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Published online 2017 Nov 29. doi: 10.1016/j.jtcme.2017.08.012
PMCID: for 1 last update 2020/05/30 PMC6035310PMC6035310
PMID: 29992107

Hira Choudhury

aInternational Medical University, School of Pharmacy, Department of Pharmaceutical Technology, 57000, Kuala Lumpur, Malaysia

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Manisha Pandey

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Chua Kui Hua

aInternational Medical University, School of Pharmacy, Department of Pharmaceutical for 1 last update 2020/05/30 Technology, 57000, Kuala Lumpur, MalaysiaaInternational Medical University, School of Pharmacy, Department of Pharmaceutical Technology, 57000, Kuala Lumpur, Malaysia

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Cheah Shi Mun

aInternational Medical University, School of Pharmacy, Department of Pharmaceutical Technology, 57000, Kuala Lumpur, Malaysia

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Jessmie Koh Jing

aInternational Medical University, School of Pharmacy, Department of Pharmaceutical Technology, 57000, Kuala Lumpur, Malaysia

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Lillian Kong

aInternational Medical University, School of Pharmacy, Department of Pharmaceutical Technology, 57000, Kuala Lumpur, Malaysia

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Liang Yee Ern

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Nik Ahmad Ashraf

aInternational Medical University, School of Pharmacy, Department of Pharmaceutical Technology, 57000, Kuala Lumpur, Malaysia

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Soohg Wai Kit

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318 pakistani dating london zeist 🔴how to 318 pakistani dating london zeist for Tan Sin Yee

aInternational Medical University, School of Pharmacy, Department of Pharmaceutical Technology, 57000, Kuala Lumpur, Malaysia

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Mallikarjuna Rao Pichika

aInternational Medical University, School of Pharmacy, Department of Pharmaceutical Technology, 57000, Kuala Lumpur, Malaysia

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bFaculty of Pharmacy, Lincoln for 1 last update 2020/05/30 University College, Petalling Jaya, Kuala Lumpur, Selangor, 47301, MalaysiabFaculty of Pharmacy, Lincoln University College, Petalling Jaya, Kuala Lumpur, Selangor, 47301, Malaysia

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Prashant Kesharwani

aInternational Medical University, School of Pharmacy, Department of Pharmaceutical Technology, 57000, Kuala Lumpur, Malaysia

cPharmaceutics Division, CSIR-Central Drug Research Institute, Lucknow, UP, 226031, India

Find articles by Prashant Kesharwani
aInternational Medical University, School of Pharmacy, Department of Pharmaceutical Technology, 57000, Kuala Lumpur, Malaysia
bFaculty of Pharmacy, Lincoln University College, Petalling Jaya, Kuala Lumpur, Selangor, 47301, Malaysia
cPharmaceutics Division, CSIR-Central Drug Research Institute, Lucknow, UP, 226031, India
Hira Choudhury: [email protected]; Prashant Kesharwani: [email protected]: [email protected]_tnahsarP
Corresponding author. International Medical University, School of Pharmacy, Department of Pharmaceutical Technology, 57000, Kuala Lumpur, Malaysia. [email protected]
∗∗Corresponding author. Pharmaceutics Division, CSIR-Central Drug Research Institute, Lucknow, UP, 226031, India. [email protected], [email protected]_tnahsarP
Received 2017 Jun 21; Revised 2017 Aug 15; Accepted 2017 Aug 16.
Copyright © 2017 Center for Food and Biomolecules, National Taiwan University. Production and hosting by Elsevier Taiwan LLC.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
This article has been cited by other articles in PMC.

Abstract

318 pakistani dating london zeist ⭐️how to 318 pakistani dating london zeist for Herbal medicine, phytomedicine or botanical medicine are synonymous, utilizes plants intended for medicinal purposes. Medicinal use of herbal medicine in the treatment and prevention of diseases including diabetes has a long history compared to conventional medicine. Diabetes is one of the major public health concerns over the world. Diabetes or hyperglycemia is considered to be one of the common public health hazard; optimal control of which is still not possible. Persistent hyperglycemia or uncontrolled diabetes has the potential to cause serious complications such as kidney disease, vision loss, cardiovascular disease, and lower-limb amputations which contributed towards morbidity and mortality in diabetes. There are various approaches to treat and prevent diabetes as well as its secondary complications, one of it is herbal medicines. However, the selection of herbs might depends on several factors, which include the stage of progression of diabetes, types of comorbidities that the patients are having, availability, affordability as well as the safety profile of the herbs. This review focuses on the herbal and natural remedies that play the role in the treatment or prevention of this morbid disorder – diabetes, including their underlying mechanisms for the blood glucose-lowering property and the herbal products already been marketed for the remedial action of diabetes.

Keywords: Herbal medicine, Insulin secretion, Insulin resistivity, Active component, Diabetes control

Graphical abstract

1. Introduction

Use of herbal products are not only limited to dietary uses, such as food, nutrition, etc., it has its distinct role in remedy of several diseases. Herbal medicine, sometimes known as phytomedicine or botanical medicine, utilizes different parts of the plants, including its flowers, fruits, seeds, leaves, berries, bark and roots intended for medicinal purposes.1 The use and delivery of herbal medicine as dosage form in treating and preventing of diseases has a long history started with use in Mesopotamia in 2600 B.C.,2 although the oldest record on practice of medicinal plants for drug preparation was engraved on a Sumerian clay slab, created over 5,000 years ago.3 The use of medicinal plants are still continuing in this modern era, and it has been estimated that approximately one fourth of prescription medicines worldwide are derived from plants.1 World Health Organization has also reported the use of traditional medicine for primary health care needs in most countries.4 Herbal products in Malaysia have molded an essential component in the medicine system, where the Malaysian market for herbal products stands at approximately RM4.6 billion with a 15–20% annual projected growth rate.5 Therefore increased interest of Malaysians''s model. It stimulates intracellular glucose transport and result to increase glucose uptake by various cells.44 In absence of insulin, resveratrol showed its stimulatory action on glucose transport.45 Numerous research findings have shown that resveratrol enhance insulin sensitivity in experimentally induced insulin resistance animal model.46

Hence, reviewing these studies it can be concluded that long term diabetic treatment with certain anti-diabetic medicinal plant could result in better control of blood glucose via improvement of cellular sensitivity towards endogenous insulin, thus more clearance of the glucose molecules became possible to achieve a healthier lifestyle.

