Fruits are the pivotal sources of vitamins, minerals, and several other phytochemicals consumed by people across the world as part of their daily diets. Several parts of fruit plants, including fruit, root, seed, leaf, and bark, are widely popular due to their medicinal properties in the management of several disease conditions. In developed countries, such as the US, Canada, Germany, Australia, and New Zealand, 20–25% of total drugs are made from medicinal plant parts, including fruits, while in fast developing countries, including India, Brazil, Indonesia, China and Russia, the ratio is skyrocketing to 80–85% ^[1][15]. The local use of fruit plants and other natural sources to treat diabetes is hugely promoted across the globe because of low cost, availability, and less side effects ^[2][16]. A vast number of plant parts and their fruits are used by the traditional healers of Kokrajhar district in India, Manisa, Turkey, and Urmia in Iran for their activity against diabetes ^[3][4][5][17,18,19]. Furthermore, a study reported that medicinal plants and their fruits were traditionally used for the treatment of diabetes in Manisa, Turkey ^[5][19]. Aegle marmelos (Bengal Quince), Phyllanthus embelica (Indian Gooseberry), Carica Papaya (Papaya) fruits are used in ethnic society of Bhopal region, Madhya Pradesh, India to treat diabetes ^[1][15]. Besides, in South Western Nigeria, many types of fruits are also used to treat diabetes mellitus, including lime (as lemonade) and orange (as lemonade as well as Infusion) ^[6][20]. Jujube dried fruits would be taken by ethnic people of Manisa, Turkey ^[5][19]. Juices from fruits and leaves are also popular in diabetes management i.e., Citrus aurantifolia (Key Lime) fruit juice along with decoction of Magnifera indica leaves are consumed by ethnic people of Agboville, Africa, while lime, orange, and coconut are consumed in the Dominican Community of New York City to treat diabetes mellitus ^[7][8][21,22]. In Nalbari district, Assam, India, leaves and fruits of Bengal quince as well as mango leaves are processed and consumed daily with cow’s milk ^[9][23]. Seed powder of muskmelon is used for its antidiabetic potentials in some areas as well ^[9][23].

2. Phytochemicals from Fruits and Other Plant Parts

Phytochemicals are the key factors that exert the pharmacological actions of medicinal plants ^[10][11][9,11]. Thus, the presence of notable phytochemicals can explain the pharmacological properties of plants such as antidiabetic, anticancer, antidiarrheal, and antihypertensive activities. Several types of phytochemicals including tannins, saponins, flavonoids, glycosides, and phenolic compounds are very promising agents against diabetic complications. Phytochemicals with antidiabetic potentials isolated from these aforementioned species have been presented in Table 1 along with their mechanisms of action. Besides, prospective phytochemicals corroborated with antidiabetic potentials have been also classified according to chemical classes in Table 2.

3. Clinical Trials of Prospective Fruit Plants and Their Phytochemicals to Treat Diabetes Mellitus

Despite the fact that fruit plants are excellent sources for the treatment of a variety of diseases, including diabetes, many plants have not been thoroughly researched clinically yet. Some plants have been subjected to clinical trials which actually provide hints about the immense potential of fruit plants in the management of diabetic complications. Based on previously reported studies, the administration of 4–24 g of the powder of black plum seed to 28 diabetic individuals reportedly showed hypoglycemic action through a diminution in the mean fasting and postprandial glucose contents in the blood. Besides, a considerable antihyperglycemic effect was seen in thirty individuals with uncomplicated type 2 diabetes due to the ingestion of 12 g powder of black plum seed for a course of three months in three divided doses ^[98][262]. Again, the aqueous extract of guava leaf tends to exert antidiabetic action in twenty hospitalized non-insulin-dependent diabetes patients by declining the postprandial blood glucose content from 160 mg/dL to 143 mg/dL ^[99][263]. In patients with non-insulin-dependent diabetes, the extract tablets of lychee seed (30 g/day) for a duration of 12 weeks exhibited a hypoglycemic effect by lowering the fast plasma glucose content. In the same patients, the blood sugar level was reportedly lower at a concentration of 3.6–5.4 g/day after the administration of lychee seed extract tablets ^[100][264]. According to another study, the oral administration of 5 g of the leaf of Bengal quince for a duration of one month in 10 patients with type 2 diabetes exerted significant hypoglycemic action by declining the pre and postprandial blood sugar levels. Moreover, in 4 groups of a total of 120 type 2 diabetes subjects, the ingestion of 2 g of leaf powder and 2 g of the combination of pulp and seed powder of Bengal quince for 3 months tends to show a substantial lowering in fasting blood sugar content ^[101][29]. Furthermore, a double-blind, randomized, controlled clinical trial that lasted 8 weeks and involved 52 obese type 2 diabetic patients (26 men and 26 women; ages 30 to 50) discovered that administration of P. granatum supplements significantly decreased fasting blood glucose from 161.46 mg/dL to 143.50 mg/dL. Additionally, the patients’ GLUT-4 gene expression increased ^[102][265]. Another single-blind, randomized-controlled clinical study on 44 type 2 diabetic patients (age range, 56–6.7 years; 23 men, 21 women) discovered that P. granatum juice significantly reduced oxidative stress, indicating that consumption of it could delay the onset of oxidative stress-related diabetes mellitus ^[102][265] Phytochemicals have also been subjected to clinical trials to discover new sources of antidiabetic medications. Based on previous clinical trials on 36 patients with non-insulin-dependent diabetes, 500 mg of berberine three times a day is likely to lower the fasting blood glucose level from 10.60 ± 0.9 to 6.9± 0.5 mmol/L in a three-month time frame. According to another study, 500 mg of berberine along with 5 gm of each glipizide and metformin in 60 type 2 diabetes patients is reported to enhance the state of glucose metabolism and insulin sensitivity by lowering the fasting blood glucose content ^[103][266]. In 45 patients with non-insulin-dependent diabetes, the administration of hesperidin at 500 mg/day for 8 weeks can lead to an increment in insulin content and a potential reduction of fast blood glucose content ^[104][267]. The administration of 180 mg ellagic acid capsules in 22 type-2 diabetes patients for 8 weeks remarkably reduced the fasting blood sugar content and thereby showed antihyperglycemic action ^[105][268]. In 33 patients with non-insulin-dependent diabetes, pinitol at 400 mg thrice a day for a tenure of 3 months is reported to exert antidiabetic action by declining the fasting plasma glucose content and enhancing the secretion of insulin ^[106][269]. Cetrulline, another prospective phytochemical, is reported to exhibit notable antihyperglycemic action by remarkably lessening the fasting plasma glucose content at an oral administration of 3 g per day for 8 weeks in 23 patients with type-2 diabetes ^[107][270].

