Key words
incretins - glucagon-like peptide-1 - GLP-1 - glucose-dependent insulinotropic polypeptide
- GIP - dipeptidyl peptidase-4 - DPP-4
Abbreviations
DPP-4:
dipeptidyl peptidase-4
FDA:
Food and Drug Administration
GIP:
glucose-dependent insulinotropic polypeptide
GLP-1:
glucagon-like peptide-1
GLUT:
glucose transporter
IDX-1:
islet/duodenum homeobox-1
i. p.:
intraperitoneal
i. v.:
intravenous
PEPCK:
phosphoenolpyruvate carboxykinase
SGLT:
sodium-glucose linked transporter
T2D:
type 2 diabetes mellitus
TGR5:
Takeda G-protein-coupled receptor 5
Introduction
When glucose is administrated orally, the insulin secretion response is two- to threefold
higher than the response elicited by a comparable intravenous glucose administration,
a phenomenon denominated “incretin effect”. Incretins are peptide hormones that are
rapidly released in the gut in response to food and, together with an increase in
blood glucose, stimulate insulin secretion [1], [2], [3], [4], [5]. GIP and GLP-1 are the most representative incretin hormones secreted by the upper
(GIP, K cells) and lower (GLP-1, L cells) gut [4], [5]. In the blood, GLP-1 can be found as two molecular forms with equivalent effects,
GLP-1(7-37) and GLP-1(7-36)amide, with the latter being predominant in the blood after
a meal [6].
In the fasted state, the GLP-1 circulating level is low, but increases after eating
([Fig. 1 A]). However, both GLP-1 and GIP have a short half-life, quickly decreasing due to
enzymatic degradation by DPP-4 ([Fig. 1 B]) together with renal clearance [6]. This situation can be pharmacologically modified by employing two approaches: (1)
using DPP-4 inhibitors such as sitagliptin and vildagliptin that preserve native GLP-1
or (2) with DPP-4-resistant GLP-1 analogs ([Fig. 1 C]), such as exenatide and liraglutide, among others [7], [8].
Fig. 1 Incretins and their role in the organism. A Physiological effects. B Role of DPP-4 on incretin functions. C Effects of DPP-4 inhibitors and GLP-1 receptor agonists on pancreatic cells.
In the pathogenesis of T2D and in its initial stage, altered glucose tolerance, experimental
evidence shows a significant decrease in the incretin effect [9], [10], [11]. Interestingly, the insulinotropic and glucagonostatic effects of GLP-1 are well
preserved in T2D patients, and the pharmacological stimulation of GLP-1 receptors
significantly improves glycemic control [4], [6].
GLP-1 exerts several effects in different organs or systems. Among them, it is important
to mention the reduction in appetite and food intake, thus leading to weight loss
in the long term. This fact, together with the key finding that GLP-1 secretion seems
to be impaired in obese subjects, suggests a pathogenic role in obesity [4].
The effects of GIP and GLP-1 are related to the activation of structurally different
receptors associated with G proteins, located in different organs, including the stomach,
hypothalamus, and endocrine pancreas [2], [3], [12], [13], [14]. Activation of these receptors on pancreatic β-cells increases cAMP and cytosolic Ca2+ levels, which in turn increases insulin secretion in response to oral glucose administration
[3], [15]. Sustained activation of this pathway leads to the activation of protein kinase
A, gene expression, and enhanced insulin synthesis, together with stimulation of β-cell replication [16]. GLP-1 also inhibits glucagon secretion [2], [17], [18]. An additional site of action has also been demonstrated for GLP-1, which is the
hepatoportal glucose “sensor” that is activated whenever a glucose gradient is established
between the portal region and the periphery as it occurs in the postprandial period
[19]. Glucose detection by the abovementioned sensor requires not only a GLUT but also
an activated GLP-1 receptor, in turn establishing a gluco-incretin receptor system
of physiological relevance [19].