318 pakistani dating london zeist ⭐️how to 318 pakistani dating london zeist for 3.1.3. Herbs have impact on glucose absorption

The utilization of α-glucosidase inhibitor is one of the remedies for diabetes as it suppresses carbohydrate digestion, thus decelerating the process of glucose assimilation and resulting in significant reduction of postprandial plasma glucose and insulin level with a significant decrease of HbA1c postprandially. There is a wide use of α-glucosidase inhibitor in the control of T2DM, for e.g., acarbose, voglibose, miglitol, etc.47 Several researches are ongoing in search of potential natural candidates for the effective control of diabetes consequently, several herbs, such as cinnamon, China aster, mistletoe fig and bitter oleander have been found to exhibit inhibitory actions on α-glucosidase. Besides that, inhibition of α-amylase has also been associated with anti-hyperglycemic actions of medicinal herbs like Camellia sinensis, Aloe vera, basil, etc.48 In addition to the inhibitory effect on these two enzymes, polyphenol-rich herbs such as jute and soybean have additional benefit in managing diabetes and hypertension due to inhibitory activities on angiotensin converting enzyme (ACE).49 Other herbs that showed potential in treating diabetes include olive leaves, which has been shown to reduce digestion and absorption of starch, as well as black seed, where the inhibition of sodium-dependent glucose transport has been demonstrated. Below are examples of herbs that influence glucose absorption via their respective mechanism of actions:

Phyllanthus urinaria is a wild plant in Indonesia of Euphorbiaceae family being used traditionally in urinary tract disorders and diabetes. Chromatographic separation of hydro-methanolic extract of P. urinaria leaves and subsequent purification of the active fractions using preparative HPLC revealed corilagin, gallic acid and macatannin B constituents, which showed in vitro inhibitory effect against pancreatic amylase isolated from swine (21%, 23% and 33%, respectively at 1 m.mol.L−1 concentration)50.

Another popular herb, Ocimum basilicum (basil) is found to be used in culinary and folk medicine. Phytochemical analysis have shown that aqueous extract of O. basilicum leaves contains cardiac glycosides, flavonoids, glycosides, reducing sugars, saponins, steroids and tannins. Leaf extract of the plant exhibited remarkable dose dependently inhibition of intestinal maltase and sucrase of rats and pancreatic α-amylase of swine (IC50 = 21.31 mg ml−1, 36.72 mg ml−1 & 42.50 mg ml−1, respectively). Greater inhibition of maltase may be attributed to the high total polyphenols and flavonoids contents.51

Contrary, the bark of Cinnamomum zeylanicum (a species of cinnamon), a spice that has been traditionally consumed to cure diabetes, known to contain flavonoids, glycosides, anthraquinones, terpenoids, coumarins and tannins. Due to its affordable cost, high availability and safety profile, cinnamon is considered as one of the low risk options for diabetic patients.52 The dose-dependent, competitive and reversible inhibitory effect of cinnamon bark extract on both yeast and mammalian α-glucosidase was evident in in vitro studies (IC50 = 5.83 μg ml−1 & 670 μg ml−1, respectively). The reversible inhibition is desirable as the enzyme remains intact even after the removal of the inhibitor, thus probably could decrease the risk of hypoglycemia due to chronic malabsorption of carbohydrate. Besides that, oral intake of 300 mg kg−1 of cinnamon extract exhibited effective suppression of post-meal blood glucose spikes in STZ-induced diabetic rats loaded with maltose and sucrose by 78.2% and 52.0%, respectively compared to normal rats. Alternatively, postprandial hyperglycemia was not effectively suppressed when cinnamon extract was administered to glucose-loaded rats, indicating that the major mechanism involved is through the inhibition of α-glucosidase.53 On the other hand, another species of cinnamon might be a better option for diabetic patients who is having comorbidity of hypertension. Species of cinnamon, C. cassia is having the most established data in TD2M treatment. The details of the study outcomes has been depicted in clinical section.54 Therefore, cinnamon may be a potential supplement effective in controlling postprandial hyperglycemia and reducing the risk of diabetic vascular complications associated with it.

Similarly, in vitro studies have shown significant inhibition of the α-glucosidase enzyme (IC50 = 8.14 μg ml−1) by hydroalcoholic extract of Callistephus chinensis flower. Further testing was carried out on the stepwise polarity fractions of exracts and the ethyl acetate fraction was found to exhibit the greatest inhibiting action on α-glucosidase enzyme. Enzyme assay guided fractionation led to the isolation of 8 compounds: apigenin, apigenin-7-O-β-D-glucoside, hyperin, kaempferol, kaempferol-7-O-β-D-glucoside, luteolin, naringenin and quercetin. Among the compounds isolated, quercetin demonstrated the greatest α-glucosidase inhibition (IC50 = 2.04 μg ml−1), which is equivalent to that of acarbose (IC50 = 2.24 μg ml−1).55

