Antidiabetic Potential of Commonly Available Fruit Plants in Bangladesh: Updates on Prospective Phytochemicals and Their Reported MoAs

Diabetes mellitus is a life-threatening disorder affecting people of all ages and adversely disrupts their daily functions. Despite the availability of numerous synthetic-antidiabetic medications and insulin, the demand for the development of novel antidiabetic medications is increasing due to the adverse effects and growth of resistance to commercial drugs in the long-term usage. Hence, antidiabetic phytochemicals isolated from fruit plants can be a very nifty option to develop life-saving novel antidiabetic therapeutics, employing several pathways and MoAs (mechanism of actions). This review focuses on the antidiabetic potential of commonly available Bangladeshi fruits and other plant parts, such as seeds, fruit peals, leaves, and roots, along with isolated phytochemicals from these phytosources based on lab findings and mechanism of actions. Several fruits, such as orange, lemon, amla, tamarind, and others, can produce remarkable antidiabetic actions and can be dietary alternatives to antidiabetic therapies. Besides, isolated phytochemicals from these plants, such as swertisin, quercetin, rutin, naringenin, and other prospective phytochemicals, also demonstrated their candidacy for further exploration to be established as antidiabetic leads. Thus, it can be considered that fruits are one of the most valuable gifts of plants packed with a wide spectrum of bioactive phytochemicals and are widely consumed as dietary items and medicinal therapies in different civilizations and cultures. This review will provide a better understanding of diabetes management by consuming fruits and other plant parts as well as deliver innovative hints for the researchers to develop novel drugs from these plant parts and/or their phytochemicals.


Traditional Uses of Fruit Plants in the Management of Diabetes
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 vast spectrum of pharmacological attributes, including bactericidal, anti-inflammatory, antineoplastic, antioxidant, hypoglycemic, anti-osteoporosis, and anthelmintic activities [48].
The hydro-methanol extract obtained from the spadix of C. nucifera tends to display remarkable antihyperglycemic activity in streptozotocin-induced diabetic Albino Wistar rats at 250 and 500 mg/kg body weight by escalating the insulin secreting power of the pancreatic β-cells [49]. According to a study, methanol extract of C. nucifera (200 mg/kg b.w. dose) manifested an antidiabetic effect by improving the content of not only sugar but also insulin in the blood stream in diabetic rats [48]. The extract obtained from C. nucifera husk using methanol tends to exert antihyperglycemic action in alloxan-induced diabetic rats having an IC 50 range of 51.70 ± 4.66 µg/mL by significantly hindering the α-amylase activity [50]. The lyophilized coconut water of mature C. nucifera (1000 mg/kg b.w. dose) has been used to lower the glucose content from 275.32 ± 4.25 mg/dL to 129.23 ± 1.95 mg/dL in alloxan-induced male Sprague-Dawley rats [51].

Elephant Apple (Dillenia indica L.)
Dillenia indica L., locally known as "Chalta" in Bangladesh, is an evergreen tree [52] which belongs to the Dilleniaceae family [53] and mostly grows in the moist forests of sub-Himalayan region to Assam; it is a very familiar tree in household of Bangladeshi rural area [52]. D. indica has been reported to have phytochemicals, such as flavonoids, tannins and terpenoids, polyphenolic compounds, and saponins [54], which exert significant biological activities, namely antidiabetic, antimicrobial, antioxidant, dysentery, anti-inflammatory, and analgesic properties.
The extract of D. indica has shown the possible mode of antidiabetic action by enhancing the insulin impact by raising the insulin secreting potential of the pancreatic β-cells or its bound-state release or cell rejuvenation [52]. The methanol extract of D. indica demonstrated a notable antihyperglycemic action in alloxan and streptozotocin induced diabetic rats [53]. Furthermore, the methanol extracts of the leaves of D. indica enhanced the serum-insulin level by halting the function of α-amylase and α-glucosidase enzymes [55]. Based on a study, the leaves of D. indica, which have concentrations of 250 and 500 mg/kg b.w., were administered via the oral route and showed favorable impacts on the glucose content of blood [53].The alcohol extract of D. indica leaves given at doses of 100,200, and 400 mg/kg for 45 days exerted remarkable depletion in the increased blood sugar content of rats at a fasting state (266.17 ± 7.07, 221.83 ± 5.70, 182.17 ± 3.59 mg/dL respectively). Consequently, the given doses cause a notable elevation in the insulin levels of serum (8.92 ± 0. 15, 9.83 ± 0.13, 11.48 ± 0.39 mU/mL) [54]. The glucose content was prominently lessened in the blood by the methanol-leaf extracts of D. indica in streptozotocin-induced diabetic rats having the doses of 250 and 500 mg/kg [53].

Guava (Psidium guajava L.)
Psidium guajava L. is a large-sized everlasting tropical shrub belonging to the Myrtaceae family [56]. It is a popular pan-tropical fruit [57] and locally known as "Peyera" in Bangladesh. Though it is aboriginal to Central America, it is also found in southern Florida, Bermuda, and throughout the West Indies, from the Bahamas and Cuba through Trinidad and all the way south to Brazil [58]. It incorporates various bioactive phytoconstituents, such as saponins, alkaloids, tannins, cardiac glycosides, terpenes, flavonoids, and sterols. These compounds are likely to exert an extensive range of therapeutic attributes, including antidiabetic, antitumor, antimicrobial, antioxidant, and hepatoprotective activities [58].
The ethanol of stem bark of P. guajava tends to exhibit antihyperglycemic action (250 mg/kg oral dose) in alloxan-induced hyperglycemic rats [59]. In an in-vitro study, the ethanol and aqueous extracts of P. guajava leaf (1 mL concentration) halted the function of the enzyme alpha-amylase by 97.5% and 72.1%, respectively [60]. According to a study, ethanol extract of bark and leaf of P. guajava demonstrated hypoglycemic action by hindering α-glucosidase activity at an IC 50 of 0.5 ± 0.01 and 1.0 ± 0.3 µg/mL, respectively [57]. The fruits also exhibited noteworthy glucose-diminishing activities in streptozotocin-induced diabetic rats. P. guajava reportedly safeguarded the pancreatic β-cells resulting from lipid peroxidation and DNA strand breakage mediated by streptozotocin and thus preserved insulin secretion. It also arrested the protein manifestation of pancreatic nuclear factor-kappa B caused by streptozotocin induction and attributed to its antihyperglycemic efficacy [61].

