Antidiabetic plants improving insulin sensitivity.

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Review

Journal of Pharmacy And Pharmacology

Antidiabetic plants improving insulin sensitivity Mohamed Eddouks, Amina Bidi, Bachir El Bouhali, Lhoussain Hajji and Naoufel Ali Zeggwagh Faculty of Sciences and Techniques Errachidia, Moulay Ismail University, Errachidia, Morocco

Keywords cellular effects; diabetes; insulin sensitivity; medicinal plants Correspondence Mohamed Eddouks, Faculty of Sciences and Techniques Errachidia, BP 21, 52000 Errachidia, Morocco. E-mail: [email protected] Received December 29, 2013 Accepted February 23, 2014 doi: 10.1111/jphp.12243

Abstract Background Globally, the prevalence of diabetes mellitus is increasing at an alarming rate. This chronic pathology gravely troubled the human health and quality of life. Both insulin deficiency and insulin resistance are involved in the pathophysiology of diabetes mellitus. Moreover, insulin resistance is being diagnosed nowadays in a growing population of diabetic and obese patients, especially in industrialized societies. There are lots of conventional agents available to control and to treat diabetes, but total recovery from this disorder has not been reported up to this date. Plants provided a potential source of hypoglycemic drugs and are widely used in several traditional systems of medicine to prevent diabetes. A few reviews with less attention paid to mechanisms of action have been published on antidiabetic plants. Objectives The present review focuses on the various plants that have been reported to be effective in improving insulin sensitivity associated with diabetes. Key findings In this work, an updated systematic review of the published literature has been conducted to review the antidiabetic plants improving insulin sensitivity and 111 medicinal plants have been reported to have a beneficial effect on insulin sensitivity using several in-vitro and in-vivo animal models of diabetes. Conclusion The different metabolic and cellular effects of the antidiabetic plants improving insulin sensitivity are reported indicating the important role of medicinal plants as potential alternative or complementary use in controlling insulin resistance associated with diabetes mellitus.

Introduction Diabetes mellitus was considered as becoming a global epidemic health problem that imposes high cost to national health services around the world. The prevalence of diabetes is increasing at an alarming rate in the world’s population, reaching an epidemic proportion. The number of diabetic patients will increase dramatically to over 300 million within 20 years.[1] Lifestyle and food habit changes are known to be the major causes of diabetes. There are three main types of diabetes; type 1, type 2 and gestational diabetes, but other specific types of diabetes also exist.[1] Main causes include lack of physical work, obesity and lifestyle modificaiton. Indeed, most diabetic patients require oral antihyperglycaemic drug therapy; yet, the relatively high rate of failure of these drugs and the chronic nature of the disease, which is associated with progressive dysfunction and exhaustion of pancreatic insulin-producing β-cells, lead in many cases to insulin therapy.[2] When diabetes is not well controlled, many complications such as coronary artery disease, peripheral vascular disease, retinopathy, cerebrovas-

cular disease, neuropathy and nephropathy arise in diabetic patients and cause morbidity or mortality.[1] Diabetes mellitus is caused by a combination of insulin resistance and β-cell failure and can be treated with insulin-sensitizing drugs that target the nuclear receptor peroxisome proliferator-activated receptor (PPAR) γ. Insulin resistance, a reduced biological effect of endogenous or exogenous insulin, is a common biochemical entity that is associated, either directly or indirectly, with a range of noncommunicable human diseases. Moreover, insulin resistance, which precedes type 2 diabetes mellitus, is a widespread pathology associated with the metabolic syndrome, myocardial ischemia, and hypertension.[3] Insulin resistance involved in the pathogenesis of the metabolic diseases such as type 2 diabetes represents a potential target for insulin-sensitizing agents. Type 2 diabetes mellitus involves pancreatic β-cells, the liver and peripheral target tissues such as skeletal muscle and adipose tissue.[4] In the muscle, defective glucose metabolism, impaired insulin signalling

© 2014 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, 66, pp. 1197–1214

1197

Antidiabetic plants

Mohamed Eddouks et al.

and reductions in glucose transport play a major role in the pathogenesis of insulin resistance. While in the fat cells, reduction of the facilitative glucose transporter, glucose transporter 4 (GLUT4), excessive release of free fatty acids, excessive release of adipocytokines (e.g. tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6)) and the impaired release of adiponectin from fat tissue as well as inhibition of other cytokines may contribute to the evolution of insulin resistance.[4] Finally, in the liver, glycogenolysis and gluconeogenesis are enhanced in the presence of insulin resistance because suppression of glucose production is impaired.[4] The causes and development mechanisms of insulin resistance are not well elucidated; consequently, this pathological state represents the main challenge in both type 2 and long-standing type 1 diabetes pharmacotherapy. Essentially, thiazolidinediones (TZDs) are used to improve insulin resistance via activation of a nuclear factor regulating the transcription of genes involving in lipid and glucose metabolism known as PPARγ. Thiazolididiones have been identified to act via several sites such as improvement of insulin sensitivity, decreasing hyperinsulinemia and have been found to avoid the appearance of insulin resistance complications such as diabetic dyslipidemia, hypercoagulation, fibrinolysis and hypertension.[5] Recently, the Food and Drug Administration has withdrawn some thiazolididiones from the list because of serious side-effects and new generation of pharmacological agents has been investigated to renew hopes to control insulin resistance.[6] In this view, a special interest was focused on the potential use of plants or their constituents in the treatment of type 2 diabetes. Some plants used in the folk medicine have been shown to contain some compounds able to stimulate the insulin sensitivity or insulin-signalling pathways such as the activity of PPARα and PPARγ.[7] In addition, protein tyrosine phosphatases, known to be expressed in insulinsensitive tissues, have been demonstrated to modulate negatively the insulin signal transduction by dephosphorylation of tyrosyl residues.[8] Moreover, protein tyrosine phosphatase 1B (PTP1B), a prototypical member of the protein tyrosine phosphate superfamily, is known to be a key negative regulator of both insulin and leptinsignalling pathway by dephosphorylating the insulin receptor, insulin receptor substrates and Janus kinase 2.[9] Natural inhibiters of PTP1B such as trodusquemine, pentacyclic triterpenoids including oleanolic acid and its derivatives may improve type 2 diabetes by increasing insulin sensitivity.[10–14] In addition, some synthetic inhibitors were discovered; however, few of them were subject of clinical trials.[15] Insulin sensitivity may be improved via other signalling pathways. For example, the famous resveratrol isolated from the roots of white hellebore has been shown to improve insulin sensitivity in type 2 diabetic 1198