Additionally, GLP-1 inhibits gastric emptying and food ingestion, and enhances glucose
disposal by neural mechanisms, contributing to glucose homeostasis [20]. GIP and GLP-1 also have effects on adipose cells, bone, and the cardiovascular
system. Regarding the latter, recent findings suggest that GLP-1 receptor agonists,
such as liraglutide, reduce cardiovascular events and prolong life in high-risk patients
with T2D [4].
Although the evidence is not complete, GLP-1 receptors have also been identified in
hepatocytes of rodents and humans [21], [22], and it has been postulated that their activation would directly reduce hepatic
steatosis in several experimental models [23], [24]. These effects could be possibly mediated via activation of the insulin signaling
cascade [21] as well as the AMPK pathway [25]. In this sense, Svegliati-Baroni et al. [22] showed that not only would there be receptors for GLP-1 in human hepatocytes, but
their number would be decreased in patients with nonalcoholic steatohepatitis. Despite
these evidences, other authors suggest that different peptides derived from the degradation
of GLP-1 would act through an independent pathway of the receptor, directly at the
mitochondrial level through the modulation of phosphorylation and oxidative stress
[26], [27], [28]. In addition, it has been shown that GLP-1 has a protective effect from oxidative
stress in endothelial cells both in vivo
[29] and in vitro
[30]. In summary, incretin hormones have been proven to be key players in the pathophysiology
of obesity and T2D, and, in consequence, they have very high therapeutic potential
[31], [32].
Several interesting approaches have been proposed for treating T2D, and these antidiabetic
agents act with different or similar mechanisms of action [33]. The use of biguanide and its derivatives to treat diabetes can be traced back to
the Middle Ages, when administration of the aerial parts of Goatʼs Rue herb (Galega officinalis L., Leguminosae) infusions was a common practice. Galegin, isolated from this plant,
became the main compound of several from which metformin was synthesized [34]. These studies continued until 1994, when the U. S. FDA approved metformin for the
treatment of T2D. This compound was shown to delay the progression of T2D, reduce
the risk of complications and mortality by decreasing hepatic glucose synthesis from
non-glycidic substrates, and sensitize tissues to insulin. Since then, metformin has
been the first-choice oral drug in the treatment of T2D [35]. However, in circumstances where metformin is contraindicated or not tolerated,
a second-line agent must be used. In these cases, GLP-1 agonists and/or DPP-4 inhibitors
are an option [8], [36], [37], [38]. These recently approved classes of therapeutic agents for the treatment of T2D
exert their actions through the potentiation of incretin receptor signaling or by
expanding the half-life of GLP-1 [6].
In 2005, the FDA approved the first incretin mimetic, exenatide, originally isolated
from the salivary secretions of the Gila monster (Heloderma suspectum), a venomous lizard from the western U. S. A. and Mexico [39]. Exenatide is a GLP-1 receptor analogue resistant to DPP-4 degradation used as adjunctive
therapy for patients with T2D. Because GLP-1 analogues require injection, considerable
effort has been devoted to creating an oral agent able to target the incretin pathway.
Inhibition of DPP-4 extends the half-life of native incretins, thereby prolonging
their effects. In 2006, the FDA approved the first oral incretin enhancer, sitagliptin,
a selective DPP-4 inhibitor, for use as monotherapy or in combination with metformin
or thiazolidinedione [6]. Since then, this new class of hypoglycemic agents is subject to continuous evaluations
of efficacy and safety [40], [41], [42], [43], [44], [45].
In recent years, incretin-based therapies have become an important treatment option
for patients with T2D. In order to improve the various issues related to the efficacy
and safety of these drugs, the search for new drugs is necessary. Recently, studies
have focused on identifying non-peptidic agonists for the GLP-1 receptor [46], [47]. For this reason, the aim of this review is to present new findings of medicinal
plants and natural products that exert their actions through potentiation of incretin
receptor signaling.