4. Reported Mechanism of Actions to Exert Antidiabetic Potentials

a.

Inhibition of α-glucosidase secreted from the brush border of the small intestine

Mammalian α-glucosidase is a membrane-bound hydrolytic enzyme, located in the epithelia of the small intestine’s mucosal brush border, which facilitates carbohydrate digestion. Inhibitors of this enzyme prevent carbs from being cleaved, resulting in less glucose absorption and a lower postprandial glycemic level ^[108][109][271,272].

b.

Inhibition of DPP-4 enzyme

Incretin hormones include glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which facilitate the secretion of insulin. A serine peptidase enzyme called dipeptidyl peptidase-4 (DPP-4) breaks down these hormones quickly. Hence, inhibitors of the DPP-4 enzyme have anti-diabetic properties by stimulating insulin secretion and inhibiting glucagon secretion ^[110][111][273,274].

c.

Inhibition of α-amylase secreted from the salivary gland

Inhibition of the enzyme, α-amylase, which is found mainly in saliva and pancreatic juice, can lead to lower postprandial blood glucose levels. As it breaks down starch and glycogen and increases the blood sugar level. Hence, this enzyme’s inhibition helps to control diabetes ^[112][275].

d.

Increased secretion of insulin

An increase in intracellular calcium ion [Ca²⁺]_i stimulates pancreatic β cells and facilitates insulin secretion. Some phytochemicals, e.g., p-methoxy cinnamic acid acting on the L-type Ca²⁺ channels have been demonstrated to boost insulin release by increasing cAMP via the inhibition of phosphodiesterase ^[113][114][276,277].

e.

Increased insulin sensitivity and improved glucose uptake by muscle cells and adipose tissue

The sensitivity of non-pancreatic cells to insulin is enhanced by certain phytochemicals, resulting in better glycemic management. Glucose uptake is increased in skeletal muscle and adipose tissue due to the activation of a sequence of processes that occur in response to a rise in insulin levels. Insulin promotes the phosphorylation of protein substrates and increases the uptake of circulating glucose by adipose tissue and muscle cells when it interacts with insulin receptors ^[115][278].

f.

Nourishment of Pancreatic β-Cells

Insulin-secreting pancreatic β cells can be impaired by autoimmune processes mediated via macrophages, cytokines, and T cells weaken them in type 1 diabetes and by oxidative stress, elevated lipid or glucose levels, and inflammatory mediators in type 2 diabetes. They can be strengthened against reactive oxygen species accumulation and lipid peroxidation-mediated cell death by increasing antioxidants, such as reduced glutathione (non-enzymatic) and catalase, superoxide dismutase, glutathione peroxidase, glutathione S transferase (enzymatic) ^[116][117][279,280].

g.

Reduction of HbA1c and glycated plasma protein levels

In diabetes mellitus, blood glucose content is increased and monosaccharides react non-enzymatically with blood proteins (mostly hemoglobin A and albumin) in a process known as glycation. Glycation inhibitors obstruct this process by a variety of methods, including competitive interaction with the protein’s amino group, cleaving the open chain of monosaccharides, binding at the glycation site, and attaching with the intermediates of glycation reaction. As a result, HbA1c and glycated plasma protein concentrations are reduced, and the consequences of glycation and diabetes problems can be avoided ^{[118][119][120]}[281,282,283].

h.

Improvement of Glucagon-like peptide-1 (GLP-1)

GLP-1 (glucagon-like peptide-1) is a hormone produced by L cells in the gastrointestinal system’s distal ileum and colon. It slows stomach emptying, suppresses hunger, and imparts a sense of fullness by increasing glucose-dependent insulin secretion and decreasing glucagon release. Alternative drugs that operate as agonists for the gluco-protein-coupled receptor (GLp-1R) have been identified as viable options for achieving the desired effect. They boost insulin production via raising insulin gene transcription and intracellular Ca²⁺ levels, as well as activating the pancreatic duodenal homeobox 1 transcription factor that promotes insulin gene expression (Pdx-1) ^[121][122][284,285].

i.

Regulation of Glucose transporter type 4 (GLUT-4)

Glucose transporter type 4 (GLUT-4) is a transporter with a 12-transmembrane domain that facilitates insulin-induced glucose influx into skeletal muscle and fat cells. The transporter is normally found intracellularly, but it moves to the cell membrane in response to insulin stimulation or during exercise via separate processes. Insulin receptor (IR) tyrosine kinase is activated when insulin binds to its receptor in target cells, triggering phosphorylation-mediated activation of other protein kinases that finally mobilize the effectors, especially Rab proteins ^[102][123][265,286].