patients via the phosphorylated protein kinase (Akt) pathway and by upregulating the sirtuins (SIRT1 and SIRT2) involved in many cellular processes such as fatty acid metabolism.[16,17] Insulin stimulates glucose uptake in muscle and adipose tissue by recruiting the insulinsensitive glucose transport isoform GLUT4 from an intracellular storage pool to the plasma membrane. In type 2 diabetic patients, insulin resistance has been shown to be secondary to defective glucose metabolism and transport. Thus, glucose metabolism and transport play a major role in the pathogenesis of insulin resistance.[18,19] Finding an adequate treatment for type 2 diabetes is an important goal in medicine. There are lots of chemical agents available to control and to treat diabetic patients, but total recovery from diabetes has not been reported up to this date. In addition most of the oral drugs are costly and have a lot of side-effects. Alternative to these synthetic agents, plants provide a potential source of hypoglycaemic drugs and are widely used in several traditional systems of medicine to prevent diabetes.[20] Furthermore several medicinal plants, used to control diabetes along with lifestyle management, have been investigated for their beneficial effect in different types of diabetes and are being more desired, owing to lesser side-effects and low cost. In addition, during the past few years, many phytoconstituents responsible for antidiabetic effects have been isolated from hypoglycaemic plants.[21] There are about 200 pure compounds from plant sources reported to show blood glucoselowering activity. The compounds may be flavonoids, terpenoids, alkaloids, carbohydrates, glycosides, steroids, peptides and amino acids, lipids, phenolics, glycopeptides and iridoids.[21] Many antidiabetic products of herbal origin are now available in the market. More than 1200 species of plants have been screened for activity on the basis of ethnomedicinal uses.[22] The mechanisms of medicinal plants for glucose control in diabetes include the inhibition of glucose absorption, improvement of insulin sensitivity, protection of β-cell damage, increase of insulin release, enhancement of antioxidant defence, attenuation of inflammation, modulation of carbohydrate metabolism pathway and regulation of insulin-dependent and insulinindependent signalling pathways.[23] Some recent reports on the natural products with antidiabetic effects have provided evidence for possible mechanisms of action. Nonetheless, the majority of investigators only speculated on a wide range of possible mechanisms or simply demonstrated an antihyperglycaemic effect for the crude plant extracts or the isolated compounds of interest.[24] A few reviews with less attention paid to mechanisms of action have been published on medicinal plants and diabetes.[24–31] The present review focuses on the various plants that have been reported to be effective in improving insulin sensitivity associated with diabetes.



The data information related to medicinal plants and insulin sensitivity were collected from the available literature at various databases, including PubMed, Science Direct and Scopus until October 2013. Most of the articles used were published within the past 5 years, although some older articles that were seminal in understanding the role of medicinal plants in the management of insulin sensitivity were also included. Key search words included: medicinal plants, insulin resistance, antidiabetic plants, glucose uptake and insulin sensitivity. Moreover, the cellular and metabolic effects involved in improving insulin sensitivity, the experiment model used in these studies and the determined phytochemical groups are also discussed in the present review.

Antidiabetic plants improving insulin sensitivity In this review, 111 medicinal plants have been reported to have a beneficial effect in diabetes by improving insulin sensitivity. About 70% of the studies have used mostly the in-vivo animal models of diabetes especially streptozotocininduced diabetic rats or mice and db/db diabetic mice. The other studies have used other animal models such as alloxan-induced diabetic rats or mice, partially pancreatectomized diabetic rats, sand rats, Zucker diabetic rats, ob/ob mice, Meriones shawi rats, KKAy mice, highsucrose diet rats, high-fat diet mice or rats, high-fructose fed rats, albino rats rendered glucose intolerant by tetracycline and monosodium L-glutamate-treated insulin resistance mice (Table 1). As far as the in-vitro studies are concerned, different cell lines have been used mainly 3T3-L1 adipocytes and HepG2 cells. The other in-vitro models were C2C12 muscle cells, L6 myotubes, 3T3-F442A murine adipocytes, Min6 cells, FL83B mouse hepatocytes, human liver cell culture, human subcutaneous adipocytes, isolated rat hemidiaphragm and L8 muscle cells (Table 1). However, a few studies (about 2%) have been performed in human especially in healthy adults with prediabetes, type 2 diabetic patients and obese and slightly dyslipidemic premenopausal women (Table 1). These medicinal plants with beneficial action on insulin sensitivity act via various cellular and metabolic targets. The principle sites targeted by these medicinal plants are the peripheral tissues (muscles and adipocytes) or the liver. As summarized in Figure 1, in these organs, these medicinal have been demonstrated to stimulate: • The insulin signalling (the expression levels of insulin receptor α subunit (InsR-α), insulin receptor substrate-1 (IRS-1), phosphatidylinositol 3-kinase (PI3K), tyrosine induced phosphorylation of insulin receptor substrate, the phosphorylation of adenosine monophosphate-

