1. R1 = glc (1→2)-glc, R2 = H (ginsenoside Rg3) 2. R1 = glc (1→2)-glc, R2 = glc (1→6)-glc (ginsenoside Rb1) 3. R1 = glc (1→2)-glc, R2 = ara (1→6)-glc(p) (ginsenoside Rb2) 4. R = glc, R2 = H (ginsenoside Rh2) Dammarane-type 7. R1 = H, R2 = CH3 (oleanolic acid) 8. R1 = OH, R2 = CH3 (maslinic acid) 9. R1 = OH, R2 = CH2OH (arjunolic acid)
Oleanane-type triterpenoids
10. R1 = H, R2 = H (ursolic acid) 11. R1 = OH, R2 = H (corosolic acid) 12. R1 = OH, R2 = OH (tormentic acid) 13. R1 = H, R2 = OH (pomolic acid)
Ursane-type triterpenoids 5. R = CH3 (lupeol) 6. R = COOH (betulinic acid)
Lupane-type triterpenoids
Natural Triterpenoids for the Treatment of Diabetes Mellitus:
A Review
Han Lyu, Jian Chen and Wei-lin Li*
Institute of Botany, Jiangsu Province and Chinese Academy of Sciences, Nanjing 210014, China [email protected]
Received: January 28th, 2016; Accepted: July 18th, 2016
Triterpenoids, an important group of secondary metabolites, are widely distributed in nature. Many triterpenoids have been found with potential therapeutic effect against diabetes mellitus. However, the use of triterpenoids for the treatment of diabetes has not been systematically discussed previously. This review summarized the anti-diabetic activity of natural triterpenoids reported since the late 1980s with the emphasis on the molecular mechanisms.
Keywords: Natural triterpenoids, Diabetes mellitus.
Diabetes Mellitus (DM) is a multi-cause metabolic disease characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. On the basis of etiology, diabetes mellitus is categorized into two main types. Type 1 DM, also known as insulin-dependent diabetes mellitus (IDDM), arises from little or no endogenous insulin secretory capacity. Type 2 DM, or non-insulin-dependent diabetes mellitus (NIDDM), is a much more prevalent category and often results from a combination of resistance to insulin action and an inadequate compensatory insulin secretory response [1].
Insulin and oral antidiabetic agents such as sulfonylureas, biguanides, α-glucosidase inhibitors, and glinides are often used as monotherapy or in combination to treat diabetes [2]. However, many of the existing synthetic antidiabetic drugs have serious side effects. There is an increasing demand for more effective and safer novel antidiabetic agents. Many natural products, such as triterpenoids and flavonoids, have been extensively explored in the field of drug discovery and have led to remarkable successes [3-6]. Triterpenoids, a large class of natural products, are a rich reservoir of candidate compounds for drug discovery. More than 20,000 triterpenoids exist in nature [7]. Triterpenoids are composed of six isoprene (C5H8)6 units; they often occur as free triterpenoids, triterpenic glycosides (saponins), or their esters. Triterpenoids are structure-wise mainly classified into two chemical types, tetracyclic and pentacyclic. Triterpenoids can further be sub-classified into diverse groups including dammaranes, cycloartanes, lanostanes, cucurbitanes (tetracyclic triterpenoids), lupanes, oleananes, ursanes, friedelanes (pentacyclic triterpenoids), and miscellaneous compounds [8].
Triterpenoids have been proven to have a broad spectrum of pharmacological activities: diabetic, cancer, anti-inflammatory, analgesic, antiviral, anti-HIV, antimicrobial, antiplasmodial, cardioprotective and hepatoprotective effects [4,5,7,8]. Among them, a large number of studies were focused on their anti-diabetic properties. Pharmacological activities in diabetes and diabetic complications of some pentacyclic triterpenoids have been discussed earlier [4]. By collecting evidence in vitro and in
vivo bioassay of triterpenoids (tetracyclic triterpenoids and
pentacyclic triterpenoids) of plant origin (semi-synthetic
triterpenoid analogs or triterpenoids derived from animal and microbial species are not included), this review will highlight their anti-diabetic mechanisms, especially potential molecular mechanisms. Given the diverse mechanistic insights of these compounds, this review is structured according to the suggested antidiabetic mechanisms of triterpenoids.