Hog Plum (Spondias mombin L.)
Spondias mombin L. is a rapid-growing perennial tree from the Anacardiaceae family. This is regarded as one of the renowned tropical fruits in Bangladesh, and is locally known as 'Amra'. It is indigenous to America and Brazil, especially in the western Atlantic and Amazon forest [62]. The effective bioactive phytochemicals extracted from this plant are alkaloids, flavonoids, saponins, phenolic compounds, and tannins [63]. These phytochemicals reportedly exert a broad spectrum of notable pharmacological attributes, including anti-inflammatory, antioxidant, antidiabetic, antimicrobial, and antipsychotic activities [62].
The ethyl-acetate-soluble fraction obtained from the methanol extract of leaves of S. mombin manifested antihyperglycemic action in vitro by halting α-amylase and αglucosidase with an IC 50 level of 28.12 ± 0.48 µg/mL and 12.05 ± 0.002 µg/mL, respectively [64]. According to a study, methanol extract of leaves of S. mombin at concentrations of 200 and 400 mg/kg b.w. lowered blood sugar content by 20.03% and 33.33%, respectively in alloxan-induced diabetic male Wister rats. Consequently, in the same experimental animals, the applied doses displayed antidiabetic action by declining the glycosylated hemoglobin having concentrations of 7.72 ± 0.21% and 5.16 ± 0.09%, respectively [65].
Ethanol extract of P. emblica fruit (200 mg/kg b.w. for 45 days) exhibited substantial decrease in blood glucose and a notable rise in plasma insulin in streptozotocin-induced type 2 diabetic mice. Furthermore, P. emblica fruit extract inhibited α-glucosidase and α-amylase (IC 50 values = 94.3 and 1.0 g m/L, respectively) [69]. P. emblica fruit extract also displayed positive hypoglycemic potency in an investigation conducted before [70]. Aqueous extract of P. emblica fruit, at a dosage of 200 mg/kg b.w., sufficiently reduced blood-glucose levels in alloxan-induced diabetic mice by suppressing gluconeogenesis and glycogenolysis [14]. The aqueous-methanol extract of its fruit resulted in a notable reduction in the blood-sugar level at fasting state, whereas uphill-serum insulin in diabetic rats, while also insulin-to-glucose ratio via rising β-cell size and number in diabetic rats, proving its antidiabetic activity through the upregulation of β-cell actions that decreases glucose intolerance and enhances insulin secretion [71]. According to a previous study, P. emblica fruit juice and hydroalcohol extract have rendered significant anti-diabetic action, as they could reduce blood glucose concentration and dramatically enhance glucose liberality in streptozotocin-induced type 1 diabetic rat models [72]. Another study demonstrated that oral administration of a hydroalcohol and methanol extract of P. emblica leaves culminated in a considerable suppression of fasting blood glucose and a rise in insulin content [73]. The aqueous extract of P. emblica fruit is proved efficient in lowering blood glucose and glycosylated hemoglobin (HbA1C), which were comparable to that of the antidiabeticmedication chlorpropamide [74]. Furthermore, fresh juice and hydroalcohol extracts of E. officinalis fruits were claimed to lower high-fastingblood-glucose levels, while increasing serum-insulin levels in streptozotocin-induced diabetic rats [74].
The methanol extract of E. floribundus leaf rendered noteworthy decrement of αglucosidase enzyme having an IC 50 value lesser in comparison to acarbose that establishes the antidiabetic activity of E. floribundus [75]. Based on another study, the stem bark of E. floribundus had also showed notable α-glucosidase inhibitory actions with an IC 50 of 14.56 ± 1.20 µg/mL [78].

Indian Jujube (Zizyphus mauritiana Lam.)
Zizyphus mauritiana Lam. is a shrub belonging to the Rhamnaceae familyis, found from western Africa to India in the warm temperate zone [79], and widely cultivated in Bangladesh; it is also locally known as "Boroi". Z. mauritiana has been shown to contain a variety of phytochemicals, including flavonoids, alkaloids, terpenoids, pectin, saponins, triterpenoic acids, lipids, and jujuboside saponins, which exerted potential sedative and hemolytic properties, sweetness-inhibitory effects and as an anxiolytic [79]. The cyclopeptide alkaloids were reported to have antibacterial, anticonvulsant, hypoglycemic, anti-infectious, diuretic, analgesic, antiplasmodial, and anti-inflammatory properties [80].
A study conducted on a hyperglycemic rat model with petroleum ether, chloroform, acetone, ethanol, aqueous, and crude aqueous extracts of Z. mauritiana fruits reveal to have antihyperglycemic action. The non-polysaccharide fraction of the aqueous extract of fruits of Z. mauritiana is said to have substantial antihyperglycemic and hypoglycemic effects [80]. Furthermore, aqueous and petroleum ether extracts of Z. mauritiana at 200 and 400 mg/kg dosages demonstrated significant antidiabetic effects [81]. The combination of aqueous and ethanol extracts of Z. mauritiana seeds (800 mg/kg extract of seeds and 10 mg/kg glyburide) improved glucose tolerance in both diabetic and normal mice. This finding implies the synergistic hypoglycemic action of Z. mauritiana extracts. According to the same study, aqueous and ethanolic extracts of Z. mauritiana seeds contain strong principles that may exert numerous activities involving several pathways to exert hypoglycemic and antihyperglycemic effects [82]. Diospyros malabarica (Desr.) Kostel. is an intermediate evergreen shrub that may reach a height of 15 m, has dark grey or black bark, and exfoliates in rectangular scales [83,84]. Its fruits are locally known as "Gaab" which belongs to the Ebenaceae family. It thrives throughout the humid tropical climates of India and Bangladesh which constitutes phenols, tannins, proteins, flavonoids, alkaloids, and saponins [85]. D. malabarica has been reported to exert antioxidant, hypoglycemic, antidiarrheal, antiviral, antiprotozoal, anthelmintic, and cytotoxic activities [86].
Ethanol extract of D. malabarica bark restored the cell number and size of islet cells in diabetic rats. It also greatly enhanced the glucose tolerance test and blood glucose lowering action for up to 4 h [83]. Based on another research, methanol extract from D. malabarica fruits reduced fasting blood glucose, pancreatic thiobarbituric acid reactive compounds (TBARS), and serum lipid levels of alloxan-induced diabetic mice [84]. Furthermore, methanol extract of D. malabarica bark had a strong antihyperglycemic effect, resulting in an increased concentration of plasma protein and adrop in cholesterol and triglyceride levels [87]. Artocarpus heterophyllus Lam. from the Moraceae family, is a medium-sized [88] everlasting monoecious tree locally known as "Kathal" [89]. Various studies revealed that A. heterophyllus was first introduced in the rain forests of the Western Ghats of Southwestern India though it also grows largely in Malaysia, Burma, Sri Lanka, Bangladesh, Indonesia, Philippines, and Brazil. [90]. It incorporates several bioactive phytochemicals like carotenoids, flavonoids, volatile acids, sterols, and tannins which exerted a vast array of therapeutic actions including, antioxidant, antidiabetic, antibacterial, and antitumorigenic properties [91].
The aqueous extract of A. heterophyllus fruit exerted antidiabetic action by impeding hemoglobin glycation with an IC 50 value of 56.43% [92]. The hot water extract of leaves of A. heterophyllus displayed hypoglycemic action in the usual subjects and the diabetic patients at 20 g/kg equivalent dose by enhancing glucose tolerance [89]. According to a study, A. heterophyllus aqueous leaf extract enhances the glucose content of rat plasma in vitro, having concentrations from 125 to 2000 µg/mL by halting the function of αamylase [90]. The ethyl acetate extract of leaves also showed notable antihyperglycemic action against streptozotocin-induced diabetic animal models (20 mg/kg b.w. dose) by enhancing insulin secretion of β-cells [91].  [88] evergreen tree which belongs to the Myrtaceae family [88], is a non-climacteric tropical Bangladeshi fruit [93] and locally known as "Jamrul". Alongside Bangladesh, it is also available across Malaysia and also in the surrounding countries such as Thailand, Indonesia, and Taiwan [93]. It comprises several bioactive phytochemicals like phenols, flavonoids, flavonol glycosides, proanthocyanidins, anthocyanins, ellagitannins, chalcones, carotenoid, and triterpenoids which showed an extensive spectrum of potent therapeutic attributes, including antioxidant, anti-inflammatory, hypoglycemic, and antitumorigenic activities [94].
The methanol extracts of leaves of S. samarangense impeded serum glucose content by 59.3% in glucose-induced hyperglycemic mice at a 400 mg/kg b.w. dose [95]. Furthermore, according to a report, S. samarangense methanolic leaf extracts displayed antidiabetic action by impeding the alpha-glucosidase activity [96]. S. samarangense methanolic fruit extract showed hypoglycemic action in streptozotocin-induced diabetic rats at 100 mg/kg b.w. dose by effectively elevating the insulin-secreting power of the β-cells residing in the pancreas [94]. The aqueous extract of S. samarangense fruit tends to exert a remarkable antihyperglycemic action on the insulin-resistant FL83B mouse hepatocytes by effectively increasing glucose utilization and thereby improving the glycogen level [97].