Antidiabetic plants

activated protein kinase (AMPK)/ acetyl-CoA carboxylase (ACC) and mitogen-activated protein kinases (MAPKs) • PPARγ • Glucose transport by enhancing the glucose uptake and the expression of the GLUT4 as well as its translocation and glucose transporter 2 (GLUT2). • Activity of hexokinase, phosphofructokinase, pyruvate kinase, glucose-6-phosphatase, fructose-1,6-bisphosphatase and glucose-6-phosphate dehydrogenase, liver glucokinase and liver glycogen content • The gene expression of resistin In addition, several medicinal plants have reported to inhibit; • The activity of PTP1B • Hepatic glucose production • The tyrosine dephosphorylation • Hepatic gluconeogenesis • The serum levels of leptin • TNF-α All the cited cellular and metabolic targets cited in Table 1 are well documented such as the role of insulinsignalling pathways, the glucose transport and metabolism in the regulation of glucose homeostasis.[23–30] PPARγ plays a critical role in glucose homeostasis and serves as the molecular target for a class of insulin-sensitizing drugs called TZDs. TZDs are PPARγ ligands and widely used for treatment of type 2 diabetes, they had very minimal activity toward PPAR-α or PPAR-β. Effects on insulin action in tissues would occur as a consequence of alterations in signalling molecules produced by fat, such as free fatty acids, TNF-α, leptin or others.[156] PPARs are dietary lipid sensors that control energy homeostasis and playing an important role in the management of metabolic disorders, such as type 2 diabetes, hyperlipidemia, insulin resistance and cardiovascular diseases.[157] In this review, several medicinal plants are reported to modulate PPARs and then improving insulin sensitivity (Table 1). In addition, the AMPK is a highly conserved sensor of cellular energy. It was shown to be activated by metformin, currently the major drug for treatment of type 2 diabetes.[158] Although the known metabolic effects of AMPK activation are consistent with the idea that it mediates some of the therapeutic benefits of metformin, it now appears that AMPK is the sole target of the drug in improving insulin sensitivity.[158] Several medicinal are reported in this review to act through AMPK pathway.[106,137] Moreover, adiponectin is a protein produced exclusively by adipocytes. Its circulating levels are decreased in individuals with obesity, atherosclerosis and insulin resistance, suggesting that its deficiency may have a causal role in the etiopathogenesis of these diseases.[159] Studies have shown that adiponectin administration has insulin-sensitizing effect in type 2 diabetes and many studies have demonstrated a significant inverse association between adiponectin


1199

Antidiabetic plants


Table 1

Antidiabetic plants improving insulin sensitivity

N°

Scientific name

Family

Model used in the study

1

Abelmoschus moschatus

Malvaceae

Rats fed high-fructose diet

2

Abutilon indicum

Malvaceae

Diabetic rats and 3T3-L1 cells

3 4

Justicia adhatoda Allium sativum

Acanthaceae Amaryllidaceae

5

Aloe vera

Asparagaceae

L6 myotubes Rats feeding fructose rich diet Insulin resistant mice and randomized controlled trial in type 2 diabetic patients

6

Alpinia pricei

Zingiberaceae

Sucrose-containing drinking water in C57BL/6J mice

7

Amorpha fruticosa

Leguminosae

8

Ananas comosus

Bromeliaceae

9 10 11

Anemarrhena asphodeloides Angelica gigas Artemisia herba-alba

Asparagaceae Apiaceae Compositae

Diet-induced obese and db/db mice HepG2 cells and high-fat diet-fed and low-dose streptozotocin-treated diabetic rats KK-Ay mice High-fat diet mice High-diet mice

12

Artemisia sphaerocephala

Compositae

Streptozotocin-induced type 2 diabetic rats

13

Astragalus membranaceus

Leguminosae

14

Atractylis japonica

Compositae

Fat fed streptozotocin-treated rats 3T3-L1 cells

15 16

Aucklandia lappa Bidens pilosa

Asteraceae Compositae

17

Brassica juncea

Brassicaceae

18

Bumelia sartorum

Sapotaceae

19

Calotropis gigantea

Apocynaceae

1200

HepG2 cells Chronic fructose treatment in rats Rats fed fructose-enriched diet Alloxan-induced diabetic rats High-fructose diet-induced insulin resistance in rats

Metabolic and cellular effects

Ref

Stimulates insulin-signalling cascades and improves insulin-signalling transduction by modification of Ser/Thr phosphorylation of IRS-1 Regulates adipocyte differentiation through PPARγ agonist activity, and increased glucose utilization via GLUT1 Activates GLUT 4 transporter ND

[32]

Ameliorates insulin sensitivity calculated using the homeostasis model assessment for insulin resistance formula but the cellular mechanism is not determined Reduces serum levels of leptin and tumor necrosis factor-a and significantly increases level of adiponectin Activates selective peroxisome PPARγ

[36,37]

ND

[40]

ND ND Reduces insulin resistance as measured by the homeostasis model assessment but the cellular mechanism is not determined Elevates liver glucokinase, liver glycogen, and reduces liver fat accumulation Decreases the elevated expression and activity of PTP1B in the skeletal muscles Promotes glucose transport by increasing the GLUT-4, PI3K and IRS-1 levels Inhibits oxidative stress ND

[41]

Restores the pre-diabetic state of insulin resistance Increases glucose uptake in skeletal muscle and inhibits glycogenolysis in the liver Decreases insulin resistance using insulin resistance index but the cellular mechanism is not determined

[50]

[33]

[34] [35]

[38]

[39]

[42] [43,44]

[45]

[46]

[47]

[48] [49]

[51]

[52]



Table 1 N°

Antidiabetic plants

Continued. Scientific name

Family


20

Canna indica

Cannaceae

L8 muscle cells

21

Cayratia trifolia

Vitaceae

22

Cecropia obtusifolia

Urticaceae

23

Centaurium erythraea

Gentianaceae

Isolated rat hemi-diaphragm 3T3-F442A murine adipocytes High-fat diet mice

24

Cinnamomum cassia

Lauraceae

25 26

Cistus salviifolius Citrus junos

Cistaceae Rutaceae

27

Cleome droserifolia

Cleomaceae

28 29

Coriandrum sativum Cornus kousa

Apiaceae Cornaceae

30

Cornus officinalis

Cornaceae

db/db obese diabetic mice and streptozotocin diabetic rats

31

Crocus sativus

Iridaceae

C2C12 cells

32 33

Cryptolepis sanguinolenta Curcuma comosa

Apocynaceae Zingiberaceae

Type 2 diabetic mice Ovariectomized rats

34

Cyclea peltata

Menispermaceae

Type 2 diabetic rats

35

Dryopteris fragrans

Dryopteridaceae

Streptozotocin rats

36

Echinacea purpurea

Compositae

Cultured adipocytes

37

Elaeis guineensis

Arecaceae

38 39

Enicostemma littorale Euryale ferox

Gentianaceae Nymphaeaceae

40

Ficus deltoidea

Moraceae

Healthy adults with pre-diabetes Fructose fed rats Streptozotocin-induced diabetic mice Healthy adults with pre-diabetes