HO R
R2O H R1O HO HO R2 COOH H R1
HO COOH H R1 R2
Figure1: Structures of some active triterpenoids Antidiabetic activity of triterpenoids in vivo
Increasing studies have suggested that various triterpenoids exhibited antidiabetic activity in normal or/and diabetic animal models (Table 1). Triterpenoids were shown to reduce the plasma glucose level and enhance glucose tolerance of experimental animals [9-33]. These findings, which strongly suggest the antidiabetic potential of triterpenoids, have initiated increasing efforts in the field to explore the molecular mechanism responsible.
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Table 1: Antidiabetic activities of triterpenoids tested in animal models.
Compounds (type*) Model Antidiabetic activities Plant resource (family) References ginsenoside Rg3(D) db/db diabetic mice ↓plasma glucose
↑insulin secretion Panax ginseng C. A. Mey. (Araliaceae) [9] ginsenoside Rb2(D) STZ-induced rats ↓plasma glucose
↑hepatic glycogen ↓G6Pase
Panax ginseng C. A. Mey. (Araliaceae) [10]
ginsenoside Rh2(D) fructose-rich-fed STZ-rats
normal rats ↓plasma glucose ↑response to exogenous insulin ↓plasma glucose ↑insulin secretion
Panax ginseng C. A. Mey. (Araliaceae) [11]
ginsenoside Rg1(D) alloxan-diabetic mice
normal mice ↓plasma glucose ↑hepatic glycogen Panax ginseng C. A. Mey. (Araliaceae) [12] ginsenoside Re(D) STZ-induced diabetic rats ↓plasma glucose Panax ginseng C. A. Mey. (Araliaceae) [13]
phanoside(D) normal rats ↓plasma glucose
↑insulin secretion Gynostemma pentaphyllum (Thunb.) Mak. (Cucurbitaceae) [14] isoastragaloside I(Cy),
astragaloside II(Cy) db/db diabetic mice ↑adiponectin level ↑AMPK activity ↑insulin sensitivity
Astragalus membranaceus (Fisch.) Bunge
(Leguminosae) [15]
astragaloside IV(Cy) STZ-induced daibtetic rats ↓plasma glucose, HbA1C
↑insulin secretion Astragalus membranaceus (Fisch.) Bubge (Leguminosae) [16] momordicoside S, T(Cu) normal and high-fat-fed mice ↑glucose tolerance Cucumis sativus L.( Cucurbitaceae) [17] gymnemic acid II(O),
gymnemic acid III(O), gymnemasaponin V(O), gymnemoside-f(O)
STZ-diabetic mice ↓plasma glucose
↓sugar absorption in small intestinal Gymnema sylvestre R. BR. (Asclepiadaceae) [18] senegin II(O),
senegin III(O) normal mice KK-Ay diabetic mice ↓plasma glucose Polygala senega L. var. latifolia Torr. et Gray (Polygalaceae) [19] kaikasaponin III(O) STZ-induced diabetic rats ↓plasma glucose Pueraria thunbergiana Benth.
(Leguminosae) [20]
arjunolic acid(O) STZ-induced diabetic rats ↓plasma glucose ↓TNF-α,NO
↑antioxidant enzymes in pancreas
Terminalia arjuna (Roxb.) Wight & Arn.