Corchorus olitorius (jute) leaves have been used historically as a medicinal plant to treat certain degenerative conditions due to the rich contents of polyphenolic compounds and flavonoids, which have been reported in in vitro studies to have α-glucosidase inhibitory activity, making it a potential source of anti-diabetic agent for the management of postprandial hyperglycemia and diabetic complications as a result of oxidative stress. A study demonstrated inhibition of α-amylase and α-glucosidase proportional to doses of C. olitorius extracts, results showing substantially greater inhibition against α-amylase and α-glucosidase (IC50 = 17.5 μg mL−1 & 11.4 μg mL−1, respectively). The major phenolic compounds were found to be chlorogenic acid and isorhamnetin in the free extract and caffeic acid in the bound extract as evidenced via reversed phase HPLC analysis.56 The abundance of these compounds in the leaves of C. olitorius may have contributed to the inhibitory activities against important enzymes associated with T2DM and hypertension, hence justifying its traditional use in treating these ailment. Studies also have demonstrated hypoglycemic activity of Holarrhena antidysenterica seed extract in STZ-induced diabetic rat.57, 58 The presence of carbohydrates, flavonoids (quercetin), phenolic compounds (gallic acid), saponins, steroids, and tannins have been shown through phytochemical screening.58, 59 A recent study has demonstrated inhibitory activity on the α-glucosidase enzyme (IC50 = 0.52 mg ml−1), thus result in fall in postprandial glucose level in starch loaded normoglycemic rat.59 Glycine max (L.) Merrill (soybean) is a type of legume and the major dietary protein source all over the world. Soybean is rich in polyphenolic compounds, for example, isoflavones. In vitro studies on both the free and bound phenolic extracts of soybean demonstrated a dose-dependent inhibition on two crucial enzymes related to T2DM - α-amylase and α-glucosidase, and another enzyme which plays an important role in hypertension - ACE. Nevertheless, the greater α-glucosidase inhibitory activity shown by free phenolic extract confers an advantage over conventional α-glucosidase inhibitors used in the management of diabetes such as acarbose because the adverse effects of these pharmaceutical agents are associated with greater inhibition of α-amylase.60 By inhibiting these enzymes, the breakdown of disaccharides into glucose can be delayed, thus lowering intestinal absorption of glucose. Therefore, normoglycemia and normotension can be achieved through the α-glucosidase and ACE inhibitory effect of soybean extracts.

318 pakistani dating london zeist 👍how to 318 pakistani dating london zeist for Another medicinal herb of Moraceae family, Ficus deltoidea, has increased popularity as an alternative remedy for diabetes, been experimentally shown to lower elevated blood sugar at various prandial states.61 The crude extracts and fractions of two fruit varieties of F. deltoidea (var. angustifolia and var. kunstleri) has shown a dose-dependent inhibition on intestinal α-glucosidases of yeast and rats.62 However, improved basal and insulin-mediated glucose uptake into adipocytes cells for extracts of F. deltoidea leaves are due to the insulin-mimetic and/or insulin-sensitizing properties.61 Furthermore, Choo et al have successfully isolated two bioactive constituents, namely vitexin and isoviten, from F. deltoidea leaf extracts via bioactivity guided fractionation. Significant reduction in the post-meal blood sugar level was shown in normoglycemic mice loaded with sucrose after receiving 1 mg kg−1 of vitexin/isovitexin orally. Oral administration of 200 mg kg−1 and 100 mg kg−1 of vitexin and isovitexin, respectively in sucrose-loaded STZ-induced diabetic rats showed great reduction (19.7%) of postprandial blood glucose.63 Such popular F. deltoidea is an alternative remedy for diabetes that has led to the rise in commercially available forms as capsules and teas.

From these studies, it is clear that the herbal medicines could potentially be a natural alternative to conventional α-amylase and α-glucosidase inhibitors used in the management of diabetes (Table 2) and thus control postprandial hyperglycemia by delaying the intestinal absorption of carbohydrate.

Table 2

List of medicinal herbs affecting the absorption of carbohydrates from the gastrointestinal environment by inhibiting α-glucosidase and α-amylase.

HerbBotanical namePart usedType of extractChemical constituentAnimal modelOutcome (effects)
LeafflowerPhyllanthus urinariaLeaves50% aqueous methanolic extractCorilagin, gallic acid and macatannin BCorilagin, gallic acid and macatannin B demonstrated low inhibitory activity against amylase (21%, 23% and 33% respectively in 1 mmol.L−1 concentration)
CinnamonCinnamomum zeylanicumBarkMethanol extractTannins, flavonoids, glycosides, terpenoids, coumarins and anthraquinonesSTZ-induced diabetic ratsIn vitro: Inhibition of yeast and mammalian α-glucosidase (IC50 = 5.83 μg ml−1 & 670 μg ml−1 respectively)
In vivo: Decreased postprandial hyperglycemia by 78.2% and 52.0% compared to normal rats
Black seedNigella sativaSeedsAqueous extractFlavonoids, unsaturated fatty acids, nigellone, thymoquinone (TQ), p-cymene and carvoneIn vitro: Inhibition of sodium-dependent glucose transport
In vivo: Chronic treatment improved glucose tolerance and reduced body weight similarly as metformin
China asterCallistephus chinensisFlower70 % ethanol extractApigenin, apigenin-7-O-β-D- glucoside, hyperin, kaempferol, kaempferol-7-O-β-D- glucoside, luteolin, naringenin and quercetinInhibition of α-glucosidase by quercetin (IC50 = 2.04 μg ml−1) comparable to that of acarbose (IC50 = 2.24 μg ml−1)
BasilOcimum basilicumLeavesAqueous extractCardiac glycosides, flavonoids, glycosides, reducing sugars, saponins, steroids and tanninsInhibition of α-amylase: rat intestinal maltase and sucrase, porcine pancreatic amylase (IC50 = 21.31 mg ml−1, 36.72 mg ml−1 & 42.50 mg ml−1 respectively)
JuteCorchorus olitoriusLeavesFree & bound extractsCaffeic acid, chlorogenic acid and isorhamnetinInhibition of α-amylase, α-glucosidase & ACE (IC50 = 17.5 μg mL−1, 11.4 μg mL−1 & 15.7 μg mL−1, respectively)
Mistletoe figFicus deltoidea(a) Leaves
(b) Flowers
(a) Ethanolic, methanolic extracts
(b) Crude extracts
Vitexin, isovitexin, proanthocyanidin, flavonoids, 3-flavanol monomers and flavones glycosidesSTZ-induced diabetic ratsIn vitro: Inhibition on α-glucosidases and improvement on basal and insulin-mediated glucose uptake into adipocytes cells
In vivo: Reduction in the postprandial blood glucose level by 19.7% with 200 mg kg−1 & 100 mg kg−1 of vitexin & isovitexin respectively
Bitter oleanderHolarrhena antidysentericaSeedsHydro-methanolic (2:3) extractGallic acid and quercetinStarch loaded normoglycemic ratsIn vitro: Inhibition of α-glucosidase (IC50 = 0.52 mg ml−1)
In vivo: Decreased postprandial hyperglycemia
OliveOlea europaea LLeavesAlcoholic extractOleuropein, hydroxytyrosol, oleuropein
aglycone, and tyrosol
In vivo: STZ-induced diabetic rats
RCT: Type II DM patients
In vivo: Reduction in starch digestion and absorption
RCT: Lower HbA1c (8.0%–1.5% vs. 8.9%–2.25% in placebo) and fasting plasma insulin levels (11.3–4.5 vs. 13.7–4.1 in placebo)
SoybeanGlycine max (L.) MerrillSoybeanFree and bound phenolic extractsPhenolic compoundsInhibition of α-amylase, α-glucosidase & ACE

