Fruit Plants in the Management of Diabetes: Comparison
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Diabetes mellitus is a chronic metabolic disorder characterized by a lack of insulin action and/or generation. Discrepancies in protein, carbohydrate, and lipid metabolism can emerge due to the insufficiency of insulin. Low insulin levels, insulin resistance in target tissues, insulin-receptor expression, especially in adipose tissue and skeletal muscles, and to a lesser extent in the liver, effector enzymes, and/or signal transduction system all can play vital roles in metabolic disorders. Herbal products, such as fruit, seed, bark, fruit peel, and leaf, are always considered as promising sources of bioactive phytochemicals to treat different ailments including diabetes, pain, fever, cancer, hypertension, and so on. Phytomedicines are believed to be sanctified with lesser side effect, and thus, almost 80% of drug moieties are directly plant-extracted or their modified versions. Fruits are one of the most notable natural sources which provide fiber, minerals, vitamins, and many other essential nutrients which are included in daily diets. Fruits are also rich sources of flavonoids, saponins, polyphenols, carotenoids, isothiocyanates, and several other bioactive phytochemicals. Fruits are thought to be useful in the management of diabetes, cancer, obesity, and other disease states, including cardiovascular complications. From ancient Chinese therapies to modern approaches, local fruits are heavily incorporated to treat diabetic patients. Ayurveda medicines in the Indian subcontinent, including Bangladesh, also use a wide variety of locally produced fruits. It is believed that fruits and other plant parts can exhibit antidiabetic potential through several mechanism of actions.

 

  • diabetes
  • insulin
  • fruit
  • Antidiabetic
  • Blood glucose
  • Glycemic control
  • HbA1c

1. 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 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]. 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]. 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]. Furthermore, a study reported that medicinal plants and their fruits were traditionally used for the treatment of diabetes in Manisa, Turkey [5]. 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]. 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]. Jujube dried fruits would be taken by ethnic people of Manisa, Turkey [5]. 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]. 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]. Seed powder of muskmelon is used for its antidiabetic potentials in some areas as well [9].

2. Phytochemicals from Fruits and Other Plant Parts

Phytochemicals are the key factors that exert the pharmacological actions of medicinal plants [10][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.
Table 1.
Commonly available Bangladeshi fruit plants and their antidiabetic properties along with responsible phytochemicals and their modes of action.
Coumarins Flavonoids Polyphenols and Phenolic Compounds Terpenes and Triterpenoids Fatty Acids Tannins and Ellagitannins Xanthones Miscellaneous
Aegelin 2 Scopoletin Swertisin Ferulic acid Ursolic acid n-hexadecanoic acid Punicalagin 5-hydroxy mangiferin Pinitol (Cyclic polyol)
Aegeline Umbelliferon Apigenin Gallic acid Limonene Cinnamic Acid Punicalin 6-O-galloyl-5′-hydroxy mangiferin Neohesperidin (Glycoside)
Berberine   Avicularin Gentisic acid Arjunolic acid Oleic acid Vescalagin Mangiferin Citrulline (Non-essential amino acid)
    Catechin p-coumaric acid Betulinic acid Punicic acid Punicalagin   Diosgenin (Steroidal sapogenin)
    Didymin Carvacrol Lanosterol   Valoneic acid dilactone    
    Diosmin Methyl gallate Lupeol        
    Tangeretin Vanillic acid Mascilinic acid        
    Epicatechin Vanillin Oleanolic acid        
    Guaijaverin Mombintane I β-amyrin        
    Hesperetin Mombintane II α-Pinene        
    Hesperidin Sitosterol          
    Isoquercetin Stigmasterol          
    Kaempferol β-sitosterol          
    Luteolin Phlorizin          
    Morin 6-gingerol          
    Myricitrin Caffeic acid          
    Naringenin Oligonol          
    Naringin Ellagic Acid          
    Nobiletin            
    Quercetin            
    Rhoifolin            
    Rutin            
    8-Prenylnaringenin  
S.L. Species Plant Part Phytochemicals Mode of Actions References
1 Aegle Marmelos Leaf Aegeline Blood glucose-lowering activity [12]
Aegelin 2; sitosterol; scopoletin Blood glucose-lowering activity [13]
2 Annona squamosa Leaf Rutin Inhibition of α-glucosidase activity and improved insulin secretion [14]
Quercetin Improving insulin secretion [14][15]
Isoquercetin Inhibiting the activity of DPP-4 [14]
3 Ananas comosus Fruit Catechin α-glucosidase inhibitory actions [16][17]
Epicatechin Promoting β-cell regeneration [17][18]
Gallic acid Improved glucose transporters and insulin sensitivity through PPAR-γ and Akt signaling [17][19]
p-coumaric acid Lowering the blood glucose level, increasing the level of insulin [17][20]
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) [17][21]
Caffeic acid Reducing blood glucose concentration by inhibiting the activity of glucose-6-phosphatase and increasing insulin secretion [17][22]
Ellagic acid Stimulating insulin secretion and decreases glucose intolerance by acting on β-cells of the pancreas [17][23]
Vanillin Reducing serum glucose level and increasing insulin level [17][24]
4 Artocarpus heterophyllus Whole Plant Morin Down-regulation of miR-29a expression level to improve insulin signaling and glucose metabolism [25]
Bark from the main trunk, Root Betulinic acid Activating AMPK, reducing blood glucose level, and stimulating mRNA expression of GLUT-4 [25][26]
Root Ursolic acid Lowering blood glucose level [25][27]
Leaves, Stem, Root β-sitosterol Improving insulin resistance and insulin signaling along with reducing fasting blood glucose level and glycated hemoglobin [25][28]
5 Averrhoa carambola Fruit 2-dodecyl-6-methoxycyclohexa-2,5-diene-1, 4-dione Improved blood sugar level and inhibition of the TLR-4/TGF-β signaling pathway [29]
6 Baccaurea motleyana Fruit Limonene Inhibiting protein glycation [30][31]
Carvacrol α-amylase inhibitory actions [30][31]
7 Borassus