(Combretaceae) [21]
momordin Ic(O),
oleanolic acid 3-O-glucuronide(O) normal rats ↓plasma glucose ↓sugar absorption in small intestinal Kochia scoparia (L.) Schrad. (Chenopodiaceae) [22,23] 18 β-glycyrrhetinic acid(O) STZ-induced diabetic rats ↓plasma glucose,HbA1C
↑insulin secretion Glycyrrhiza uralensis Fisch. (Leguminosae) [24] oleanolic acid(O) normal rats ↓plasma glucose
↑insulin secretion Cornus officinalis Sieb. et Zucc. (Cornaceae) [25] maslinic acid(O),
pomolic acid(U) normal rats db/db/Ola diabetic mice ↓plasma glucose ↓glycosuria Eriobotrya japonica (Thunb.) Lindl. (Rosaceae) [26] elatosides E(O) normal rats ↓plasma glucose Aralia elata (Miq.) Seem. (Araliaceae) [27,28] escins-IIa(O),
escins-IIb(O) normal rats ↓plasma glucose Aesculus hippocastanum L. (Hippocastanaceae) [29] tormentic acid(U) normal rats ↓plasma glucose
↑insulin secretion Eriobotrya japonica (Thunb.) Lindl. (Rosaceae) [30] ursolic acid(U) high-fat diet mice
NA-STZ-induced diabetic mice ↓plasma glucose ↑insulin secretion ↑hepatic glycogen
Cornus mas L. (Cornaceae) [31]
corosolic acid(U) normal mice ↓plasma glucose
↓gluconeogenesis Lagerstroemia speciosa L. (Lythraceae) [32] euscaphic acid(U) normal rats
alloxan-diabetic mice ↓plasma glucose Eriobotrya japonica (Thunb.) Lindl. (Rosaceae) [33]
*In this review, the first appearance of a triterpenoid will be followed with the abbreviation of its chemical type in a parenthesis, D=dammarane-type, Cy=cycloartane-type, Cu=cucurbitane-type, La=lanostane-type, Lu=lupane-type, O=oleanane-type, U=ursane-type, T=Taraxastane-type
Stimulation of insulin secretion
Insulin is a metabolic hormone secreted from pancreatic islet β-cells. The main function of insulin is to maintain normal glucose homeostasis. Insulin stimulates hepatic glycogen synthesis, decreases glycogenolysis and the release of glucose from hepatic gluconeogenesis. Insulin also promotes glucose uptake in the skeletal muscle and adipose tissue. Patients with Type 1 DM, who have little or no endogenous insulin secretory capacity, require insulin therapy to maintain normoglycaemia. Insulin therapy has also been used to prevent or slow the progression of diabetic microvascular complications in patients with type 2 DM [34,35]. Several triterpenoids were reported to be able to increase the plasma insulin level in normal or diabetic animals (Table 1). These findings were also recapitulated in vitro studies. Phanoside at a dose up to 500 μM stimulated insulin secretion in isolated rat pancreatic islets [14]. Oleanolic acid (50 µM) and oleanolic aldehyde (O) (6.25-50 mg/mL) enhanced insulin secretion in INS-1 832/13 pancreatic β-cells. Oleanolic acid (30 µM) also enhanced acute glucose-stimulated insulin secretion in isolated rat islets. Chronic treatment
with oleanolic acid increased total cellular insulin protein and mRNA levels [36,37]. In spite of the well-documented activities, it remains unclear how these triterpenoids stimulated insulin secretion. Insulin secretion is modulated by several hormones and neurotransmitters, among which acetylcholine (ACh) is an important mediator [38]. Ginsenoside Rh2 (1.0 mg/kg) and oleanolic acid (5, 10 and 20 mg/kg ) increased plasma insulin levels of Wistar rats by releasing ACh from nerve terminals and then stimulating muscarinic M3 receptors in pancreatic cells [11,25].
ATP-sensitive K+ channels (KATP channels) in the pancreatic β-cells take part in cell energy metabolism by coupling cell metabolism to electrical activity. The KATP channels in pancreatic β-cells are critical in the regulation of glucose-induced and sulfonylurea-induced insulin secretion. The opening of KATP channels will suppress β-cells hyperpolarization and insulin secretion [39]. 20(S)-Ginsenoside Rg3 (2-8 μM) enhanced the insulin secretion in HIT-T15 cells in vitro, which was likely associated with the closure of the KATP channels in β-cells [9].
Table 2: Inhibitory activities of PTP1B.