High-fat diet-fed and low-dose streptozotocin-induced diabetic mice and insulin-resistant HepG2 cells 3T3-L1 adipocytes Mice fed a high-fat diet and C2C12 myotubes Albino rats rendered glucose intolerant by tetracycline Meriones shawi rats 3T3-L1 cells



Ref

Stimulates the glucose transport by stimulation of GLUT1 protein synthesis and the activation of PI3K Has a stimulatory effect of insulin on GLUT4 protein Stimulates glucose uptake

[53]

Reduces insulin resistance as measured by the homeostasis model assessment Increases the consumption of extracellular glucose

[56]

Stimulates glucose uptake Increases peroxisome PPARγ and AMPK activities Inhibits the hepatic glucose output

[58]

ND Increases glucose uptake through PPARγ activation and insulin signalling Stimulates the insulin signalling and inhibits gluconeogenesis, increases the insulin-sensitive glucose transporter GLUT4 mRNA as well as its protein expression in diabetic rats and ameliorates glucose transport Enhances glucose uptake and the phosphorylation of AMPK/ACC and MAPKs Stimulates glucose uptake Enhances insulin-mediated glucose uptake in skeletal muscle and increases muscle GLUT4 protein levels Improves glycogen in peripheral tissue such as skeletal muscle Improves glucose utilization and insulin resistance Activates PPARγ and increased insulin-stimulated glucose uptake Has positive effects on glucose and lipid levels ND Regulates glucose metabolism

[61]

Has positive effects on glucose and lipid levels

[69]

[54]

[55]

[57]

[59]

[60]

[62]

[63]

[63]

[64] [65]

[66]

[67]

[68]

[69]

[70] [71]

1201

Antidiabetic plants

Table 1 N°



Family


41

Ganoderma lucidum

Ganodermataceae

C57BL/6 db/db diabetic mice

42

Gastrodia elata

Orchidaceae

43

Gleditsia sinensis

Leguminosae

44

Glycyrrhiza foetida

Leguminosae

45

Guazuma ulmifolia

Malvaceae

46 47

Hedysarum polybotrys Helianthus tuberosus

Fabaceae Compositae

Rats fed a high-fat diet and 3T3-L1 adipocytes 3T3-L1 adipocytes and HepG2 cells Diet-induced obese and db/db mice 3T3-F442A Preadipose cell line Diabetic rats Partially pancreatectomized diabetic rats

48 49

Helicteres isora Ilex hunanensis

Malvaceae Aquifoliaceae

C57BL/KsJdb/db mice High-fat diet rats

50

Justicia spicigera

Acanthaceae

51 52

Kigelia pinnata Krameria lappacea

Bignoniaceae Krameriaceae

Insulin-resistant murine 3T3-F442A and human subcutaneous adipocytes Skeletal muscle cells Cultured myotubes

53 54

Lagerstroemia speciosa Larix laricina

Lythraceae Pinaceae

55 56

Lindera aggregata Liriope spicata

Lauraceae Asparagaceae

Rat adipocyte Diet-induced obese C57BL/6 mice HepG2 cells KKAy mice

57

Litsea coreana

Lauraceae

Rats with hyperlipidemia

58

Lyophyllum decastes

Lyophyllaceae

KK-Ay mice

59

Malva parviflora

Malvaceae

Streptozotocin-induced diabetic rats

60

Mangifera indica

Anacardiaceae

3T3-L1 adipocytes

1202


Ref

This fungus regulates the tyrosine phosphorylation level of the IR β-subunit and the level of hepatic glycogen Potentiates glucose uptake

[72]

Increases PPARγ2 expression

[74]

Activates peroxisome proliferator-receptor γ Stimulates glucose uptake

[39]

ND Improves hepatic insulin sensitivity explained by potentiated insulin signalling (tyrosine phosphorylation of insulin receptor substrate 2-phosphorylation of Akt) and phosphorylation of AMPK-phosphorykation of ACC and decreases PEPCK expression Has insulin-sensitizing activity Regulates lipid metabolism and antioxidants and upregulates PPARα expression in liver Stimulates glucose uptake

[76]

Stimulates of GLUT4 translocation Inhibits human recombinant PTP1B in vitro and enhances insulin-stimulated glucose uptake Enhances glucose uptake Increases glucose uptake

[82]

ND Increases expression of insulin receptor subunit, IRS-1, PI3K, and peroxisome proliferators-activated receptors γ, inhibits hepatic gluconeogenesis and increases hepatic glycolysis as well as hepatic glycogen content Regulates effects on the disturbance of lipid metabolism and decreases leptin level increases GLUT4 protein content in the plasma membrane Restores glucose-6-phosphatase, glucokinase and hexokinase activities in liver Enhances insulin-stimulated glucose uptake through translocation and activation of the glucose transporter (GLUT4) in an IRTK and PI3K dependent fashion

[86]

[73]

[75]

[77]

[78] [79,80]

[81]

[83]

[84] [85]

[87]

[88]

[89]

[90]

[91]



Table 1 N°

Antidiabetic plants


Family


61

Magnolia dealbata

Magnoliaceae

Murine 3T3-F442A and human subcutaneous adipocytes Type 2 diabetic rats Alloxan-induced diabetic rats, normal rats, streptozotocin -induced diabetic hamsters hepatocytes, HepG2 cells High-fructose diet-induced insulin resistance in rats Dahl salt-sensitive, insulin-resistant rat ob/ob mouse Streptozotocin mice Zucker diabetic fatty rats and high-fat diet mice

