environmental and climatic factors of the growing season
[88]. Fruit juices with sorbitol and a fructose-to-glucose ratio greater than one are more likely to result in carbohydrate malabsorption, which can induce diarrhoea and stomach pain
[89]. For example, white grape and orange juices have an almost equal amount of glucose and fructose and do not contain sorbitol. In pear and apple juices, there is a higher concentration of fructose than glucose, and they contain sorbitol. The carbohydrate composition of the first-mentioned juices favours carbohydrate absorption
[89]. This is an important aspect to consider when selecting the type of foods used to produce functional beverages directed at the control of diabetes.