Compdouds (type) IC50 (μM) Plant resource(family) References
ursolic acid 3.8
2.3 3.1
Symplocos paniculata (Thunb.) Miq. (Symplocaceae) Phoradendron reichenbachianum (Seem.) Oliv. (Santalaceae) Diospyros kaki Thunb. (Ebenaceae)
[49] [50] [51]
corosolic acid 7.2
7.0 Symplocos paniculata (Thunb.) Miq. (Symplocaceae) Rhododendron brachycarpum G. Don (Ericaceae) [49] [55]
rotungenic acid(U), pomolic acid(U), 24-hydroxyursolic acid(U),
19α,24-dihydroxyurs-12-en-3-on-28-oic acid (U)
10.9 Diospyros kaki Thunb. (Ebenaceae) [51] 3.9
12.8 8.1
2a,3b-dihydroxy-24-nor-urs-4(23),11-dien-28,13b-olide (U), 29.1 Weigela subsessilis (Nakai) L.H.Bailey (Caprifoliaceae) [52] 2a,3b-dihydroxy-24-nor-urs-4(23),12-dien-28-oic acid (U) 5.3
3β-hydroxyurs-12-en-27-oic acid (U) 4.9 Astilbe koreana (Kom.) Nakai (Saxifragaceae) [54] 3-oxoolean-12-en-27-oic acid (O), 6.8 Astilbe koreana (Kom.) Nakai (Saxifragaceae) [54] 3β-hydroxyolean-12-en-27-oic acid (O), 5.2
3α, 24-dihydroxyolean-12-en-27-oic acid (O), 11.7 3β, 6β-dihydroxyolean-12-en-27-oic acid (O) 12.8 moronic acid (O),
morolic acid (O) 13.2 9.1 Phoradendron reichenbachianum (Seem.) Oliv. (Santalaceae) [50] 3β-acetoxyolean-12-en-28-acid (O),
3β-acetoxyolean-12-en-28-aldehyde (O) 7.8 9.3 Styrax japonica Sieb. et Zucc. (Styracaceae) [53]
oleanolic acid 9.5
7.6
Phoradendron reichenbachianum (Seem.) Oliv. (Santalaceae) Diospyros kaki Thunb. (Ebenaceae)
[50] [51]
spathodic acid (O) 18.8 Diospyros kaki Thunb. (Ebenaceae) [51]
rhododendric acid A (T) 6.3 Rhododendron brachycarpum G. Don (Ericaceae) [55] lupeol (Lu),
lupenone (Lu) 13.7 3.7 Sorbus commixta Hedl. (Rosaceae) [56]
betulinic acid (Lu),
betulinic acid methyl ester (Lu) 0.7 0.9 Saussurea lappa C.B.Clarke (Compositae) [57] Reversing insulin resistance
Insulin resistance is a pathologic state in which target cells fail to respond to normal levels of circulating insulin. Reduced insulin sensitivity may result in inappropriate insulin levels, impaired fasting glucose or defective glucose tolerance. The resistance of target tissues to insulin is the major pathophysiological event resulting in the development of type 2 DM [40].
Studies showed that triterpenoids could reverse insulin resistance. In animal studies, ginsenoside Rh2 (1 mg/kg) could increase the responses to exogenous insulin and delay insulin resistance induction by fructose-rich chow in streptozotocin (STZ)-induced diabetic rats [41]. As the pathophysiological process accounting for insulin resistance is still unclear, to fully understand the molecular basis of these compounds will rely on in-depth mechanistic studies. Below describes that how insulin resistance is possibly reversed by triterpenoids treatment, including the activation of insulin signaling, increasing adiponectin level, inhibiting protein tyrosine phosphatase 1B etc.
Activation of insulin signaling molecules：Insulin receptor
signaling is initiated by insulin binding to its cell surface receptor, followed by receptor autophosphorylation, and activation of receptor tyrosine kinases, which result in tyrosine phosphorylation of insulin receptor substrates and successive activations of phosphoinositide 3-kinase (PI3K), 3-phosphoinositidedependent protein kinases (PDK-1 and PDK-2), Akt/protein kinase B (PKB) and atypical protein kinase C λ and ζ (PKCλ/ζ). These complex actions stimulate insulin-mediated translocation of glucose transporter type 4 (GLUT4) from intracellular vesicles to the plasma membrane. Mitogen activated protein (MAP) kinase and the PI3K signaling are two major pathways involved in insulin-receptor signaling, and the metabolic response to insulin is primarily mediated via the PI3K pathway [42]. Defects in insulin receptor signaling may contribute to impaired GLUT4 translocation and insulin resistance [42,43].