flabellifer Fruit pulp Tyrosol, Glucosyl-(6-1)-glycerol α-glucosidase inhibitory actions [32]
8 Carica papaya Seed Hexadecanoic acid, methyl ester; 11-octadecenoic acid, methyl ester; N, N-dimethyl-; n-hexadecanoic acid, and oleic acid Inhibiting α-amylase and α-glucosidase [33]
9 Carissa carandas Leaf Ursolic acid Lowering blood glucose level [34][35]
Fruit Myo-inositol Improved insulin-stimulated glucose uptake in mature adipocytes; increased insulin sensitivity and glucose uptake [36][37]
β-amyrin Improvement in blood sugar level and plasma insulin along with preservation of β cell integrity [36][38]
10 Citrullus lanatus Fruit Citrulline Improving insulin sensitivity [39][40]
6-gingerol Lowering fasting blood glucose levels and improving glucose tolerance [39][41]
Arjunolic acid Protective action on pancreatic β-cells, Reducing blood glucose level [39][42]
Lycopene Reducing blood glucose level [22]
11 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 [43][44]
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 [43][44]
Rutin Reducing blood glucose, elevating glycogen concentration [43][44]
Nobiletin Enhancing glucose uptake via the PI3K/Akt signaling pathway [43][44]
Kaempferol Inhibiting the activities of α-amylase and α-glucosidase along with glucose-lowering activity [44][45]
Naringenin lowered the increased plasma glucose concentration, increased the activity of Superoxide dismutase (SOD) [43][44]
Apigenin Reduction in serum glucose level, enhancing serum insulin level, nourishment of pancreatic β cell [44][46][47]
12 Citrus limon Fruit Peel Nobiletin Enhancing glucose uptake via the PI3K/Akt signaling pathway [43][48]
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 [43]
Fruit Rhoifolin Insulin mimetic activity [43]
Didymin Improving insulin sensitivity, inhibitory action on α-glucosidase and diminished hepatic glucose production in insulin-resistant HepG2 cells [43]
Hesperidin Reducing serum insulin and blood glucose level, normalizing the enzymatic activities of glucose-6-phosphatase and glucokinase enzyme [43]
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 [43]
Rutin Reducing blood glucose, elevating glycogen concentration [43]
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 [43]
13 Citrus maxima Fruit β-sitosterol Improving insulin resistance and insulin signaling along with reducing fasting blood glucose level and glycated hemoglobin [28][49]
Naringenin Increased glucose uptake [49][50]
Naringin Improved serum insulin level; enhanced mRNA expression of insulin receptor β-subunit and GLUT-4 [49][51]
14 Citrus reticulata Fruit alpha-pinene Decreasing fasting blood glucoselevels [52][53]
Limonene Inhibiting protein glycation [31][52]
Rutin Reducing blood glucose, elevating glycogen concentration [43]
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 [43]
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 [43][54]
Naringenin Lowered the increased plasma glucose concentration, increased the activity of Superoxide dismutase (SOD) [43]
Didymin Improving insulin sensitivity, inhibitory action on α-glucosidase and diminished hepatic glucose production in insulin-resistant HepG2 cells [43]
Hesperidin Reducing serum insulin and blood glucose level, normalizing the enzymatic activities of glucose-6-phosphatase and glucokinase enzyme [43]
8-Prenylnaringenin Regulating the expression of Galectin-3 (Gal-3) protein which is overexpressed during the diabetic state, promoting glycation end products (AGEs) production [43]
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 [43]
Fruit peel Nobiletin Enhancing glucose uptake via the PI3K/Akt signaling pathway [43]
Tangeretin Increasing glucose uptake, improving glycogen level and the activities of glycogen synthase and glycogen phosphorylase, regeneration of pancreatic β-cells in the islets [43]
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 [43][55]
Albedo of fruit Neohesperidin Improved glucose tolerance and insulin sensitivity along with abatement in the blood glucose level [43][56]
15 Cocos nucifera Coconut water Myo-inositol Improved insulin-stimulated glucose uptake in mature adipocytes; increased insulin sensitivity and glucose uptake [37][57]
16 Cucumis melo Seed Gallic acid Improved glucose transporters and insulin sensitivity through PPAR-γ and Akt signaling [19][58]
Vanillic acid Translocation of GLUT-4 via the AMPK-dependent pathway [58][59]
4-Hydroxybenzoic acid Increasing serum insulin levels and liver glycogen content [58][60]
17 Dillenia indica Leaf 3,5,7,-Trihydroxy-2-(4-hydroxy-benzyl)-chroman-4-one Enhanced serum insulin level and reduced fasting blood glucose level [61]
Betulinic acid, Quercetin, β-sitosterol, Stigmasterol Inhibiting activities of α-amylase and α-glucosidase [18]
18 Diospyros malabarica Leaf Betulinic acid Activating AMPK, reducing blood glucose level, and stimulating mRNA expression of GLUT-4 [26][62]
Fruit, Leaf β-sitosterol Improving insulin resistance and insulin signaling along with reducing fasting blood glucose level and glycated hemoglobin [28][62]
19 Elaeocarpus floribundus Leaf Myricitrin α-amylase inhibitory actions [63]
20 Limonia acidissima Whole Plant Stigmasterol lowering serum glucose level [64][65]
Umbelliferone Improving glucose uptake [65][66]
Lupeol Improving serum insulin level, reducing glycated hemoglobin, serum glucose [64][65]
β-sitosterol Improving insulin resistance and insulin signaling along with reducing fasting blood glucose level and glycated hemoglobin [28][65]
21 Litchi chinensis Fruit Epicatechin Promoting β-cell regeneration, enhancement of glucose consumption in HepG2 cells [67]
Seed (2R)-naringenin-7-O-(3-O-α-L-rhamnopyranosyl-β