3.1.4. Herbs regulate multiple actions on glucose regulation

We have observed that hypoglycemic herbs are widely used traditionally; however, those herbal medicines are projected towards well characterized and demonstrated mechanism of diabetic control. Apart from the described herbs, several herbs investigated to have multiple mechanism in the control of diabetic condition. Few of the medicinal herbs has been described in this section those have multiple mode of action, including regeneration of pancreatic B cells, increases insulin sensitivity, enhance glucose utilization and antioxidant property. Long term elevated blood glucose level in diabetic patients could develop variety of vascular complications due to excessive production of reactive oxygen species (ROS) and the reduction of activities of endogenous antioxidants, such as superoxide dismutase (SOD) and catalase (CAT); hence, by correcting the impaired antioxidant status in diabetic patients will be a benefit in treating diabetes mellitus and also its vascular complications.

Several studies have portrayed blood glucose, cholesterol level and urea lowering effect of garlic extract. Sulphur compounds in garlic are believed as the main biological compound to exhibit hypoglycemic effect. Garlic extract stimulates the secretion of insulin from pancreatic beta cells. It also provides sparing insulin effect by preventing insulin from inactivation by SH group in albumin. Besides, it causes marked reduction of serum glucose by increasing glucose utilization.64 Reduction of blood cholesterol level also shown in garlic extract may be due to hydroxy methyl glutaryl-CoA reductase inhibition which suppresses the cholesterol producing metabolic pathway. Garlic extract will also decrease serum urea and creatinine level due to reduction activity of xanthine oxidase and lipid peroxidation which participates in oxidative degradation of lipid. Anti-inflammatory effect of garlic extract can be displayed by the reduction of aspartate transaminase (AST) and alanine transaminase (ALT) level.64 Similarly, Panax ginseng is also known to have anticancer and anti-inflammatory effects where the berry and root have been explored for its antidiabetic and hypoglycemic effect, respectively. Ginsenosides are the main biological active components for the antidiabetic effect. Its metabolic activity is not well understood. However, it is believed that the mode of action includes enhancement of insulin sensitivity due to lesser insulin demand. Besides, Panax ginseng will stimulate insulin signaling pathway such as protein kinase B and insulin receptor substrate-1 in order to increase secretion from pancreatic β-cells. Its hyperglycemic effect also includes in enhancing gastrointestinal absorption by intestinal bacteria. Increase of translocation of glucose transporter type 4 (GLUT 4) to cell membrane will also enhance the glucose uptake as well as glucose utilization. Antioxidant effect of the extract is also contributed to the antidiabetic effect. Reduction of oxidative stress can be displayed and therefore preventing endothelial inflammation that may lead to the complication of diabetes 65, 66. On the other hand, Aloe vera leaves are used widely used for the treatment of diabetes now-a-days, where the antidiabetic activity of A. vera is due to increasing secretion of insulin from pancreatic β-cells, along with its antioxidant property by reducing the free radical formation, in streptokinin induced diabetic adult female albino rats. This can be the 1 last update 2020/05/30 further explained by reduction of serum malondialdehyde (MDA) level which is the product of fatty acid peroxidation while there is an increase of antioxidant enzyme such as SOD and glutathione (GSH). Antioxidant potential is directing towards prevention of progression of diabetes mellitus, further, the anti-inflammatory property of Aloe vera extract will also provide benefit in lowering blood glucose level. Emodin and mannose-6-phosphate in Aloe vera extract are believed as the main active ingredients for the anti-inflammatory properties, where insulin sensitivity will also increase due to prevention of inflammation. Lastly, Aloe vera extracts control hyperglycemia condition by inhibiting pancreatic α-amylase activity which aids in hydrolyses starch and glycogen to simple sugar.67Several studies have portrayed blood glucose, cholesterol level and urea lowering effect of garlic extract. Sulphur compounds in garlic are believed as the main biological compound to exhibit hypoglycemic effect. Garlic extract stimulates the secretion of insulin from pancreatic beta cells. It also provides sparing insulin effect by preventing insulin from inactivation by SH group in albumin. Besides, it causes marked reduction of serum glucose by increasing glucose utilization.64 Reduction of blood cholesterol level also shown in garlic extract may be due to hydroxy methyl glutaryl-CoA reductase inhibition which suppresses the cholesterol producing metabolic pathway. Garlic extract will also decrease serum urea and creatinine level due to reduction activity of xanthine oxidase and lipid peroxidation which participates in oxidative degradation of lipid. Anti-inflammatory effect of garlic extract can be displayed by the reduction of aspartate transaminase (AST) and alanine transaminase (ALT) level.64 Similarly, Panax ginseng is also known to have anticancer and anti-inflammatory effects where the berry and root have been explored for its antidiabetic and hypoglycemic effect, respectively. Ginsenosides are the main biological active components for the antidiabetic effect. Its metabolic activity is not well understood. However, it is believed that the mode of action includes enhancement of insulin sensitivity due to lesser insulin demand. Besides, Panax ginseng will stimulate insulin signaling pathway such as protein kinase B and insulin receptor substrate-1 in order to increase secretion from pancreatic β-cells. Its hyperglycemic effect also includes in enhancing gastrointestinal absorption by intestinal bacteria. Increase of translocation of glucose transporter type 4 (GLUT 4) to cell membrane will also enhance the glucose uptake as well as glucose utilization. Antioxidant effect of the extract is also contributed to the antidiabetic effect. Reduction of oxidative stress can be displayed and therefore preventing endothelial inflammation that may lead to the complication of diabetes 65, 66. On the other hand, Aloe vera leaves are used widely used for the treatment of diabetes now-a-days, where the antidiabetic activity of A. vera is due to increasing secretion of insulin from pancreatic β-cells, along with its antioxidant property by reducing the free radical formation, in streptokinin induced diabetic adult female albino rats. This can be further explained by reduction of serum malondialdehyde (MDA) level which is the product of fatty acid peroxidation while there is an increase of antioxidant enzyme such as SOD and glutathione (GSH). Antioxidant potential is directing towards prevention of progression of diabetes mellitus, further, the anti-inflammatory property of Aloe vera extract will also provide benefit in lowering blood glucose level. Emodin and mannose-6-phosphate in Aloe vera extract are believed as the main active ingredients for the anti-inflammatory properties, where insulin sensitivity will also increase due to prevention of inflammation. Lastly, Aloe vera extracts control hyperglycemia condition by inhibiting pancreatic α-amylase activity which aids in hydrolyses starch and glycogen to simple sugar.67