Triterpenoids could act as an insulin sensitizer by influencing either the upstream signaling pathway or the downstream mediators. Ginsenoside Rb1 (D)(0.001-1 μM) stimulated basal and
insulin-mediated glucose uptake in 3T3-L1 adipocytes and C2C12 myotubes. Ginsenoside Rb1 (1 μM) promoted GLUT1 and GLUT4 translocations to the 3T3-L1 adipocytes cell surface and enhanced translocation of GLUT4 in Chinese Hamster Ovary (CHO) cells. Meanwhile, ginsenoside Rb1 increased the phosphorylation of insulin receptor substrate-1 and PKB, and facilitated receptor [44]. It was also suggested that ginsenoside Rb1 (at up to 10 μM) enhanced basal and insulin-mediated glucose uptake accompanied by the up-regulation of mRNA and protein level of GLUT4 in 3T3-L1 adipocytes [45]. These data together may suggest the compounds multiple functions in modulating the insulin signaling pathway. Ursolic acid increased the activity of insulin on tyrosine phosphorylation of the insulin receptor β-subunit and the number of activated IRs in CHO/IR. Ursolic acid potentiated insulin-mediated tyrosine phosphorylation of the IR β-subunit, phosphorylation of Akt, glycogen synthase kinase-3β, and enhanced translocation of GLUT4 in 3T3-L1 adipocytes [46]. Likewise, 250 nM of corosolic acid enhanced glucose uptake in L6 myotubes and facilitated GLUT4 translocation in Chinese-hamster ovary cells expressing human IR cells. These actions could be blocked by PI3K inhibitor and regulated by insulin pathway activation [47].
Inhibition of protein tyrosine phosphatase: Dephosphorylation of
signaling molecules by protein tyrosine phosphatases (PTPs) play a critical negative regulatory role in insulin signal transduction. The enhanced activity of one or more PTPs may lead to insulin resistance. Current data indicate that inhibition of PTP1B, a member of the PTP family, in peripheral tissues may be useful for treating metabolic-related disorders such as obesity and type 2 DM [48]. A large number of triterpenoids showed PTP1B inhibitory activities
in vitro [49-57] (Table 2).These triterpenoids mainly belong to the
oleanane- and ursane-types. Structure-activity relationship findings suggest that a hydroxyl group at C-3 and a carbonyl group at either C-28 or C-27 of the oleanane-and ursane-type triterpenoids may be essential structural features to exert the PTP1B inhibitory activity. Triterpenoids with a 3β-hydroxy group may show a better inhibitory activity than those with a 3α-hydroxy moiety [51].
Increasing adiponectin level: Adiponectin is an adipocyte-secreted,
insulin-sensitizing hormone. Reduced circulating levels of adiponectin may be exhibited in conditions of insulin resistance and diabetes. Administration of recombinant adiponectin may increase glucose uptake, hepatic glucose production in liver and ameliorate whole body insulin resistance [58].
Isoastragaloside I and astragaloside II (5 μg/mL each) increased adiponectin concentration in 3T3-L1 adipocytes. The same action was found in mouse primary adipocytes after treatment with these compounds. These actions were confirmed in animal tests: Isoastragaloside I and astragaloside II induced significant increases in serum adiponectin, which resulted in alleviation of hyperglycemia, glucose tolerance and insulin resistance in db/db mice and dietary mice [15].
Increasing the activity of AMP-activated protein kinase:
Adenosine 5'-monophosphate-activated protein kinase (AMPK) plays an important role in mediating cell energy metabolism. AMPK is involved in the stimulation of glucose uptake by muscle contraction. AMPK also regulates insulin synthesis and secretion in pancreatic islet β-cells. Increased activity of AMPK may be effective in correcting insulin resistance in patients with forms of impaired glucose tolerance and Type 2 DM [59].
Chronic treatment with (50 mg/kg) isoastragaloside I and astragaloside II for 6 weeks resulted in a significant elevation in phosphorylation of AMPK in both liver tissue and soleus muscle of db/db mice [15].
Ten μM momordicoside Q, R, S, and T (Cu), and karaviloside XI (Cu) isolated from Momordica charantia L. (Cucurbitaceae) (bitter melon), stimulated GLUT4 translocation to the cell membrane in both L6 myotubes and 3T3-L1 adipocytes, associated with an increased activity of AMPK [17].