-D-glucopyranoside); narirutin; quercetin; phlorizin		 dose-dependent α-glucosidase inhibitory actions
Fruit Oligonol Ameliorating insulin resistance
Flower Gentisic acid Inhibiting α-amylase and α-glucosidase [68][69]
Epicatechin Promoting β-cell regeneration, enhancement of glucose consumption in HepG2 cells [67][68][70]
22 Mangifera indica Kernel 6-O-galloyl-5′-hydroxy mangiferin; mangiferin; 5-hydroxy mangiferin; methyl gallate Reducing the blood glucose levels [71]
Leaf 1,2,3,4,6 Penta-O-galloyl-β-d-glucose Inhibiting 11-β-HSD-1 and ameliorating high-fat diet-induced diabetes [72]
23 Manilkara zapota Fruit peel Gallic acid Improved glucose transporters and insulin sensitivity through PPAR-γ and Akt signaling [19][73]
Ellagic acid Stimulating insulin secretion and decreases glucose intolerance by acting on β-cells of the pancreas [23][73]
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) [21][73]
Catechin α-glucosidase inhibitory actions [16][73]
Epicatechin Promoting β-cell regeneration [70][73]
Quercetin Improving insulin secretion [15][73]
24 Musa sapientum Pulp Quercetin Improving insulin secretion [15][74]
Pectin Reducing blood glucose level, improving liver glycogen [15][74]
Leaf β-amyrin Improvement in blood sugar level and plasma insulin along with preservation of β-cell integrity [38][74]
Lanosterol Reducing blood glucose level [74][75]
25 Phyllanthus embelica Fruit Coliragin Regulating fasting blood glucose, plasma insulin, and glycated hemoglobin (HbA1c) level [76][77]
Gallic acid Improved glucose transporters and insulin sensitivity through PPAR-γ and Akt signaling [19][77]
Ellagic acid Stimulating insulin secretion and decreases glucose intolerance by acting on β-cells of the pancreas [23][77]
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 [78][79]
26 Psidium