Different part of bitter melon, Momordica charantia L., has been used widely for antioxidant and antidiabetic activity. Efficacy of Momordica charantia L is evaluated with aqueous extracts and its main active ingredient -charantin shows hyperglycemic property in alloxan-induced diabetic mice. The mode of action includes stimulation glucose utilization of adipocytes and skeletal muscle. Besides, bitter melon extract will downregulate MAPKs and NF-κB to lower the impaired insulin signaling as well as provides protection to pancreatic beta cells. Upregulation of peroxisome proliferator-activated receptor gamma (PPAR-γ gene) expression which involve in glucose metabolism also one of the mechanism of Momordica charantia L on antidiabetic effect. Modulation of protein-tyrosine phosphatase 1B (PTP1B) acts as negative regulator of the insulin signaling pathway also contribute to the hypoglycemic effect. It stimulates insulin secretion from pancreatic beta cells as well as enhances glucose uptake by translocation of GLUT4 to the cell membrane. The fruits of Momordica charantia L stimulate glucose uptake by activating the action of glucose-6-phosphatase dehydrogenase which involve in pentose phosphate pathway.68, 69 Further, the seed of fenugreek has widely been used for the treatment of diabetes mellitus for multiple benefits. Mechanism of fenugreek alkaloid on glycemic control is believed to prevent the catabolism process, such as proteolysis, glycogenolysis and lipolysis. Improvement of weight of liver and kidney is exerted which indicates the preferable outcome of fenugreek in regulating muscle protein synthesis. Hypoglycemic effect of fenugreek alkaloid also contributed by its antioxidant effect. Antioxidant effect is exhibited by inhibiting reactive oxygen species (ROS) and proinflammatory cytokines that can result in insulin resistance. Dietary fibers in fenugreek seed also aid in its hypoglycemia effect by modulating insulin secretion. Delayed gastric emptying in order to slow down intestinal glucose absorption also contributed to its antidiabetic properties. Regeneration of pancreatic β cell to enhance insulin secretion is also one of the mode of action of fenugreek to control hyperglycemic condition. Besides, fenugreek extract will enhance glucose uptake by adipose and muscle tissue and improve the utilization of glucose through elevation of glucose-6-phosphate dehydrogenase activity.70, 71 Peel extract of Punica granatum has shown to control glucose level in experimental guinea pigs,71 whereas leaves of the same plant have also displayed to produce beneficial effect in prevention of diabetic as evidenced by effective deterrence of nephropathy, structural and functional abnormality of kidney.72