Ursolic acid, betulinic acid, oleanolic acid, and 30-norhederagenin (T), isolated from the methanol extract of the bark of Paeonia
suffruticosa Andr. (Ranunculaceae) (Moutan Cortex), increased
glucose uptake and enhanced glycogen synthesis in HepG2 cells under high glucose conditions. Ten μM concentrations of these compounds significantly stimulated AMPK, glycogen synthase kinase-3β and ACC phosphorylation [60].
Activation of peroxisome proliferator-activated receptors:
Peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptor proteins that function as transcription factors. The PPAR family consists of 3 subtypes of proteins encoded by separate genes: PPAR α (NR1C1), PPAR β/δ (NR1C3) and PPAR γ (also known as γ or NR1C2). PPARs regulate lipid and lipoprotein metabolism, and glucose homeostasis. PPAR α and PPAR γ are essential for the actions of the many insulin sensitizers [61,62]. Ginsenoside Rb1 (10 μM) increased the expression of mRNA and the protein of PPARγ in 3T3-L1 adipocytes [45].
Ten μM 20(S)-protopanaxatriol (D) increased
PPARγ-transactivation activity in 3T3-L1 adipocytes by increasing the expression of PPARγ target genes such as aP2, LPL and PEPCK, in parallel with a significant increase in expression of GLUT4 [63].
Decreasing free fatty acid: Increased plasma free fatty acid (FFA)
levels, a common symptom in individuals with obesity or type 2 DM, have been considered as an important factor associated with insulin resistance. Increased FFA can reduce insulin-stimulated
skeletal muscle glucose uptake. In liver, elevated FFA can impair insulin-mediated suppression of hepatic glucose output. TNFα is a cytokine largely expressed in adipose tissue, which may be linked with increased plasma FFA level and impaired insulin sensitivity in obesity and type 2 DM [42,64].
One hundred μM astragaloside IV antagonized TNFα-induced insulin resistance and increased insulin stimulated 2-deoxy-D-[1-3H]-glucose uptake in 3T3-L1 adipocytes [65].
Promoting glycogen synthesis and inhibiting glycogen degradation
In most mammalian cells, glycogen is stored as a reserve for the production of glucose 6-phosphate as a metabolic fuel for glycolysis. Storage of available glucose to supply the tissues is found principally in the liver. A defect in glycogen synthesis is a potential factor contributing to postprandial hyperglycemia in patients with type 2 DM [66]. Glycogen phosphorylase (GP) is a key enzyme involved in glycogen breakdown to produce glucose and related metabolites for energy supply. Pharmacological inhibition of GP has been regarded as a promising therapeutic approach for treating diabetes [67].
Administration of ginsenoside Rb2 (10 mg/rat/d) for six days produced a significant decrease in blood glucose level in STZ-induced rats. A moderate increase in the hepatic glycogen content and a significant decrease in the activity of glucose-6-phosphatase, a gluconeogenic enzyme in liver, were found at the same time [10]. Ginsenoside Rg1 (200 mg/kg) promoted the synthesis of liver glycogen in normal mice. In vitro, 0.1 µg/mL of ginsenoside Rg1 stimulated the uptake of 3H-glucose in isolated rat hepatocytes [12]. Ursolic acid supplement (0.01, 0.05 g/100 g diet) increased hepatic glycogen content by decreasing hepatic glucose-6-phosphatase
activity, increasing glucokinase activity, and the
glucokinase/glucose-6-phosphatase ratio in nicotinamide-streptozotocin-induced diabetic mice [68].
Hederagonic acid (O), gypsogenin (O), echinocystic acid (O), oleanolic acid, hederagenin acid (O) and gypsogenic acid (O), isolated from the ethanol extract of the roots of Gypsophila
oldhamiana Miq. (Caryophyllaceae), were found to be inhibitors of
GP in vitro; percent inhibition (10 μM) of these compounds were 11.1, 45.1, 19.0, 73.1, 73.1 and 45.1%, respectively [69].
Maslinic acid inhibited phosphorylase GP activity in homogenates of cultured astrocytes with an IC50 value of 5.7 μM. Moreover, pre-incubation with maslinic acid increased cellular glycogen content and prevented norepinephrine-induced excessive glycogenolysis [70].