62 63

Momordica charantia Nigella sativa

Cucurbitaceae Ranunculaceae

64

Nyctanthes arbortristis

Oleaceae

65

Olea europaea

Oleaceae

66 67 68

Ophiopogon japonicus Opuntia dillenii Panax ginseng

Asparagaceae Cactaceae Araliaceae

69 70

Passiflora nitida Phellodendri cortex

Passifloraceae Rutaceae

Alloxan-diabetic mice 3T3-L1 adipocytes

71

Pongamia pinnata

Leguminosae

L6-GLUT4myc myotubes

72

Populus balsamifera

Salicaceae

Diet-induced obese C57BL/6 mice

73

Prosopis glandulosa

Leguminosae

Streptozotocin rats

74

Prunus mume

Rosaceae

75 76 77

Psacalium peltatum Psidium guajava Pterocarpus marsupium

Asteraceae Myrtaceae Leguminosae

78

Pueraria thomsonii

Leguminosae

High-fat diet mice and C2C12 myotubes Streptozotocin mice FL83B mouse hepatocytes Diabetic C57BL/6 mice Diabetic and fructose-fed diabetic rats 3T3-L1 adipocytes

79

Rehmannia glutinosa

Plantaginaceae

80

Rhodiola crenulata

Crassulaceae

Type 2 streptozotocin rats, 3T3-L1 adipocytes and HepG2 cells Zucker diabetic fatty rats



Ref

Stimulates glucose uptake

[92]

ND Inhibits the enzymes involved in the neoglucogenesis pathway in the liver and increases insulin signalling pathways

[93]

Decreases the insulin resistance index but the cellular mechanism is not determined ND

[52]

ND ND Regulates the expression of genes involved in PPAR and inhibited hepatic gluconeogenesis through AMPK activation. Enhances phosphorylation of AMPK and GLUT4 Inhibits metabolic syndrome Enhances tyrosine phosphorylation and reduces tyrosine dephosphorylation and accelerates insulin-stimulated glucose uptake Increases translocation of GLUT4 to plasma membrane associated with activation of AMPK pathway Decreases the leptin/adiponectin ratio, and increases adiponectin levels Improves insulin sensitivity of isolated cardiomyocytes Increases glucose uptake and the activation of PPARγ ND Increases glucose uptake Stimulates translocation of GLUT4 and phosphorylation of AMPKα

[99]

Improves insulin sensitivity using insulin resistance index but the cellular mechanism is not determined Increases the gene expression of resistin and increases glucose consumption Decreases the index of the homeostasis model assessment of insulin resistance but the cellular mechanism is not determined

[114]

[94–97]

[98]

[100] [101–103]

[104] [105]

[106]

[107]

[108]

[109]

[110] [111] [112,113]

[115–117]

[118]

1203

Antidiabetic plants

Table 1

Continued.

N°

Scientific name


Family


81

Rhus coriaria

Anacardiaceae

Streptozotocin rats

82

Sambucus nigra

Adoxaceae

Human

83

Scoparia dulcis

Plantaginaceae

L6 myotubes

84

Schisandra chinensis

Magnoliaceae

3T3-L1 adipocytes and Min6 cells

85

Smallanthus sonchifolius

Compositae

86

Sorbus decora

Rosaceae

87

Spergularia purpurea

Caryophyllaceae

Obese and slightly dyslipidemic premenopausal women Type 1 diabetic rat (STZ), the genetic KK-A y type 2 diabetic mouse, high glucose-fed rat and skeletal muscle cells in culture Streptozotocin mice

88

Stevia rebaudiana

Compositae

High-fat diet-fed mice

89

Suaeda fruticosa

Amaranthaceae

Sand rats

90

Sutherlandia frutescens

Leguminosae

High-fat diet rats, 3T3-L1 adipocytes and human liver cell culture

91

Swertia punicea

Gentianaceae

Streptozotocin-induced type 2 diabetic BABL/c mice

92

Symplocos cochinchinensis

Symplocaceae

93 94 95 96

Syzygium cumini Syzygium jambo Syzygium samarangense Tecoma stans

Myrtaceae Myrtaceae Myrtaceae Bignoniaceae

97

Tetrastigma obtectum

Vitaceae

High-fat diet-low streptozotocin induced type 2 diabetic rats FL83B mouse hepatocytes FL83B mouse hepatocytes FL83B mouse hepatocytes Insulin-sensitive and insulin-resistant murine 3T3-F442A and human subcutaneous adipocytes HepG2 cells

1204


Ref

Improves insulin sensitivity index but the cellular mechanism is not determined Activates PPARγ and stimulated insulin-dependent glucose uptake Increases Glut 4 expression and translocation to plasma membranes Increases glucose disposal rates and enhances hepatic insulin sensitivity by working as a PPARγ agonist Restores lipid metabolism

[119]

Improves insulin resistance using HOMA insulin resistance parameter but the cellular mechanism is not determined

[124]

Inhibits endogenous glucose production Improves the glucose utilization in peripheral tissues and inhibits the hepatic glucose production mediated via inhibition of phosphoenolpyruvate kinase expression Ameliorates the metabolic parameters of glucose and lipids Normalizes glucose uptake in peripheral tissues and regulated 26 genes encoding vesicle transporters, receptors, signaling molecules, transcription factors, metabolic enzymes and modulated fatty acid biosynthesis Improves insulin sensitivity by enhancing insulin signalling. The expression levels of InsR-α, IRS-1 and PI3K were also increased. ND

[125]

Increases glucose uptake Increases glucose uptake Increases glucose uptake Stimulates glucose uptake

[111]

Enhances glucose consumption and stimulates phosphorylation of AMPK

[137]

[120]

[121]

[122]

[123]

[126,127]

[128]

[129–132]

[133]

[134]

[111] [111] [135,136]



Table 1

Continued.