Key Lime (Citrus aurantiifolia (Christm.) Swingle)
Citrus aurantifolia (Christm.) Swingle is a shrub that belongs to the Rutaceae family [98]. It has emerged from East Asian origins and more specifically, from northern Malaysia or India which is next to North Africa [99]. Locally, it is known as "Kagoji Lebu" and constitutes numerous phytochemicals among which pectins, flavonoids, and vitamins are biologically active. C. aurantifolia is likely to display promising antibacterial, antifungal, analgesic, anti-inflammatory, antioxidant, anthelmintic, [100] antidiabetic as well as antihyperglycemic potencies. The phytoconstituents present in C. auirantifolia are mainly flavonoids and coumarins which exerted antidiabetic actions [98]. In hyperglycemic rats, intraperitoneal administration of C. aurantifolia oil (100 mg/kg for 14 days) exerted a substantial decrease in fasting hepatic and blood glucose though the hepatic glycogen concentration was considerably enhanced [101].
Methanol and ethanol extracts of C. aurantifolia dried fruit have been reported to show substantial α-amylase inhibition and also being potent hypoglycemic agents [102]. Methanol extract of C. aurantifolia elevated TGF-β expression with an increased number of β-cells whereas LDL concentration and islets of Langerhans got dropped in hyperglycemic rats [103]. A methanol extract of its fruit peel demonstrated a progressive drop in fasting blood glucose volume and reduction in serum triglycerides in diabetic rats, establishing the antidiabetic potential of C. aurantifolia [104].

Lemon (Citrus limon (L.) Osbeck)
Citrus limon (L.) Osbeck from the Rutaceae family is a tiny, thorny, and evergreen tree attaining height of 10-20 feet and a native in Asian regions. In Bangladesh, C. limon is known as 'Lebu'. The chief bioactive phytoconstituents that are secluded from both C. limon fruit and its juice are flavonoids, volatile oils [105], phenolic acids, coumarins, and amino acids [106]. Recently, notable therapeutic attributes of C. limon have been reported that include anti-inflammatory, antimicrobial, cytotoxic, and antiparasitic actions [106].
The extract of C. limon peel acquired using hexane remarkably lessened the glucose content in the bloodstream in alloxan-induced diabetic rats [107]. At 400 mg/kg daily dose via oral route for twelve days, the blood sugar range had been depleted notably by the ethanol extract of C. limon peels in streptozotocin-induced diabetic rats [106]. It can also inhibit the incidence of gluconeogenesis to prevent diabetic disorders [106].

Lotkon (Baccaurea motleyana (Müll.Arg.))
Baccaurea motleyana (Müll.Arg.) is an everlasting, deciduous tree that attains an altitude of 30 m. It is widely known as Rambai and as "Lotkon" in Bangladesh which belongs to the Phyllanthaceae family [108]. It is also found in Peninsular Malaysia to Sumatera, Borneo, and Halmahera [108]. B. motleyana contains phenols, flavonoids, fats, organic acids, and vitamins. [108,109]. Different parts of the Rambai tree were claimed to exert antibacterial, antihyperglycemic, and skincare properties [110]. Based on a previous study, the fruit of B. motleyana is quite beneficial for keeping blood sugar under control [108].
The crude extract of the seed of L. chinensis tends to exhibit antihyperglycemic action by hindering α-glucosidase activity at an IC 50 of 0.691 µg/mL [115]. Again, in another study, L. chinensis seed water extract rendered hypoglycemic action in alloxan-induced diabetic rats by obstructing the glucose utilization of blood capillaries [116]. The pulp extract of L. chinensis demonstrated antidiabetic action with an IC 50 of 10.4 mg/mL by halting alpha-glucosidase activity [112]. Based on a research study, an in vitro analysis of methanol and ethyl acetate extracts of L. chinensis exhibited noteworthy inhibitory actions on rat lens aldose reductase (RLAR) having IC 50 values of 3.6 and 0.3 mg/mL, respectively [113].

Mango (Mangifera indica L.)
Mangifera indica L., a rapid-growing everlasting tree and also a member of the Anacardiaceae family, is said to be a renowned tropical Bangladeshi fruit [117] that is locally known as 'Aam' [118]. Despite having origins in semitropical countries like India, Bangladesh, and Myanmar, this is, however, still extensively farmed in the Philippines, Malaysia, Indonesia, Singapore, and Thailand [119]. Bioactive phytochemicals of this plant include saponins, flavonoids, terpenoids, steroids, tannins, anthraquinones, cardiac glycosides, and alkaloids. Based on previous reports, M. indica can render potential antidiabetic, antibacterial, antioxidant, and anti-inflammatory actions [119]. The ethanolic leaf extract of M. indica tends to exert notable antidiabetic action against streptozotocin-induced diabetic animal models (250 mg/kg b.w. dose) by elevating insulin secretion from β-cells [117]. According to a report, the extract of M. indica leaves obtained with ethanol normalizes blood glucose content at an IC 50 dose of 2.28 mg/mL by impeding the activity of pancreatic α-amylase [119]. The alcohol extract of M. indica leaf can also display antihyperglycemic action in rabbits at dose concentrations of 50, 100, 150, and 200 mg/kg body weight [118]. The ethyl acetate fraction from M. indica methanol leaf extract manifested antihyperglycemic action in vitro by halting α-amylase and α-glucosidase enzyme at an IC 50 of 24.04 ± 0.12 µg/mL and 25.11 ± 0.01 µg/mL, respectively [64]. According to a study, M. indica leaf extract rendered antidiabetic action in rats at an IC 50 value of 1.45 mg/mL by hindering α-glucosidase activity [120]. An in vitro essay of M. indica methanol leaf extract exhibited notable hypoglycemic action by blocking the function of dipeptidyl peptidase-4 (DPP-4) with an IC 50 value of 182.7 µg/mL [119].

Muskmelon (Cucumis melo L.)
Cucumis melo L. is an ancient herb that belongs to the Cucurbitaceae family [121]. This horticulture crop is found across the globe and widely cultivated in Bangladesh which is locally known as "Bangi". C. melo contains enormous phytochemicals for example phenolic compounds, glycolipids, carbohydrates, flavonoids, and terpenoids following apocaretonoids which possess several biological activities including antidiabetic, antibacterial, anti-inflammatory, anti-hypothyroidism, antioxidant, and antiangiogenic activities [121].
The toluene soluble fraction of the ethanol extract of C. melo fruit was found to be highly effective in lowering blood glucose levels which are attributed to enhanced insulin secretion, suppression of glucose absorption from the gut, enhanced glucose absorption by adipose tissues and skeletal muscle, and ultimately reduction of glucose synthesis from hepatic cells [121]. Administration of C. melo leaf extract to streptozotocin-induced diabetic rats notably lessened the blood sugar together with glycated hemoglobin content [122]. On the basis of a previous report, seeds roasted at various temperatures of 150 • C, 200 • C, 250 • C, and 300 • C suppressed α-amylase at 2.0 mg/mL by 61.8 percent, 60.9 percent, 50.5 percent, 72.0 percent, and 45.7 percent, respectively. Furthermore, the hexane extract of C. melo seeds inhibited α-glucosidase activity significantly [123].