Coptis chinensis is also well known for its antidiabetic effect through regeneration of size of the pancreatic islets of Langerhans in order to enhance the insulin secretion for glycemic control. In due course, C. chinensis stimulate AMP-activated protein kinase (AMPK) phosphorylation in skeletal muscle and liver which is important for cellular energy homeostasis. AMPK activation will stimulate skeletal muscle and hepatic fatty acid oxidation, inhibit lipolysis lipogenesis as well as enhance pancreatic β-cell to secrete insulin. Besides, C. chinensis increases glucose uptake in adipose tissue through phosphorylation of insulin receptor substrate 1 (IRS-1). IRS-1 transmit the signal from insulin to intracellular pathways PI3K/Akt and Erk-MAP kinase. Moreover, elevation of expression of GLUT 4 in adipose tissue and skeletal muscle mediates glucose uptake in response to insulin is another mode of action of C. chinensis to control hyperglycemic condition. Insulin will increase GLUT 4 translocation to cell membrane of adipocytes and skeletal muscle in order to aid in glucose uptake. Studies have demonstrated that downregulation of expression of hepatic genes which involve in glucogenesis, glucose oxidation and glycogenolysis provide the antidiabetic effect of C. chinensis.73 Alternatively, water decoction of Catharanthus roseus is also used in the management of diabetes where vindoline, tetrahydroalstonine and catharanthine are discovered as the main biological ingredients for the hypoglycemic effect. It exerts the activity of antidiabetic effect by enhancing intestinal glucose uptake through activity of glucose-6-phosphate dehydrogenase in pentose phosphate pathway. Several studies have shown that there is an improvement of activity of glucokinase which facilitates Phosphorylation of glucose to glucose-6-phosphate to possess glycemic control. On the other hand, there is an elevation of malate dehydrogenase for catalyzing the oxidation of malate to oxaloacetate and enhancement of succinate dehydrogenase that involves in citric acid cycle and the electron transport chain. The changes of the enzyme indicates that Catharanthus roseus provides better utilization of glucose by liver. Besides, level of GSH is observed to be increased in streptokinin induced diabetic rats. Antioxidant is capable to prevent important organ damage by free oxygen radicals. Alternatively, vindoline in C. roseus is known as protein tyrosine phosphatase-1B inhibitor which mimics the action of insulin as well as increases the insulin sensitivity by elevating the phosphorylation of insulin receptor. Besides, its direct antidiabetic effect. it is strongly associated with inhibition of α-glucosidase in the gastrointestinal environment that subsequently inhibit hydrolyses of carbohydrates.74, 75

Curry leaves, or scientifically Murrya koenigii exhibits potent antihyperglycemic and anti-obesity effect that is useful for the glycemic control as well as maintain optimal body weight. Ethanolic extract Murrya koenigii is reported to improve glucose intolerance in hyperglycemic condition in high fat diet induced obese and diabetic rats which is associated with insulin resistance and may progress to T2DM. It has also been shown that Murrya koenigii exerts insulin sensitizing and antioxidant activities, besides its α-glucosimidase inhibitory activity that can aid in glycemic control.76, 77 Ocimun tenuiflorum leaves are traditionally used in diabetes in Malaysia. Investigation on the hypoglycemic effects of O. tenuiflorum extract revealed preventing of hepatic gluconeogenesis as well as activation of glucose uptake in adipose tissues and skeletal muscle. It is also known to enhance the insulin sensitivity attributed by phenolic and flavonoids in the extract, whereas regeneration of beta cells in pancreas may account for its potent antidiabetic effect and glycemic control. Antioxidant property of the plant extract contributes to the glucose homeostasis and α-amylase and α-glucosidase inhibiting activity in the control of hyperglycemic condition.78 On the other hand, phenolic compound of Mangifera indica seeds found to enhance glucose metabolism by inhibition of carbohydrate digesting enzymes, α-amylase and α-glucosidase for the management of T2DM. Preventing the breakdown of starch to simple sugar may lead to enhancement of glucose uptake of circulating glucose, thus lowers the blood glucose level. Besides, inhibition of aldose reductase will prevent degradation of sorbitol for the formation of glucose as well as alleviate the complications of diabetic mellitus. Moreover, inhibition of iron induced lipid peroxidation in pancreas is also one of the modes of action for Mangifera indica which will prevent disruption of the fluidity and permeability of cell membrane and thus prevents cell death and damage.79

318 pakistani dating london zeist 🔴how to 318 pakistani dating london zeist for Thus, multimodal mechanisms in the control of diabetes will always be effectively control the diseased condition by lowering the plasma glucose level, increasing the number of β-cells in the islets of Langerhans, preventing absorption of glucose from the gastrointestinal tract, providing antioxidant role against endogenous ROS, etc. This might be possible by the presence of multiple active ingredients within the crude extract (Table 3). Therefore, characterization and validation of the active principles of the herbs will definitely pave the novel path for the effective control of this dreadful disease.

Table 3

Multimodal activities of listed herbs in the effective control of diabetic symptoms.

HerbBotanical namePart usedType of extractCasesOutcome (effects)
GarlicAllium sativum LGarlicEthanolStreptokinin induced diabetic ratsStimulate the secretion of insulin from pancreatic B cells, sparing insulin effect, increasing glucose utilization, hydroxy methyl glutaryl CoA reductase inhibitor, antioxidant, anti-inflammatory
GinsengPanax GinsengBerryMethanolStreptokinin induced diabetic ratsEnhancement of insulin sensitivity, stimulate insulin signaling, increase translocation of GLUT4, antioxidant
Aloe veraAloe Barbadensis MillerLeavesMethanolStreptokinin induced diabetic ratsIncrease secretion of insulin from pancreatic beta cells., antioxidant, anti-inflammatory, inhibiting pancreatic α-amylase activity, increase insulin sensitivity
Bitter MelonMomordica charantiaFruitAqueous extractAlloxan-induced diabetic miceStimulate glucose utilization, protection of B cell, downregulate MAPKs and NF-κB, upregulate PPAR, modulation of PTP1B, enhance glucose uptake, stimulate insulin secretion
FenugreekTrigonella foenum-graecumSeedMethanolSTZ-induced diabetic guinea pigsPrevent catabolism, antioxidant, modulating insulin secretion, regeneration of pancreatic B cell, improve glucose utilization, and slow down glucose absorption.
HuanglianCoptis chinensisRhizomeEthyl acetateHigh fat diet induced diabetic miceRegeneration of pancreatic cell, stimulate fatty acid oxidation, inhibit lipogenesis, increase glucose uptake
Madagascar periwinkleCatharanthus roseusSeedMethanolStreptokinin induced diabetic ratsIncrease glucose uptake and glucose utilization, antioxidant, increases the insulin sensitivity, inhibit alpha glucosidase
Curry treeMurraya koenigiiLeavesMethanolHigh fat diet induced obesity and diabetic ratsAntioxidant, antiobesity, increase insulin sensitivity, alpha glucosidase inhibitor
Holy basilOcimun tenuiflorumLeavesMethanolStreptokinin induced diabetic ratsIncrease glucose uptake, antioxidant, increase insulin sensitivity, regeneration of pancreatic beta cell, α-amylase and α-glucosidase inhibitor
MangoMangifera indicaSeedEthanolic extractDiabetic ratsInhibition of carbohydrate digesting enzymes, aldose reductase, lipid peroxidation