At a dose of 100 mg/kg, methyl-3β-hydroxylanosta-9,24-dien-21-oate (La), isolated from the chloroform extract of the stem bark of
Protorhus longifolia (Bernh. ex C. Krauss) Engl. (Anacardiaceae),
increased hepatic glycogen content with increases both in hexokinase and glucokinase activity and a decrease in glucose-6-phosphatase activity in STZ-induced diabetic rats [71].
Suppression of hydrolysis of starch and glucose transport in small intestine
Glycosidase enzymes, such as α-glucosidase and α-amylase, have the ability to degrade dietary starch and promote the rate of blood sugar absorption from the small intestine. The inhibition of α-glucosidase and α-amylase enzymes can significantly reduce the
postprandial increase in blood glucose. Inhibition of α-glucosidase and α-amylase can be used in patients with predominately postprandial hyperglycemia. α-Glucosidase inhibitors, such as acarbose, voglibose and miglitol, were developed in the 1990s and commonly used in clinical therapy [72,73].
Corosolic acid (10 mg/kg) significantly reduced the hydrolysis of sucrose in the small intestine of mice [74].
An oleanolic acid and ursolic acid (2:1) mixture was a potent α-amylase inhibitor with an IC50 value of 4 μM in vitro. Oleanolic acid, ursolic acid (1, 2.5, 5 μg/mL) and lupeol (5 μg/mL) showed inhibitory effects against α-amylase [75].
Bartogenic acid (O), isolated from the seeds of Barringtonia
racemosa Roxb. (Lecythidaceae), showed both α-glucosidase (IC50 = 168.1 μg/mL) and α-amylase inhibitory properties [76]. Cichoridiol (18α,19β-20(30)-taraxasten-3β,21α-diol) (T), isolated from Cichorium intybus L. (Asteraceae), showed an α-glucosidase inhibitory activity (IC50 = 51.9 μM) [77].
α-Amyrin-3-O-β-(5-hydroxy) ferulic acid (U) and lupine (Lu), isolated from the root bark of Euclea undulata Thunb. var. myrtina (Ebenaceae), inhibited α-glucosidase (IC50 = 7.76, 14.69 μM, respectively) [78].
2,3-Seco-20(29)-lupene-2,3-dioic acid (Lu), isolated from leaves and twigs of Fagus hayatae Palib. ex Hayata (Fagaceae), showed an α-glucosidase inhibitory activity (IC50 = 62.1 μM) [79].
Pistagremic acid (D), isolated from galls of Pistacia integerrima J.L. Stewart ex Brandis (Anacardiaceae), showed inhibitory activity against both yeast α-glucosidase (IC50 = 89.1 μM), and rat intestinal α-glucosidase (IC50 = 38.9 μM) [80].
Inhibition of nutrient absorption is the basis of an agent used clinically to inhibit intestinal catabolism of complex carbohydrates. Agents that can delay or inhibit glucose absorption may have a promising impact in managing diabetes [81].
Gymnemic acids II, III, and IV (O) (0.5 mM), gymnemasaponin V (O) and gymnemoside-f (O), isolated from the leaves of Gymnema
sylvestre, showed an inhibitory effect on sugar absorption in rat
small intestinal fragments [82].
Momordin Ic (25 and 50 mg/kg) and oleanolic acid 3-O-glucuronide (50 mg/kg) suppressed gastric emptying in rats. An in vitro study showed that these compounds inhibited glucose uptake in rat small intestine, concentration dependently, from 0.005-0.5 mM [22,23].
Inhibition of gluconeogenesis
Gluconeogenesis is a metabolic pathway that results from the synthesis of glucose from other organic compounds. Individuals with type 2 DM often show an increase in gluconeogenesis. Gluconeogenesis inhibitors are potential therapeutic agents in the treating of diabetes [83]. Corosolic acid decreased gluconeogenesis in perfused rat liver and in isolated hepatocytes in a dose range of 20 to 100 μM [84].