Orange (Citrus reticulata Blanco)
Citrus reticulata Blanco, a small-sized thorny everlasting tree from the Rutaceae family, is a widely popular fruit in Bangladesh and locally called 'Komola', 'Kamala lebu'. Alongside Bangladesh, this fruit is grown worldwide and is also a horticultural crop in India [124]. It comprises various bioactive phytoconstituents like flavonoids, phenolics, tannins, monoterpenes, and sesquiterpenes and reportedly demonstrates a broad spectrum of remarkable antioxidant, antidiabetic, antifungal, anti-neurodegenerative, and antibacterial activities [124].
Orange peel and/or a combination of other citrus peels can exert potential action against diabetic disorders (Gosslau et al. 2018). The hydroethanolic extracts of C. reticulata fruit peel (100 mg/kg b.w./day dose) tend to exhibit hypoglycemic action in nicotinamide (NA)/streptozotocin(STZ)-induced type 2 diabetic rats by rejuvenating the function of β-cells found in the pancreas [125]. On the other hand, ethanol and aqueous peel extract manifested antihyperglycemic action by impeding the α-glucosidase by 70.8% and 14.8%, respectively, and also by hindering α-amylase 90.67% and 15.33%, respectively in rats with type 2 diabetes [126]. According to a report, the essential oil of C. reticulata rind and leaves (200 µL/kg b.w. dose) significantly lowered the blood glucose content from 251 ± 0.85 mg/dL to 90 ± 0.70 mg/dL, and 200 ± 0.67 mg/dL to 96.2 ± 0.86 mg/dL respectively in alloxan-induced diabetic rabbits [127].
The ethyl acetate extract of papaya seeds manifested antidiabetic action in vitro by impeding α-glucosidase and α-amylase enzymes at an IC 50 of 83.54 and 36.84 mg/mL, respectively [132]. According to a study, the aqueous leaf extract (400 mg/kg b.w. dose) improved the blood sugar concentration in alloxan-induced diabetic albino rats [133]. In the streptozotocin-induced diabetic rats, aqueous extract of the leaves of C. papaya displayed antihyperglycemic action at a dose of 0.75 and 1.5 g/100 mL by upgrading the islet cells' regenerative ability [134]. Consequently, the chloroform extract of C. papaya leaves also demonstrated remarkable hypoglycemic action in streptozotocin-induced diabetic rats [135].
The methanolic leaf extract of A. comosus leaves manifested a dose-dependent lowering of glucose content in the blood when given through an oral route to glucose-loaded Swiss albino mice models [137]. On the basis of a study conducted previously, the ethanol extract of A. comosus leaf notably halted the increase of glucose levels in the bloodstream having a concentration of 0.40 g/kg in diabetic rats. Also, the ethanolic leaves extract of A. comosus improved the sensitivity of insulin levels in rats with type 2 diabetes, which relates to enhancing the action of insulin in the hepatic cells [138]. Moreover, its fruit juice also showed synergistic action with glimepiride in lessening the blood sugar concentration in alloxan-induced diabetic rats [137].
The peel extract of C. maxima manifested indispensable antihyperglycemic action in Alloxan-induced diabetic Wister rats (400 mg/kg body weight dose) by lowering the sugar content in the bloodstream by 70.17% [142]. Consequently, in the same model, the juice extract of C. maxima fruit improved the glucose content at 10 mL/kg b.w. dose [143]. With the help of an in vitro model, fruit juice of red C. maxima halted the functionality of both α-amylase and α-glucosidase enzymes by 79.75% and 72.83%, respectively, and thereby demonstrating antidiabetic action [140]. According to a report, the leaf extract obtained with methanol tends to exhibit a hypoglycemic effect in streptozotocin-induced diabetic rats when an amount of 200 and 400 mg/kg body weight is administered via an oral route [141].

Pomegranate (Puncia granatum L.)
Punica granatum L., often known as pomegranate, is a shrub that grows well in warm valleys and belongs to the Punicaceae family [144]. The fruit of the plant is locally known as "Dalim". P. granatum is reported to have compounds such as alkaloids, tannins, flavonoids, anthocyanidins and hydroxybenzoic acid compounds [144]. It is efficacious as antidiabetic, antibacterial, anthelmintic, antifertility, antioxidant, antifungal, and antiulcer agents [145].
The aqueous extract of P. granatum fruit significantly raised the mRNA levels of IRS-1, Akt (Protein kinase B), GLUT-2, and GLUT-4, resulting in improved glucose uptake and storage and contributing to the regulation of both hyperglycemia and hyperlipidemia in alloxan-diabetic Wistar rats [146]. Ethyl acetate extract of its fruit peel halted α-glucosidase having an IC 50 285.21 ± 1.9 g/mL [147]. Furthermore, the methanolic flower extract of P. granatum increased cardiac PPAR-g mRNA expression and restored the down-regulated cardiac glucose transporter GLUT-4 (the insulin-dependent isoform of GLUTs) mRNA in rat models indicating that P. granatum flower extract has anti-diabetic activity due to improved insulin receptor sensitivity [148]. The methanolic extract of pomegranate fruit rinds also showed strong antidiabetic action in aldose reductase, α-amylase, and PTP1B suppression tests in a dose-dependent manner by controlling blood glucose concentrations within normal ranges in an alloxan-induced diabetes model [149].
Different phytochemicals from M. zapota seeds, leaves, and root extracts have been reported to exhibit hypoglycemic activity [150]. In addition, M. zapota leaf extract has shown improved hypoglycemic action in animal models [151]. Ethanol and aqueous extracts of M. zapota seeds displayed significant in vivo hypoglycemic action in experimental mice [152]. Another study found that alcohol and aqueous extracts of its seeds remarkably reduced the model group's blood glucose levels when compared to metformin [153]. Furthermore, ethanol extract from the seed and methanol extract from the leaf of M. zapota decreased blood glucose levels by controlling insulin production from the few remaining β-cells. According to the findings of this study, enhanced peripheral glucose consumption also aided in the lowering of blood glucose levels [154].
The methanolic leaf extract of A. carambola (400 mg/kg b.w. dose) exhibited antidiabetic action with a blood glucose-reducing potential of 34.1% in glucose-filled Swiss albino mice [95]. According to a study, the hydroalcoholic leaf extract of A. carambola exhibited promising antidiabetic action by upgrading the glucose intake of muscles in male Wistar rats [156]. The ethanol extract of its bark manifested noteworthy antihyper-glycemic action in vitro by effectively hindering the α-glucosidase enzyme at an IC 50 value of 7.15 ± 0.06 µg/mL [157]. Besides, the ethanol extract from air-dried roots also demonstrated antidiabetic action by restoring the pancreatic β-cells function in streptozotocininduced diabetic rats [158]. The juice of A. carambola fruits remarkably lowered glucose content at 25, 50, and 100 g/kg b.w. dose for three weeks in streptozotocin-induced diabetic mice [159].
A. squamosa hydroalcoholic leaf extract (350 mg/kg b.w. oral dose) tends to exert antidiabetic action with glucose reducing activity by 50.11% in streptozotocin-induced diabetic rats [162]. An in vitro analysis of methanol extracts of barks and leaves of A. squamosa manifested hypoglycemic action by impeding α-amylase at an IC 50 value of 123.91 and 153.89 µg/mL, respectively [163]. The hexane extract of the leaf of A. squamosal obtained using reportedly exerted antihyperglycemic action in vivo having a concentration of 500 mg/kg p.o by hindering the human PTP1B enzyme with an IC 50 level of 17.4 µg/mL [164]. Its ethanolic leaf extract at 50 mg/kg dose lessened the blood sugar content in alloxan-induced diabetic rabbits by 52.7% [161]. The ethanol and methanol extracts of A. squamosa seeds (200 mg/kg b.w. dose) demonstrated a notable antihyperglycemic effect by reducing the blood sugar levels by 43.96% and 45.99%, respectively, in alloxan-induced diabetic rats [165].
Previous research has revealed that the ethanol extract of C. lanatus leaf can inhibit pancreatic α-amylase with an IC 50 value of 36.75 ± 3.47 g/mL [168]. The aqueous ethanol and aqueous extracts of C. lanatus leaves profoundly rendered anti-diabetic action via α-glucosidase suppression, with IC 50 values ranging from 26.26 ± 0.29 to 180.33 ± 1.31 g/mL [166]. In another study, its juice was also discovered to have promising anti-diabetic efficacy in an experimental diabetic animal model via several mechanisms involving the regulation of glucose transporters and domination of α-glucosidase and α-amylase activity [168]. The seed extracts of yellow-skinned C. lanatus hindered α-glucosidase with IC 50 values ranging from 32.50 ± 0.36 to 313 ± 1.36 g/mL for 70 percent aqueous ethanol and aqueous extracts, respectively [166]. A recent study also found that the alcalde and tryptic hydrolysates of C. lanatus seeds had a very strong α-amylase inhibitory capacity (IC 50 values of 0.149 to 0.234 mg/mL) via a non-competitive suppression mechanism [169].