3.2. Polyherbal for diabetes

It has been observed that multiple mechanisms in the treatment of diabetes will effectively control the progress as well as modify the deteriorating condition of the patients. Similar to the previous section, to obtain multimodal activities in control of diabetes, certain purposeful mixtures of herb have been comprehensively evaluated for their effective uses in patients with diabetes. Such polyherbals are usually target the different pathological events throughout instigation and development of diabetes from different mechanistic approaches, to abolish the symptoms to improve the quality of life of the patient (Table 4). In this context we will come up with different polyherbals in the treatment of diabetes. A study conducted by Awasthi et al to assess the efficacy of standardized ayurvedic polyherbal formulation in the treatment of T2DM which consists of Cyperus rotundus, Cedrus deodara, Berberis aristata, Emblica officinalis, Terminalia bellirica and Terminalia chebula, showed no significant difference in the reduction of postprandial blood glucose level as compared with metformin after 24 weeks of study period. Besides, the HbA1c of polyherbal formulation-treated group showed a decrease from 7.38 ± 0.77 to 6.07 ± 0.64 whereas the metformin-treated group showed similar degree of decrease from 7.73 ± 0.92 to 6.43 ± 1.06. The polyherbal formulation-treated group also demonstrated greater reduction in serum cholesterol, TG and low density lipoprotein (LDL) after 6 months of study. Since the polyherbal formulation are able to reduce the postprandial blood glucose and Hb1Ac levels almost as effectively as metformin; and it seems to show more significant effect in high cholesterol management compared to metformin; hence, the use of this preparation maybe more useful for T2DM patients with hyperlipidemia since it has no side effects compared to metformin.80

Table 4

Composition of polyherbal formulations in the treatment of diabetes mellitus.

PolyherbalsBotanical composition (part used)
GSPF kwath81Gymnema sylvestre (Retz.) R.Br. (leaves), Syzygium cumini (L.) Skeels (seeds), Phyllanthus emblica L. (fruit), Curcuma longa L. (rhizome), Pterocarpus marsupium Roxb. (Heart-wood), Terminalia chebula Retz. (fruit), Cassia fistula L. (fruit), Picrorhiza kurroa Royle ex Benth. (rhizome), Swertia chirata (seeds), Terminalia bellirica (fruit)
Polyherbal formulation82Ferula assafoetida, Annona squamosal, Zingiber officinale (juice), Gymnema sylvestre (leaves), Tamarindus indica (seeds), Azadirachta indica, Trigonella foenumgraecum (seeds), Moringa oleifera (roots), Aegle marmelos (seeds), Cajanus cajan (leaves)
Polyherbal formulation118Salacia roxburghii (root and fruits), Salacia oblonga (root and fruits), Garcinia indica (fruits and seeds), Lagerstroemia parviflora (bark)
SMK00184Coptis chinensis, Trichosanthes kirilowii
DIASOL85Eugenia jambolana, Foenum graecum, Terminalia chebula, Quercus infectoria, Cuminum cyminum, Taraxacum officinale, Emblica officinalis, Gymnema sylvestre, Phyllanthrus nerui, Enicostemma littorale
DiaKure89, 90Vetiveria zizanioides (root), Hemidesmus indicus (rhizome), Strychnos
potatorum (seed), Salacia reticulata (bark), Holarhena antidysenterica (seed), Cassia auriculata (bark), Trigonella graecum (seed), Acacia catechu (bark)
ESF/AY88Aegle marmelos (leaves), Bambusa arundinacee (leaves), Eruca sativa (leaves), Aerva lanata (aerial), Catharanthus roseus (aerial), Ficus benghalensis (bark), Salacia reticulate (bark), Syzygium cumini (bark)
DRF/AY/500194Gymnema sylvestre (leaves), Syzygium cuimini (seed), Pterocarpus marsupium (stem), Momordica charantia (seed), Emblica officinalis (fruit), Terminalia belirica (fruit), Terminalia chebula (fruit), Shudh Shilajit

Treatment with ‘GSPF kwath’ has shown to have similar anti-hyperglycemic effect as glibenclamide. Due course of treatment with GSPF kwath resulted in significant decline in HbA1c, both postprandial and fasting glucose level in T2DM patients after 6 months. Other than hypoglycemic effect, GSPF kwath also found to produce antihyperlipidemic and antioxidant effects.81 The levels of total cholesterol, TG, LDL, and very low density lipoprotein (VLDL) were significantly decreased following 6 months of GSPF kwath therapy.