N°

Scientific name

Antidiabetic plants

Family


98

Teucrium cubense

Lamiaceae

99

Teucrium polium

Lamiaceae

100

Tinospora cordifolia

Menispermaceae

Insulin-sensitive and insulin-resistant murine 3T3-F442A and human subcutaneous adipocytes Sucrose-induced insulin resistance in rat High-fructose diet rats

101

Tinospora crispa

Menispermaceae

Diabetic mice

102 103

Tithonia diversifolia Trigonella foenum-graecum

Compositae Leguminosae

104

Vaccinium myrtillus

Ericaceae

105 106

Vaccinium vitis-idaea Vaccinium angustifolium

Ericaceae Ericaceae

KK-Ay-mice C57BL/6J model of type 2 diabetes induced by high-fat diet and high-fat high-sucrose diet Preclinical study: obese, nondiabetic, and insulin-resistant participants C2C12 muscle cells Obese Zucker rat

107

Vaccinium macrocarpon

Ericaceae

Normal and obese mice

108

Vatairea macrocarpa

Leguminosae

Streptozotocin-diabetic rats and type 2 diabetics

109

Xanthium strumarium

Compositae

110

Zingiber officinale

Zingiberaceae

111

Ziziphus spina-christi

Rhamnaceae

Streptozotocin diabetic rats Alloxan-induced diabetic rats Streptozotocin-induced diabetic rats and type 2 diabetic patients


Ref

Stimulates glucose uptake

[136]

Improves the liver function

[138]

Activates the following enzymes: hexokinase, phosphofructokinase, pyruvate kinase, glucose-6-phosphatase, fructose-1,6-bisphosphatase, and glucose-6-phosphate dehydrogenase Increases phosphorylation of IR and protein kinase B (Akt) as well as the expression of GLUT2 Improves glucose metabolism Improves lipid metabolism disorders

[139,140]

Improves insulin sensitivity using euglycemic hyperinsulinemic clamp but the cellular mechanism is not determined Enhances glucose uptake Increases adiponectin concentration and decreases plasma concentrations of tumour necrosis factor-α, interleukin-6 and C-reactive protein Acts on the adiponectin-AMPK pathway Improves insulin sensitivity assessed with homeostasis model of insulin resistance but the cellular mechanism is not determined Elevates glucose utilization

[146]

Acts as a scavenger of oxygen radicals Induces a reduction of liver phosphorylase and glucose-6-phosphatase activities, and a significant increase on serum pyruvate level, liver glycogen content, and pancreatic cAMP levels

[153]

[141]

[142,143] [144,145]

[147] [148]

[149]

[150,151]

[152]

[154,155]

ACC, acetyl-CoA carboxylase; AMPK, adenosine monophosphate-activated protein kinase; cAMP, cyclic adenosine monophosphate; GLUT1, glucose transporter 1; GLUT2, glucose transporter 2; GLUT4, glucose transporter 4; HOMA, homeostatic model assessment; IR, insulin receptor; IRS-1, insulin receptor substrate-1; IRTK, insulin receptor tyrosine kinase; PI3K, phosphatidylinositol 3-kinase; MAPK, mitogen-activated protein kinases; ND, not determined; PEPCK, phosphoenolpyruvate carboxykinase; PPARα, peroxisome proliferator-activated receptor-α; PPARγ, peroxisome proliferator-activated receptor-γ; PTP1B, protein tyrosine phosphatase 1B; STZ, streptozotocin.


1205

Antidiabetic plants


Medicinal plants Liver Muscle

Adipose tissue TG TG TG TG Phosphatidylinositol 3-kinase and insulin receptor substrates-1 Glucose transport (Glut 2)

Glucose transport (Glut 4)

Glycogenesis

Glycolysis/Glycogenesis (key enzymes)

Neoglucogenesis Glycogenolysis Activation of PPARγ

Glucose transport (Glut 4)

Lipolysis

Glycolysis/Glycogenesis (key enzymes/glycogen content)

Adiponectin

Activation of PPARγ

Activation of PPARγ

Improved insulin sensitivity Figure 1

Main metabolic and cellular targets involved in improving insulin sensitivity by antidiabetic plants. ↑: Stimulate. ↓: Inhibit.

and insulin resistance.[159,160] Some medicinal plants reported in this review are able to improve insulin sensitivity by regulating adiponectin levels.[39,115] Finally, uncoupling of oxidative phosphorylation represents a new alternative to inhibition for triggering cytoprotective effects of therapeutic relevance to insulin resistance in both muscle and liver.[161] However, for all antidiabetic plants reported in this review, a general remark had been noticed about the safety indicating that a little information is available in these studies concerning the toxicological studies. In the other hand, few studies have performed advanced purification determining some phytochemical groups involved in improving insulin sensitivity. These phytochemical groups are presented in Table 2. The main phytochemicals groups improving insulin sensitivity are flavonoids, terpenoids, glycosides and oligosaccharides (Table 2). A polyphenol-rich Aloe vera extract containing both aloin and aloe-emodin was able to decrease significantly body weight and blood glucose levels and protected animals against unfavorable results on insulin resistance when administered orally for a period of 4 weeks to insulin-resistant mice.[37] In a clinical study, an Aloe vera gel complex has been demonstrated to reduce the fasting blood glucose, body weight and insulin resistance in obese 1206

individuals with prediabetes or early diabetes mellitus.[37] Aloin and aloe-emodin seem to be involved in this antidiabetic effect. The central role of the nuclear receptor PPARγ in lipid and glucose metabolism is well established; however, due to some adverse effects many PPARγ-targeting drugs have limited beneficial effect. Alternatively, some natural products such as amorfrutins from Glycyrrhiza foetida and Amorpha fruticosa have been identified as potent insulin sensitizers which activate PPARγ and act differently at the gene expression level when compared with the current synthetic PPARγ drugs. These natural products have been demonstrated to improve safely insulin resistance in diet-induced obese and db/db mice.[39] Mangiferin and its glucoside have been shown to be implicated in the antidiabetic effect of Anemarrhena asphodeloides demonstrated in KK-Ay mice. This effect has been associated with a significant reduction of blood glucose levels as well as insulin resistance.[41] Decursin isolated from Angelica gigas has been demonstrated to improve glucose tolerance in mice fed a high-fat diet when administered for 7 weeks. A parallel reduction on weight gain, triglyceride content, total cholesterol content, fat size and adipocytokines such as leptin, resistin, IL-6 and monocyte chemoattractant protein-1 has been shown.[42] Another study revealed that