Tal Palm (Borassus flabellifer L.)
Borassus flabellifer L., a famous species of the Arecaceae family is locally known as "Tal" in Bengali and is a tall palm reaching up to 12-33 m height having a black stem and crown of leaves at the top [170]. It is extensively disseminated and grown in tropical Asian nations like Thailand, India, Myanmar, Sri Lanka, Malaysia, and Bangladesh. It is a promising source of alkaloids, flavonoids, glycosides, tannins and so many phenolic compounds [170]. B. flabellifer reportedly exerts an extensive spectrum of therapeutic actions like antihyperglycemic, anti-inflammatory, antipyretic, antibacterial, and anthelmintic activities [170].
Ethanolic extract of tal palm roots at 250 and 500 mg/kg displayed a promising reduction in the glucose content of serum in rats with type 2 diabetes [171]. Numerous portions of B. flabellifer like leaves, roots, pulp, and fruit fibers. are claimed to be utilized to treat diabetes [170]. Ethanolic extract of the flower of B. flabellifer significantly improved the glucose tolerance up to 4 h and lowered the glucose content of blood significantly in alloxaninduced diabetic rats. Furthermore, ethanol extracts of B. flabellifer flowers showed notable regeneration of pancreatic β cells comparable to glibenclamide [172]. Methanol extract of tal palm fruits demonstrated raised content of insulin in the plasma when compared to diabetic controls in diabetic rats. Again, methanol extract from tal palm fruits also impeded PTP1B remarkably with an IC 50 value of 23.98 mg/mL, and this decreased PTP1B expression which might increase the mass of β-cells in the pancreas which subsequently improved the release of insulin triggered by glucose and ultimately lowered the glucose content in blood [173].

Tamarind (Tamarindus indica L.)
Tamarindus indica L. from the Fabaceae family, a large-sized everlasting tree, is a nutrient-enriched tropical fruit is locally named "Tetul". Though this fruit is mostly endemic to tropical regions of Africa, still tamarind is farmed and developed well in all other tropical continents. T. indica is reported to have phytoconstituents like flavonoids, tannins, glycosides, organic acids, and phenolic compounds [174]. T. indica is reported to be useful as an antidiabetic, antimicrobial, and anti-inflammatory agent [175].
The aqueous extract of T. indica fruit pulp showed promising postprandial hypoglycemic effect by impeding the function of α-amylase and α-glucosidase enzymes and raising the glucose uptake [176]. Aqueous extract from T. indica seed and seed coat showed improvement in hyperlipidemia, which is foundnotably in rat models and humans [175]. On the basis of a study conducted previously, the aqueous extracts of T. indica seeds exerted hypoglycemic activity which was mediated by lowering the diffusion rate of blood glucose, increasing glucose adsorption, and upgrading the transportation of blood glucose at the cellular level throughout the plasma membrane [177]. According to a report, the extract of T. indica seed obtained using methanol demonstrated a significant reduction of blood glucose content at the fasting state in mice models [178]. In addition, the alcoholic extract of its stem bark functioned as a potent hyperglycemic agent in the treatment of diabetes mellitus [179]. The ethanolic fruit pulp extract also effectively changed alloxan-induced alterations in serum glucose, enzyme, and lipid profile [180].

Wood Apple (Limonia acidissima Groff)
Limonia acidissima Groff, a slow-growing, fragrant, large-sized, deciduous tree from the Rutaceae family is a popular nutrient-enriched Bangladeshi fruit and is locally known as "Kod-bael" [181,182]. Bangladesh, India, Pakistan, Sri Lanka, Myanmar, and Vietnam are among the countries where it appears to be growing naturally [182]. It incorporates major bioactive phytochemicals like coumarins, lignans, flavonoids, phenolic acids, quinones, alkaloids, triterpenoids, sterols, and volatile oils which reportedly exert a vast range of therapeutic attributes like antioxidant, cytotoxic, hypoglycemic, antimicrobial, and hepatoprotective activities [183].
The aqueous and ethanol extracts of L. acidissima stem bark (200 mg/kg b.w. dose) remarkably lessened the blood glucose content from 250-358 mg/kg to 99.8 and 112.6 mg/kg, respectively in alloxan-induced diabetic rats [181]. According to a report, the methanolic fruit extract of L. acidissima tends to exhibit antidiabetic action by lowering the glucose content by 39% and 54.5% at an oral dose of 200 and 400 mg/kg b.w., respectively in streptozotocin-induced male Albino diabetic rats [184]. The methanol and aqueous extract of its fruit manifested antihyperglycemic action in vitro (100 µg/mL concentration) by impeding the α-glucosidase at an IC 50 of 66.738 and 84.548 µg/mL, respectively and also by hindering α-amylase at an IC 50 of 119.698 and 167.505 µg/mL, respectively [185].