guajava Leaf Guaijaverin Inhibiting the activity of DPP-4 [80]
Avicularin Inhibiting glucose uptake mediated by GLUT-4
27 Punica granatum Rind Valoneic acid dilactone 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 [81]
Fruit Caffeic acid Reducing blood glucose concentration by inhibiting the activity of glucose-6-phosphatase and increasing insulin secretion [82][83]
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 [43][83]
Rutin Reducing blood glucose, elevating glycogen concentration [43][45][83]
Catechin α-glucosidase inhibitory actions [16][83]
Fruit, rind, flower Gallic acid Improved glucose transporters and insulin sensitivity through PPAR-γ and Akt signaling [19][83]
Fruit, seed, flower Ellagic acid Stimulating insulin secretion and decreases glucose intolerance by acting on β-cells of the pancreas [23][83][84]
Seed Punicic acid Increasing serum insulin levels and modulating glucose homeostasis [83][85]
Flower Tricetin 4′-O-β-glucopyranoside Inhibiting activities of α-amylase and α-glucosidase [84]
Tricetin Inhibiting activities of α-amylase and α-glucosidase [84]
Ursolic acid Lowering blood glucose level [25][83]
Mascilinic acid Improving insulin resistance, hepatic glycogen content, and inhibiting glycogen phosphorylase activity in HepG2 cells [83][86]
Luteolin Regulating blood glucose, HbA1c, and insulin level [84][87]
Fruit, Leaf, Root, Bark Punicalin α-glucosidase inhibitory actions [83][88]
Leaf Apigenin Reduction in serum glucose level, enhancing serum insulin level, nourishment of pancreatic β-cell [46][55][83]
Fruit, Root, bark Punicalagin α-glucosidase inhibitory actions [83][88]
28 Spondias mombin Leaf 3β-olean-12-en-3-yl (9Z)-hexadec-9-enoate α-amylase inhibitory actions [89]
Mombintane I; mombintane II Glucose lowering and α-amylase inhibitory actions [90]
29 Syzygium cumini Leaf Stigmasterol Lowering serum glucose level [64]
Lupeol Improving serum insulin level, reducing glycated hemoglobin and serum glucose
β-sitosterol Improving insulin resistance and insulin signaling along with reducing fasting blood glucose level and glycated hemoglobin [28][64]
30 Syzygium samarangense Leaf 2′,4′-dihydroxy-3′, 5′-dimethyl-6′-methoxychalcone Lowering blood glucose level [91]
Fruit Vescalagin Improving insulin resistance and glycemic metabolism [92]
31 Tamarindus indica Leaf Limonene Inhibiting protein glycation [31][93]
Root bark Pinitol Insulin mimetic activity and regulating glucose uptake [93][94]
Seed β-amyrin Improvement in blood sugar level and plasma insulin along with preservation of β-cell integrity [38][93]
Seed, Root bark β-sitosterol Improving insulin resistance and insulin signaling along with reducing fasting blood glucose level and glycated hemoglobin [28][93]
Fruit Lupeol Improving serum insulin level, reducing glycated hemoglobin, serum glucose [64][93]
Naringenin Increased glucose uptake [50][93]
Catechin α-glucosidase inhibitory actions [16][93]
Epicatechin Promoting β-cell regeneration [70][93]
32 Ziziphus mauritiana Aerial Part 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 [34]
Quercetin Improving insulin secretion [15][34]
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 [34][95]
Kaempferol Inhibiting the activities of α-amylase and α-glucosidase along with glucose-lowering activity [34][45]
Fruit Ursolic acid Lowering blood glucose level [25][34]
Oleanolic acid Improved blood glucose and serum insulin levels [34][96]
Leaf Swertisin Generating new β-cells [34][97]
Table 2. Chemical class-wise prospective antidiabetic phytochemicals found in fruit plants.
Alkaloids

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]. 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]. 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]. 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]. 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]. 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] 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]. 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]. 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]. 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]. 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].

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].
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].
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].
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].
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].
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].
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].
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].
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].

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