Table 2 N° 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31

Antidiabetic plants

Main phytochemical groups involved in improving insulin sensitivity activity from the antidiabetic plants presented in study Medicinal plant’s name Aloe vera Amorpha fruticosa Anemarrhena asphodeloides Angelica gigas Cecropia obtusifolia Cinnamomum cassia Curcuma comosa Echinacea purpurea Gleditsia sinensis Glycyrrhiza foetida Hedysarum polybotrys Schisandra chinensis Lindera aggregate Liriope spicata Litsea coreana Mangifera indica Olea europaea Ophiopogon japonicas Opuntia dillenii Panax ginseng Pongamia pinnata Prosopis glandulosa Psacalium peltatum Psidium guajava Ratanhiae radix Rehmannia glutinosa Sambucus nigra Swertia punicea Tetrastigma obtectum Tinospora crispa Vaccinium vitis-idaea

Active phytoconstituent(s)

Ref

Aloin and aloe-emodin Amorfrutins Mangiferin and its glucoside Decursin Chlorogenic acid Procyanidin oligomers Phytoestrogen ((3R)-1,7-diphenyl-(4E,6E)-4,6-heptadien-3-ol) Alkamide hexadeca-2E,9Z,12Z,14E-tetraenoic acid isobutylamide Aromadendrin Amorfrutins Polysaccharide Lignan Secoaggregatalactone A Polysaccharides Flavonoids 3β-taraxerol Triterpenoids Polysaccharide Polysaccharides Ginsenosides Karanjin Diavite™ Carbohydrate fraction Vescalagin Ratanhiaphenol III Oligosaccharides Naringenin Methylswertianin and bellidifolin Flavonoids Borapetoside C Quercetin and quercetin 3-O glycosides

[36,37]

chlorogenic acid isolated from Cecropia obtusifolia was able to exert an antidiabetic effect by stimulating glucose uptake in both insulin-sensitive and insulin-resistant adipocytes without appreciable proadipogenic effects.[55] In addition, the antidiabetic effect of both A- and B-type procyanidin oligomers in different Cinnamon species has been demonstrated in high-fat diet-fed and low-dose streptozotocininduced diabetic mice when administered for 14 days. Furthermore, procyanidins increased the consumption of extracellular glucose in insulin-resistant HepG2 cells and normal HepG2 cells.[57] Recently, the effect of phytoestrogen, (3R)-1,7-diphenyl-(4E,6E)-4,6-heptadien3-ol isolated from Curcuma comosa Roxb on insulin resistance has been investigated in prolonged estrogen-deprived rats. The findings demonstrated that treatment for 12 weeks with this compound markedly reduced serum total cholesterol and low-density lipoprotein levels, improved insulin sensitivity and partially restored uterine weights in rats.[65] On the other hand, alkamide hexadeca-2E,9Z,12Z,14Etetraenoic acid isobutylamide isolated from Echinacea purpurea was found to improve insulin sensitivity by

[39] [41] [42] [55] [57] [65] [68] [75] [39] [76] [72,122] [86] [87] [88] [91] [98] [99] [100] [101,102] [106] [108] [110] [111] [83] [116,117] [120] [133] [137] [141] [147]

activating PPARγ with no concurrent stimulation of adipocyte differentiation and increased insulin-stimulated glucose uptake.[68] Aromadendrin, a flavonoid isolated from Gleditsia sinensis has been shown to ameliorate insulin sensitivity in vivo. This compound significantly stimulated insulin-sensitive glucose uptake in both HepG2 cells and 3T3-L1 adipocytes. The signalling pathway is mediated through reversion of protein kinase B (Akt/PKB) phosphorylation and stimulation of the expression of PPARγ2 and aP2 mRNAs and the PPARγ2 protein.[75] Hedysarum polybotrys polysaccharides have been shown to promote insulin sensitivity in alloxan-induced diabetic mice and induced inhibition of lipid peroxidation, gluconeogenesis, the biosynthesis of fatty acid, cholesterol and cell cytokines related to insulin resistance.[76] In addition, A lignanrich fraction containing schizandrin, gomisin A and angeloylgomisin H isolated from Schisandra chinensis has been demonstrated to improve glucose homeostasis by increasing glucose disposal rates and enhancing hepatic insulin sensitivity by working as a PPARγ agonist in pancreatectomized diabetic rats treated orally for 8 weeks.


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The insulin sensitivity was assessed using the euglycemic hyperinsulinemic clamp.[122] Secoaggregatalactone A isolated from the leaves of Lindera aggregate seems to be involved in improving insulin sensitivity. The molecular mechanism of this effect remains unclear; however, the cytotoxicity of this compound is proven.[86] A study has revealed that some polysaccharides from Liriope spicata caused a remarkable decrease of fasting blood glucose and significant improvement of insulin resistance and serum lipid metabolism in diabetic mice. In addition, these polysaccharides inhibited hepatic gluconeogenesis and increased hepatic glycolysis and hepatic glycogen content.[87] Furthermore, the mechanistic analysis showed the increased expression of InsR-α, IRS-1, PI3K and PPARγ.[87] Additionally, some studies have demonstrated the role of polysaccharides isolated from Ophiopogon japonicas and Opuntia dillenii in improving insulin resistance in type 2 diabetes mellitus.[99,100] Ginsenosides from Panax ginseng have been demonstrated to improve insulin sensitivity in Zucker diabetic fatty rats by marking the effects on the expression of genes involved in PPAR actions and triglyceride metabolism.[101] Karanjin isolated from Pongamia pinnata has been shown to exert antihyperglycemic effect. In vitro, this effect seems to be mediated through the elevation of glucose uptake due to the stimulation of GLUT4 translocation.[106] Diavite™, a product consisting solely of the dried and ground pods of Prosopis glandulosa, has been shown to act as an antidiabetic agent improving insulin sensitivity in vivo in both Zucker fa/fa rats and streptozotocin-induced diabetic rats and increasing glucose uptake in vitro in isolated cardiomyocyes.[108] Vescalagin, isolated from Psidium guajava, alleviated the insulin resistance in the insulin-resistant mouse hepatocytes.[111] In addition, astragaloside II and isoastragaloside I, isolated from Radix Astragali, alleviated the insulin resistance observed in both dietary and genetic obese mice due to the elevation of circulating adiponectin.[115] A dichloromethane extract of Ratanhiae radix dose-dependently inhibited human recombinant PTP1B in vitro and enhanced insulin-stimulated glucose uptake in murine myocytes. This activity could be partly assigned to Ratanhiaphenol III.[83] Rehmannia glutinosa has been shown to improve insulin resistance in experimental type 2 diabetic rats and ameliorates adipose metabolic disturbance by increasing the gene expression of resistin. The oligosaccharides seem to be involved in this activity.[116] Extracts of Sambucus nigra have been found to activate PPARγ and to stimulate insulin-dependent glucose uptake suggesting that they have a potential use in the prevention or treatment of insulin resistance in type 2 diabetic situation. Naringenin isolated from this plant was found to activate PPARγ without stimulating adipocyte differentiation.[120] Methylswertianin and bellidifolin isolated from Swertia punicea have been shown to be useful for treating 1208