Phytochemicals from Fruits and Other Plant Parts
Phytochemicals are the key factors that exert the pharmacological actions of medicinal plants [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

Ananas comosus Fruit
Catechin α-glucosidase inhibitory actions [189,190] Epicatechin Promoting β-cell regeneration [190,191] Gallic acid Improved glucose transporters and insulin sensitivity through PPAR-γ and Akt signaling [190,192] p-coumaric acid Lowering the blood glucose level, increasing the level of insulin [190,193] Ferulic acid Restoring blood glucose and serum insulin level; improving insulin sensitivity, hepatic glycogenesis, glucose tolerance, and insulin tolerance along with reducing the activity of glycogen synthase and glucokinase and also increasing activity of glycogen phosphorylase and enzymes of gluconeogenesis (PEPCK and G6Pase) [190,194] Caffeic acid Reducing blood glucose concentration by inhibiting the activity of glucose-6-phosphatase and increasing insulin secretion [190,195] Ellagic acid Stimulating insulin secretion and decreases glucose intolerance by acting on β-cells of the pancreas [71,190] Vanillin Reducing serum glucose level and increasing insulin level [190,196] 4

Artocarpus heterophyllus
Whole Plant Morin Down-regulation of miR-29a expression level to improve insulin signaling and glucose metabolism [197] Bark from the main trunk, Root Betulinic acid Activating AMPK, reducing blood glucose level, and stimulating mRNA expression of GLUT-4 [197,198] Root Ursolic acid Lowering blood glucose level [197,199] Leaves, Stem, Root β-sitosterol Improving insulin resistance and insulin signaling along with reducing fasting blood glucose level and glycated hemoglobin [197,200] [203,204] Fruit Myo-inositol Improved insulin-stimulated glucose uptake in mature adipocytes; increased insulin sensitivity and glucose uptake [36,205] β-amyrin Improvement in blood sugar level and plasma insulin along with preservation of β cell integrity [36,206] 10

Citrus arunattifolia Fruit
Hesperetin Reducing blood glucose levels and increasing plasma insulin concentration and glycogen levels, ameliorating the abnormality resulting from hyperglycemia in pancreatic β-cells, increasing the number of insulin immune-positive cells of the islets [210,211] Quercetin Increased glucose uptake via regulation of the AMPK pathway along with improved GLUT-4 expression and regeneration of β-cells in the pancreatic islets [210,211]

Citrus limon
Fruit Peel Nobiletin Enhancing glucose uptake via the PI3K/Akt signaling pathway [210,215] Fruit, leaf Diosmin Improvement in fasting plasma glucose concentrations, glycosylated hemoglobin (HbA1c), C-reactive protein (CRP), and the activities of Lipoprotein lipase (LPL) and lecithin cholesterol acyl transferase (LCAT) enzymes [210] Fruit Rhoifolin Insulin mimetic activity [210] Didymin Improving insulin sensitivity, inhibitory action on α-glucosidase and diminished hepatic glucose production in insulin-resistant HepG2 cells [210] Hesperidin Reducing serum insulin and blood glucose level, normalizing the enzymatic activities of glucose-6-phosphatase and glucokinase enzyme [210] Hesperetin Reducing blood glucose levels and increasing plasma insulin concentration and glycogen levels, ameliorating the abnormality resulting from hyperglycemia in pancreatic β-cells, increasing the number of insulin immune-positive cells of the islets [210] Rutin Reducing blood glucose, elevating glycogen concentration [210] Quercetin Increased glucose uptake via regulation of the AMPK pathway along with improved GLUT-4 expression and regeneration of β-cells in the pancreatic islets [210]  Citrus maxima Fruit β-sitosterol Improving insulin resistance and insulin signaling along with reducing fasting blood glucose level and glycated hemoglobin [200,216] Naringenin Increased glucose uptake [216,217] Naringin Improved serum insulin level; enhanced mRNA expression of insulin receptor β-subunit and GLUT-4 [216,218] 14

Citrus reticulata
Fruit alpha-pinene Decreasing fasting blood glucoselevels [219,220] Limonene Inhibiting protein glycation [201,219] Rutin Reducing blood glucose, elevating glycogen concentration [210] Quercetin Increased glucose uptake via regulation of the AMPK pathway along with improved GLUT-4 expression and regeneration of β-cells in the pancreatic islets [210] Naringin Modifying the release of insulin from isolated islet and intestinal glucose absorption, improved expression of GLUT-4 in adipose tissue, and free circulating glucose uptake from the blood to peripheral tissues [210,221] Naringenin Lowered the increased plasma glucose concentration, increased the activity of Superoxide dismutase (SOD) [210] Didymin Improving insulin sensitivity, inhibitory action on α-glucosidase and diminished hepatic glucose production in insulin-resistant HepG2 cells [210] Hesperidin Reducing serum insulin and blood glucose level, normalizing the enzymatic activities of glucose-6-phosphatase and glucokinase enzyme [210]

8-Prenylnaringenin
Regulating the expression of Galectin-3 (Gal-3) protein which is overexpressed during the diabetic state, promoting glycation end products (AGEs) production [210] Fruits and leaves Diosmin Improvement in fasting plasma glucose concentrations, glycosylated hemoglobin (HbA1c), C-reactive protein (CRP), and the activities of Lipoprotein lipase (LPL) and lecithin cholesterol acyl transferase (LCAT) enzymes [210] Fruit peel Nobiletin Enhancing glucose uptake via the PI3K/Akt signaling pathway [210] Tangeretin Increasing glucose uptake, improving glycogen level and the activities of glycogen synthase and glycogen phosphorylase, regeneration of pancreatic β-cells in the islets [210]

Dried pericarp Hesperetin
Reducing blood glucose levels and increasing plasma insulin concentration and glycogen levels, ameliorating the abnormality resulting from hyperglycemia in pancreatic β-cells, increasing the number of insulin immune-positive cells of the islets [210,222] Albedo of fruit Neohesperidin Improved glucose tolerance and insulin sensitivity along with abatement in the blood glucose level [210,223] 15 Cocos nucifera Coconut water Myo-inositol Improved insulin-stimulated glucose uptake in mature adipocytes; increased insulin sensitivity and glucose uptake [205,224] 16

Manilkara zapota Fruit peel
Gallic acid Improved glucose transporters and insulin sensitivity through PPAR-γ and Akt signaling [192,238] Ellagic acid Stimulating insulin secretion and decreases glucose intolerance by acting on β-cells of the pancreas [71,238] Ferulic acid Restoring blood glucose and serum insulin level; improving insulin sensitivity, hepatic glycogenesis, glucose tolerance, and insulin tolerance along with reducing the activity of glycogen synthase and glucokinase and also increasing activity of glycogen phosphorylase and enzymes of gluconeogenesis (PEPCK and G6Pase) [194,238] Catechin α-glucosidase inhibitory actions [189,238] Epicatechin Promoting β-cell regeneration [235,238] Quercetin Improving insulin secretion [188,238]

Phyllanthus embelica Fruit Coliragin
Regulating fasting blood glucose, plasma insulin, and glycated hemoglobin (HbA1c) level [241,242] Gallic acid Improved glucose transporters and insulin sensitivity through PPAR-γ and Akt signaling [192,242] Ellagic acid Stimulating insulin secretion and decreases glucose intolerance by acting on β-cells of the pancreas [71,242] Cinnamic Acid Stimulation of insulin secretion, enhancement of insulin signaling pathway, the activity of pancreatic β-cell and glucose uptake, inhibition of hepatic gluconeogenesis, protein glycation, and insulin fibrillation along with the delay of carbohydrate digestion and glucose absorption [243,244]  Inhibiting the activity of aldose reductase and α-amylase enzyme, ameliorating blood glucose levels by inhibiting protein tyrosine phosphatase 1B (PTP1B), improved insulin secretion from pancreatic β cells or its release from the bound form along with insulin-mimetic actions along with rejuvenation of glucose utilization technique [149] Fruit Caffeic acid Reducing blood glucose concentration by inhibiting the activity of glucose-6-phosphatase and increasing insulin secretion [246,247] Fruit, pericarp Quercetin Increased glucose uptake via regulation of the AMPK pathway along with improved GLUT-4 expression and regeneration of β-cells in the pancreatic islets [210,247] Rutin Reducing blood glucose, elevating glycogen concentration [210,212,247] Catechin α-glucosidase inhibitory actions [189,247]