The multiherbal of different composition (mixture 1, 2, 3, 4, 5) results in better restoration of glycemic level to the near normal in comparison to individual herbals. The effect is due to the flavonoids, alkaloids, tannins, and terpenes which act as bioactive antidiabetic principles. Although, among all the mixtures, Mixture 4 showed the highest antihyperglycemic activity.82 In another study, the polyherbal treatment showed to reduce in blood glucose levels due to property of Salacia and tannins present in Lagerstroemia species. In addition, mangiferin, a major active compound of Salacia can delay the onset or progression of diabetic complications. Besides, the formulation also showed antihyperlipidemic activity due to the presence of hydroxycitric acid. Preclinical studies of polyherbal formulation in diabetic rats resulted in a significant decrease in the activities of fructose-1,6-bisphophatase and glucose-6-phosphatase which lead to decreased gluconeogenesis and thereby reducing the endogenous production of glucose.83 Further, SMK001 (also known as Dang-Nyp-Ko in Korea) contains both coptidis rhizome and trichosanthis radix and used as Chinese medicine to treat diabetes. Experimental outcomes revealed significant decrease of glucose in urine and plasma of diabetic rats succeeding the treatment of SMK001 for 28 days. SMK001 acts by increasing the pancreatic islets insulin-producing cells and decreasing the glucagon-producing cells.84 Hypoglycemic effect of SMK001 is dose-dependent, although the mechanism of SMK001 is unclear, but SMK001 has favorable effect in changing body weight as well as the blood and urine glucose levels.84

On the other hand, STZ-induced diabetic rats are evaluated with polyherbal formulation Diasol which contains extracts of Gymnema sylvestre, Eugenia jambolana, Foenum graecum, Taraxacum officinale, Terminalia chebula, Quercus infectoria, Cuminum cyminum, Emblica officinalis, Phyllanthrus nerui and Enicostemma littorale. Subsequent 14 days treatment of 250 mg kg−1 Diasol to diabetic rats showed 63.4% decrease in blood sugar level, whereas 125 mg kg−1 glibenclamide showed 50.25% reduction of plasma glucose level.85 Similarly, the effect of glibenclamide was also comparable with polyherbal formulation containing Mangifera indica, Tridax procumbens and Glycosmis pentaphylla in a ratio of 2:2:1 86. Diabetic rats treated with 500 mg kg−1 and 250 mg kg−1 polyherbal preparation showed decreased fasting blood serum glucose level as compared to diabetic control group due to activation of β-cells to release insulin that activates the glycogen synthase system and prevent glycogen depletion in the liver tissue. The polyherbal composition also brought back the hemoglobin and Hb1Ac levels with no observed adverse effects to liver glycogen and protein levels in blood, rather reversed the effect of STZ and nicotimanide on the liver and renal markers. Other than that, the treatment groups showed significant improvement in body weight, which indicates that polyherbal formulation and glibenclamide prevent the hyperglycemia-induced muscle wastage.86

It has been established that oxidative stress to the individual may lead to development of metabolic disorders, including diabetes.87 Thus antioxidant plays role in reduction of diabetes. The ESF/AY polyherbal formulation exhibited significant antioxidant activity by showing increased levels of GSH peroxidase (GPx), GSH, SOD, CAT and thus resulted in decreased level of lipid peroxidation.88 GSH, SOD and CAT functions as free radical scavenger to repair the radical that causes biological damage and inhibits free radical mediated lipid peroxidation, whereas GPx plays a role in detoxification of endogenous metabolic peroxides and hydroperoxides which catalyses GSH.88

Similarly, DiaKure''s modern medicine. Therefore, many herbs have shown to have antidiabetic activity by regulating insulin secretion, insulin sensitivity to the cells, glucose abruption, etc. in order to improve the glycemic control of the patients. Addition to the glycemic control, some of the herbs depicted effectiveness in the control of cardiovascular complications by reducing TG, cholesterol levels, and BMI. Herbal medicine are always preferred treatment options by patients or as adjunctive to conventional treatment for diabetes due to the belief on the soil and affordability, thus laboratory research has reached to the bedside of the patients though clinical trials and marketed formulations. However, the fast growth of the ethnopharmaceutical field in the control of diabetes urgently requires validated testing the 1 last update 2020/05/30 protocols in order to evaluate the quantity and quality of active pharmaceuticals present in the final products, which will finally need to be tested in human subjects via well designed clinical trials, confirmed and certified by the concerned regulatory authorities of the country to build confidence of the consumers for the safety and efficacy of the herbal formulations.Similarly, DiaKure''s modern medicine. Therefore, many herbs have shown to have antidiabetic activity by regulating insulin secretion, insulin sensitivity to the cells, glucose abruption, etc. in order to improve the glycemic control of the patients. Addition to the glycemic control, some of the herbs depicted effectiveness in the control of cardiovascular complications by reducing TG, cholesterol levels, and BMI. Herbal medicine are always preferred treatment options by patients or as adjunctive to conventional treatment for diabetes due to the belief on the soil and affordability, thus laboratory research has reached to the bedside of the patients though clinical trials and marketed formulations. However, the fast growth of the ethnopharmaceutical field in the control of diabetes urgently requires validated testing protocols in order to evaluate the quantity and quality of active pharmaceuticals present in the final products, which will finally need to be tested in human subjects via well designed clinical trials, confirmed and certified by the concerned regulatory authorities of the country to build confidence of the consumers for the safety and efficacy of the herbal formulations.

Disclosures

There is no conflict of interest and disclosures associated with the manuscript.

Conflict of interest

318 pakistani dating london zeist ⭐️how to 318 pakistani dating london zeist for The authors declare no conflict of interest.

Declare of interest

We are declaring that all the listed authors have read and approved the submitted manuscript. This manuscript/data, or parts thereof, has not been submitted for possible publication to another journal or that the work has previously been published elsewhere.

Footnotes

Peer review under responsibility of The Center for Food and Biomolecules, National Taiwan University.

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