type 2 diabetes, likely via the improvement of insulin resistance in streptozotocin-induced type 2 diabetic male BABL/c mice.[133] In another study, borapetoside C isolated from Tinospora crispa, was found to increase glucose utilization, delayed the development of insulin resistance and enhanced insulin sensitivity. The activation of insulin receptor and PKB as well as the expression of glucose transporter-2 and the enhancement of insulin sensitivity may contribute to the hypoglycaemic action of borapetoside C in diabetic mice.[141] Finally, quercetin and quercetin 3-O-glycosides isolated from Eeyou Istchee were found to have potential applications for the prevention and treatment of insulin resistance in C2C12 muscle cells by stimulating glucose uptake and the AMPK pathway.[147] In this review the in-vivo studies evaluating the whole body insulin sensitivity have used mainly the homeostasis model of insulin sensitivity index, while a few investigations have used the euglycemic hyperinsulinemic clamp, which remains the principle technique available for the precise assessment of insulin sensitivity in vivo.

Conclusion In the present review, we focused on antidiabetic plants and their ability to improve insulin sensitivity, cellular and metabolic effects of these plants are discussed. One hundred and eleven plants have been investigated either in vivo using various animal models mainly streptozotocin-induced diabetic rodents and high-fat diet rodents, or in-vitro studies using some cellular lines essentially 3T3-L1 and HepG2 cells. Their beneficial action in terms of improving insulin sensitivity has been elucidated. It has been shown that the potential plants targeted insulin action globally via several pathways: inhibition of hepatic glucose production or potentiating the peripheral glucose utilization in the muscles and adipocytes by regulating the activity and expression of key enzymes and glucose transporters. In addition, a lot of medicinal plants improved insulin sensitivity through the stimulation of the known following insulin-signalling pathways: the expression levels of InsR-α, IRS-1, PI3K, tyrosine-induced phosphorylation of insulin receptor substrate, the phosphorylation of AMPK/ACC and MAPKs. Several medicinal plants had beneficial effects on insulin sensitivity; however, there is still insufficient evidence to draw definitive conclusion about their efficacy for treatment of diabetic patients through improvement of insulin sensitivity. In addition, further advanced studies are still needed to identify the relationship between the active principles and bioactivity. Finally, well-designed randomized controlled trials with long-term consumption are still needed to guarantee the bioactivity and safety of these medicinal plants and compounds for diabetic patients.



Antidiabetic plants

Declarations

Acknowledgements

Conflict of interest

The authors extend their thanks to the Moroccan government for supporting this study.

The Author(s) declare(s) that they have no conflicts of interest to disclose.

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Antidiabetic property of Symplocos cochinchinensis is mediated by inhibition of alpha glucosidase and enhanced insulin sensitivity.

African medicinal plants with antidiabetic potentials: a review.

DIACAN: Integrated Database for Antidiabetic and Anticancer Medicinal Plants.

Extracts from Aralia elata (Miq) Seem alleviate hepatosteatosis via improving hepatic insulin sensitivity.

ANT1-mediated fatty acid-induced uncoupling as a target for improving myocellular insulin sensitivity.

Preventing High Fat Diet-induced Obesity and Improving Insulin Sensitivity through Neuregulin 4 Gene Transfer.

New oral thiazolidinedione antidiabetic agents act as insulin sensitizers.

Zinc and insulin sensitivity.

Insulin sensitivity in pregnancy.

Microbial modulation of insulin sensitivity.

resistance.

Rediscovering medicinal plants' potential with OMICS: microsatellite survey in expressed sequence tags of eleven traditional plants with potent antidiabetic properties.

Pioglitazone increases insulin sensitivity by activating insulin receptor kinase.

Chronic hyperinsulinemia decreases insulin action but not insulin sensitivity.

Antidiabetic Medicinal Plants Used by the Basotho Tribe of Eastern Free State: A Review.

Enzyme inhibitory and radical scavenging effects of some antidiabetic plants of Turkey.

Curative diet supplementation with a melon superoxide dismutase reduces adipose tissue in obese hamsters by improving insulin sensitivity.

Alpha-Glucosidase Enzyme Biosensor for the Electrochemical Measurement of Antidiabetic Potential of Medicinal Plants.

Antidiabetic plants used among the ethnic communities of Unakoti district of Tripura, India.

Pharmacological and phytochemical appraisal of selected medicinal plants from jordan with claimed antidiabetic activities.

Antidiabetic potential of some less commonly used plants in traditional medicinal systems of India and Nigeria.

Histochemistry and immunolocalisation of glucokinin in antidiabetic plants used in traditional Mexican medicine.

Genetic Modification for Improving Seed Vigor Is Transitioning from Model Plants to Crop Plants.

Genomics Approaches For Improving Salinity Stress Tolerance in Crop Plants.