S.L. Species Plant Part Phytochemicals Mode of Actions References
Fruit, rind, flower Gallic acid Improved glucose transporters and insulin sensitivity through PPAR-γ and Akt signaling [192,247] Fruit, seed, flower Ellagic acid Stimulating insulin secretion and decreases glucose intolerance by acting on β-cells of the pancreas [71,247,248] Seed Punicic acid Increasing serum insulin levels and modulating glucose homeostasis [247,249] Flower Tricetin

Berberine
Insulin mimetic activity and improving the action of insulin by activating AMPK, decreasing insulin resistance through protein kinase C-dependent up-regulation of insulin receptor expression, enhancing GLP-1 secretion and modulating its release, inhibiting actions of DPP-4 [203] Quercetin Improving insulin secretion [188,203] Diosgenin Reducing intestinal disaccharidases, blood glucose level, and activity of α-Glucosidase along with modification of hepatocyte absorption of glucose and insulin resistance and insulin secretion [203,259] Kaempferol Inhibiting the activities of α-amylase and α-glucosidase along with glucose-lowering activity [203,212] Fruit Ursolic acid Lowering blood glucose level [197,203] Oleanolic acid Improved blood glucose and serum insulin levels [203,260] Leaf Swertisin Generating new β-cells [203,261]

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 [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 [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 [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 [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 [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 [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 noninsulin-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 [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 [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 [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 [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 [270].

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 [271,272].

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 [275].

d. Increased secretion of insulin
An increase in intracellular calcium ion [Ca 2+ ] i stimulates pancreatic β cells and facilitates insulin secretion. Some phytochemicals, e.g., p-methoxy cinnamic acid acting on the L-type Ca 2+ channels have been demonstrated to boost insulin release by increasing cAMP via the inhibition of phosphodiesterase [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 [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) [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 [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 glucoprotein-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 Ca 2+ levels, as well as activating the pancreatic duodenal homeobox 1 transcription factor that promotes insulin gene expression (Pdx-1) [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 [265,286].

Pharmacokinetic and Toxicological Profiles of Phytochemicals
Several studies have evaluated the pharmacokinetic data of phytochemicals isolated from plant sources i.e., natural alkaloids such as aegeline. The pharmacokinetic property of aegeline was demonstrated by Manda et al. [287]. Experimental mice were administered an oral dose of aegeline (30 mg/kg) that produced an elimination half-life of 1.25 h. Moreover, the area under the curve (AUC) and the peak plasma concentration were 2 h × µg/mL and 0.92 µg/mL, respectively. The volume of distribution (V D ) was found to be 40 L, and the distribution was reported in the kidney, brain, and liver of the mice. The information is found to be quite significant when comparing the outcomes of the in vitro cytotoxicity test. Aegeline, extracted from the fruit and leaves of natural plants, was experimented on a human liver carcinoma cell line (HepG2) and it was found that the highest dose tested (i.e., 100 ug/mL or 336.3 µmol) caused 43.2% inhibition but failed to reach an LC50 or IC50 [288]. Multiple investigators also tested the pharmacokinetic properties of berberine which demonstrated that berberine undergoes extensive metabolism resulting in extremely low oral bioavailability of this compound [289][290][291][292][293]. The inconsistency between the pharmacological activity of berberine and its extremely low plasma bioavailability proves that the berberine metabolites may influence its bioactivities [294][295][296]. In invitro tests on human liver microsomes using coumarin showed that the elimination rate was quite rapid. This is due to the 7-hydroxylation of the compound by cytochrome (CYP) P450 2A6 [297] and 3,4-epoxidation by CYP P450 2E1 [298]. On the other hand, 3,4-epoxidation of coumarin in rat liver microsomes revealed that coumarin is slowly eliminated by forming o-hydroxyphenyl acetic acid as the main metabolite [299]. The pharmacokinetic properties of phenolic compounds and tannins have been tested in both human and animal studies [300] but the results are controversial. A study by Wiese et al. [301] reported that high molecular weight tannins do not absorb intact, but rather converted to other metabolites. However, high fructose and sucrose contents may lead to type 2 diabetes mellitus along with cardiovascular risk [302]. Thus, fruits with high fructose and sucrose level should be avoided to avoid further triggers of diabetic complications. Besides, overconsumption of citrus fruits can cause toxicity due to their essential oil content [303]. Starfruits can induce both nephrotoxicity and neurotoxicity attributed to oxalate and caramboxin content. This fruit thus should not be consumed during renal impairment and empty stomach. Moreover, the calcium carbide used in the fruit ripening process can cause skin burns, skin irritations and inflammation. Other impurities found in calcium carbide including arsenic along with other toxic and carcinogenic chemicals can worsen the situation. On the other hand, canned fruit juices can also exert toxicity based on tin levels of around 1400 ppm and above. Thus, consumption of fruits should not be excessive which can lead to problems like gastric discomfort, a spike in glucose level or other complications.