Inhibition of 11β-hydroxysteroid dehydrogenase type 1
11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) is the enzyme that converts inactive 11-ketoglucocorticoids into active 11β-hydroxyforms in metabolically relevant tissues such as the liver, adipose tissue, skeletal muscles and pancreatic β-cells. Prolonged exposure to elevated glucocorticoids as a result of
increased 11β-HSD1 activity may lead to metabolic syndrome, obesity, insulin resistance, type 2 DM and cardiovascular complications [85]. Selective inhibition or down-regulation of 11β-HSD1 results in a decrease of excessive hepatic glucose production in hyperglycemia and diabetes mellitus, and exerts a positive effect on insulin sensitivity in diabetic subjects [86]. Ursolic acid, 3-epi-orosolic acid methyl ester (U), tormentic acid methyl ester (U) and 2α-hydroxy-3-oxours-12-en-28-oic acid (U), isolated from leaves of Eriobotrya japonica (Thunb.) Lindl. (Rosaceae), selectively inhibited 11β-HSD1 with IC50 values of 1.9, 5.2, 9.4 and 17 μM, respectively [87].
Masticadienonic acid (La) and isomasticadienonic acid (La), isolated from the oleoresinous gum of Pistacia lentiscus var. chia (L.) (Anacardiaceae), selectively inhibited 11β-HSD1 (IC50 values (2.51 and 1.94 μM) [88].
Inhibition of dipeptidyl peptidase-4
Dipeptidyl peptidase 4 (DPP-4) is involved in various physiological processes by cleaving dipeptides from various peptide hormones, neuropeptides and chemotactic agents. Glucagon-like peptide 1 (GLP-1) and glucose dependent-insulinotropic polypeptide (GIP) are two incretin hormones released from enteroendocrine cells of the intestine. GLP-1 and GIP are important insulin secretion stimulators in postprandial blood glucose level control. DPP-4 could inactivate the insulin-releasing effect of GLP-1 and GIP by removal of His-Ala and Tyr-Ala dipeptides from the N-terminal end [89]. Several DPP-4 inhibitor drugs have been clinically used to treat type 2 diabetes.
Six triterpenoids isolated from the leaves of Cyclocarya paliurus (Batal.) Lljinsk. (Juglandaceae), cyclocariosides D, E, F, G and H (D), and cyclocarin A (D) (10 μM), exhibited inhibitory activities against DPP-4 [90].
Quinovic acid (U), quinovic acid-3β-O-β-D-glycopyranoside (U),
quinovic
acid-3β-O-β-D-glucopyranosyl-(28→1)-β-D-glucopyranosyl ester (U) {from Fagonia cretica L.
(Zygophyllaceae)} and lupeol {from Hedera nepalensis K. Koch (Araliaceae)} inhibited DPP-4 with IC50 values of 30.7, 57.9, 23.5 and 31.6 µM, respectively [91].
Conclusion and future directions
Natural products have been the most productive source of bioactive molecules in drug discovery because of their diverse structures and functions in numerous physiological processes [92]. Triterpenoids are widely distributed in the plant kingdom. Currently, triterpenoids have become a focus in drug research and development for their numerous biological and pharmacological properties.
Many plants with triterpenoids as their major components are used in various countries as traditional antidiabetic medicines. A large number of investigations have confirmed their positive impact as potential pharmaceutical agents in the treatment of diabetes. As demonstrated in this review, natural triterpenoids exhibit a wide spectrum of pharmacological activities against diabetes mellitus. Some triterpenoids also showed multi-target pharmaceutical effects. Ursolic acid could stimulate insulin secretion and reverse insulin resistance at the same time. Its properties involve multiple mechanisms including activation of insulin signaling pathway; inhibition of PTP1B, GP, 11β-HSD1, α-glucosidase and α-amylase; and activation of AMPK and PPARs.
All reported experimental results strongly suggest that triterpenoids are promising candidates for the development of novel therapies for diabetes mellitus. However, only very few compounds have been evaluated in preclinical animal models. The complex pathology of diabetes is a major challenge to develop suitable animal models. Many studies showed that triterpenoids, especially some triterpenoid glycosides, were metabolized and restructured into new compounds by intestinal bacteria [93,94]. Further experimental and clinical studies are required to elucidate and verify the active compounds in vivo and detailed anti-diabetic molecular
mechanisms. Toxicity of these compounds needs further examination before they can be used as potential sources for novel drug development.
Acknowledgements - This work was funded by a project of the
National Natural Science Foundation of China (21102058), Natural Science Foundation of Jiangsu Province of China (BK20141387), and a Jiangsu Province Science and Technology Infrastructure Construction plan (BM2011117).
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