Discussion
Type 1 and type 2 diabetes mellitus are the two most common types of diabetes, both of which cause hyperglycemia. Type 1 diabetes mellitus is an autoimmune disease defined by the destruction of pancreatic cells as a result of a very severe insulin deficiency state. Type 2 diabetes mellitus, on the other hand, is more well-known, and it affects 90 to 95% of total diabetic individuals. It is defined by peripheral insulin resistance and insulin secretion abnormalities [304]. Despite the fact that diabetes is a non-communicable disease, experts warn that by 2030, there will be about 438 million diabetic individuals [7], demonstrating the severity of the disease. Insulin resistance, aberrant insulin secretion, and hepatic glucose production, as well as poor lipid metabolism, are all factors that contribute to diabetes. Insulin resistance is a condition in which the potency of insulin on target cells, particularly adipocytes, hepatocytes, and skeletal muscles, is breached [305], resulting in hyperglycemia by interfering with glucose utilization and enhancing hepatic glucose output [306].
Diabetes is usually treated and controlled by prescribing synthetic antidiabetic drugs such as biguanides (metformin), sulphonylureas (glibenclamide), thiazolidinediones (pioglitazone), alpha-glucosidase inhibitors (acarbose), DPP-4 inhibitors (sitagliptin), glinides (repaglinide) and GLP-1 agonists (exenatide) [7]. Despite their widespread use, synthetic drugs have numerous side effects that gradually limit their prescription and welcome extensive research on the discovery and development of plant-based antidiabetic therapies with improved safety and efficacy profiles [307,308]. Diabetes mellitus has also been treated with plant-based drugs due to their efficacy, minimal toxicity and side effects, low cost, and availability in several localities [309,310]. To bring ethnobotanically important plants to the commercial field, isolated phytochemicals can be subjected to extensive research and clinical trials in order to validate the scientific potential of tribal or local use [311,312]. For example, in the 25 years prior to 2007, about 50% of all approved medications were plantbased natural compounds or their synthetic analogs [308,313]. The widely used diabetes medicine metformin is also produced from a plant source, Galegine officinalis [314]. Phytochemicals with antidiabetic potential include flavonoids (quercetin), alkaloids (berberine), terpenes (thymoquinone), phenolic compounds (6-gingerol), tannins (punicalagin), and others. Based on previous studies, phytochemicals can exert potent antidiabetic effects by enhancing insulin sensitivity and secretion, increasing glucose absorption by muscle and adipose tissue, and nourishing pancreatic beta cells. However, more research is required to determine these compounds' exact mechanisms of action, allowing them to be developed as medications or chemical leads. Phytochemicals not only act as medications or drug templates but also help uncover complex and novel biochemical pathways and targets involved in the disease [315]. Thus, additional research on these phytochemicals may reveal many treatment targets for diabetes mellitus, though the determination of the feasibility and toxicity profile of plant-based products is also a major research concern [7]. A wide range of fruit plants containing prospective phytochemicals with antidiabetic potential is commonly found in Bangladesh and the locals are consuming those fruits and other plant parts daily with or without knowing their health benefits (Figure 3). Fruits are packed with several bioactive secondary metabolites which may attribute to their antihyperglycemic activity [13]. Choosing fruits as antidiabetic agents can be very efficient as we generally consume fruits every day and if our daily consumption can support us to control and/or prevent diabetes, it can be at the same time cost-effective and widely available option. Besides, other fruit parts like seeds of black plum and litchi, peels and leaves of lemon, and flowers of the pomegranate can be equally prioritized in the management of diabetes. Moreover, reported antidiabetic phytochemicals from these sources (fruits and other plant parts) like swertisin, quercetin, berberine, hesperidin, kaempferol, 6-gingerol, ellagic acid, pinitol, and other prospective phytochemicals should be evaluated extensively to unveil novel therapeutics against diabetic disorders. Fruits and other parts of plants are also addressed in many indigenous medicinal applications, including in ancient Chinese cultures, Ayurveda, and Western medical therapies which also indicate their enormous potential to be a great source of notable antidiabetic drugs [7,13]. There have also been some previous studies on the antidiabetic potential of fruit plants. But in our review work, we exclusively stratified the phytochemicals according to their source narrowed down to plant parts along with their reported MoA (mechanism of action). Thus, we hope that, this review containing a balanced scoop of information of fruit plants and their antidiabetic importance can be crucial in the field of novel antidiabetic drug development. Even, consumption of fruits can be encouraged by this scientific review in order to manage diabetic complications among local people. therapies which also indicate their enormous potential to be a great source of notable antidiabetic drugs [8,14]. There have also been some previous studies on the antidiabetic potential of fruit plants. But in our review work, we exclusively stratified the phytochemicals according to their source narrowed down to plant parts along with their reported MoA (mechanism of action). Thus, we hope that, this review containing a balanced scoop of information of fruit plants and their antidiabetic importance can be crucial in the field of novel antidiabetic drug development. Even, consumption of fruits can be encouraged by this scientific review in order to manage diabetic complications among local people.

Article Search Strategy
An extensive literature search was performed employing PubMed/Medline, Scopus, ScienceDirect, Web of Science, Google Scholar, and Wiley Online Library databases. We have utilized 'Antidiabetic activity', 'Diabetes', 'Type 2 diabetes', 'T2DM', 'Fruits', 'Fruit plants', 'Bangladesh', 'Bangladeshi fruit', 'Fruit extracts', and 'Plant product' keywords to collect desired articles up to April 2022. Taking into account only peer-reviewed and published publications in the English language on the antidiabetic actions of commonly available Bangladeshi fruit plants and their isolated phytocompounds as inclusion criteria, 323 distinct articles were included in this review work. The PRISMA (was followed to search, extract, and include necessary information for this article (Figure 4) [316].

Article Search Strategy
An extensive literature search was performed employing PubMed/Medline, Scopus, ScienceDirect, Web of Science, Google Scholar, and Wiley Online Library databases. We have utilized 'Antidiabetic activity', 'Diabetes', 'Type 2 diabetes', 'T2DM', 'Fruits', 'Fruit plants', 'Bangladesh', 'Bangladeshi fruit', 'Fruit extracts', and 'Plant product' keywords to collect desired articles up to April 2022. Taking into account only peer-reviewed and published publications in the English language on the antidiabetic actions of commonly available Bangladeshi fruit plants and their isolated phytocompounds as inclusion criteria, 323 distinct articles were included in this review work. The PRISMA (was followed to search, extract, and include necessary information for this article (Figure 4) [317]. The following were the inclusion criteria of studies: (a) The study must evaluate the antidiabetic activity of the fruit plants; (b) The plants must be available in Bangladesh; (c) The study has comprehensively discussed the potential antidiabetic activities as well as cited relevant sources; (d) The data including the values presented was authentic; and (e) The study was published in the above-mentioned authentic databases.
Besides, the exclusion criteria were as follows: (a) Plant species other than fruit trees are discarded; (b) Not commonly grown fruit plants of Bangladesh are discarded; (c) No reported antidiabetic potential from the fruit plants are discarded; (d) Fruit trees with no reported phytochemical with antidiabetic action are discarded; (e) Articles not in the English language are discarded; (f) Commentary/letter to editor/correspondence are discarded; (g) Fruits with only traditional use but lack of scientific reports have been discarded; and (h) Not peer-reviewed and/or published data are discarded.

Conclusion and Future Perspectives
Though fruits and other plant parts have long been thought to be viable sources of treatments for a variety of diseases, including diabetes and others, many of those have yet to be thoroughly investigated. This review sought to investigate available Bangladeshi antidiabetic fruit-producing trees that have been shown in lab studies to have antihyperglycemic properties and may be used to treat a variety of diabetic and metabolic illnesses. Based on the review work, fruit trees can deliver a handy source of diabetes management blessed with a better safety profile while a major number of synthetic medications are compromised with side effects including weight gain, liver failure, tachycardia, and hypothyroidism as well as a higher cost. Prospective phytochemicals like quercetin, rutin, naringin, 6-gingerol, pinitol, and others may play the driving role here to exert the reported antidiabetic potential. By inhibiting the α-glucosidase, α-amylase, and DPP-4 enzymes, along with amelioration of insulin sensitivity, insulin secretion, glucose uptake by muscle cells and adipose tissue, and nourishment of pancreatic β -cells, the phytochemicals reported in this study demonstrated prominent anti-diabetic action. These various modes of phytochemicals to exert antidiabetic action illustrates the effectual diversity they can offer. Therefore, prospective and potential candidates for the development of novel antidiabetic drugs can include phytocompound(s) isolated from fruit plants that have demonstrated preclinical and clinical antidiabetic efficacy. However, over consumption of fruits with high levels of sugar content along with dried and canned fruits should be limited as despite the fact that plants are regarded as a safer and better alternative, excess amounts of those may welcome unwanted adverse effects. Further research is still recommended to identify and evaluate the precise molecular pathway of therapeutic actions revealed by these potential fruits.

Informed Consent Statement:
The authors declare that the study was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Data Availability Statement: Not applicable.

Acknowledgments:
The authors are warmly grateful to all the farmers and cultivators of Bangladesh, an agricultural country, for providing the nutritional demand and food supply to the country people.

Conflicts of Interest:
The authors declare no conflict of interest.