The Use of Food for the Control of Diabetes through Incretin Increase
The Use of Food for the Control of Diabetes through Incretin Increase
The main use of natural products for the control of glycemia was through food. In
the 1990s, different studies compared the effects of fatty acids on glucose, insulin,
GIP, and GLP-1 levels. For example, Thomsen et al. [48], [49] studied the effect of olive oil, comparing it with butter, on the levels of glucose,
insulin, and fatty acids, and demonstrated that this oil induced lower triacylglycerol
concentrations and higher HDL-cholesterol concentrations than butter. No clear differences
were observed in glycemia or insulinemia, although higher concentrations of GLP-1
and GIP were observed with the use of monounsaturated versus saturated fatty acids,
suggesting a relation between fatty acid composition, incretin responses, and triacylglycerol
postprandial metabolism in patients with T2D [49]. In the same line, Iritani et al. [50] demonstrated that oral triacylglycerols stimulated GLP-1 secretion in the gut lumen
and produced a second insulin peak at 4 h. These effects were corroborated by Prieto
et al. [51] and by Cancelas et al. [52], who observed that an olive oil-enriched diet increases both GLP-1 release and the
secretory response of insulin-producing cells to oral glucose administration, improving
glucose tolerance in Wistar rats [51] and in an animal model of T2D (adult rats injected with streptozotocin during the
neonatal period) [52]. The group of Professor Tso observed that incretins are in a higher concentration
in intestinal lymph versus plasma [53], [54] and, using a lymph fistula rat model, they tested the dose-dependent relationship
between the secretion of GIP and GLP-1 and dietary lipids, showing that the intraluminal
lipid content was greater in GLP-1- than in GIP-secreting cells [55]. In contrast, another study of interest [56] demonstrated that the GLP-1 level and glycemia were not affected by omega-3 fatty
acid supplementation. In this study, the researchers tested both fish oil (enriched
in eicosapentaenoic acid and docosahexaenoic acid) and flaxseed (Linum usitatissimum L., Linaceae) oil (enriched in α-linolenic acid) on Sprague-Dawley rats for 7 weeks.
The incretin effect after lipid consumption in humans was studied by Lindgren et al.
[57] and Manning et al. [58]. Lindgrenʼs group orally administered a lipid emulsion (Intralipid, 3 mL/kg) and
observed an increase in total and intact GIP and GLP-1 levels. However, when they
administered the lipids i. v., no significant modifications were detected, concluding
that oral lipid ingestion elicits a clear insulin response in association with increased
GIP and GLP-1 concentrations. To test the differences between cooking with unheated
sunflower (Helianthus annuus L., Compositae) oil and thermally oxidized sunflower oil, Manning et al. [58] measured the plasma concentrations of GLP-1. There were no significant differences
in plasmatic GLP-1 concentrations while eating either meals; however, the concentration
was significantly increased from 30 min to a peak at 60 min after the ingestion of
an unheated sunflower oil-cooked meal versus the thermally oxidized sunflower oil-cooked
meal.
Another edible plant, beets (Beta vulgaris L., Amaranthaceae), was tested as a potential antidiabetic medicinal plant. Indeed,
the aqueous extract of B. vulgaris (whole plant) was the only active fraction (50 mg/kg) from a hydroethanolic extract
fractioned with solvents of different polarity. Administration of this extract at
different doses to T2D mice (db/db) significantly increased GLP-1 and enhanced insulin secretion, confirming the antihyperglycemic
activity of this plant [59].
Medicinal Plant Products and Their Effect on Incretin Secretion
Medicinal Plant Products and Their Effect on Incretin Secretion
Some researchers focus their studies on natural fractions from medicinal plants. This
is the case of Ellis et al. [60] and Gatenby et al. [61], who have demonstrated that guar gum, at concentrations found in the diet (20 or
40 g/kg), reduces glucose absorption and insulin and GIP secretion during the postprandial
period (4 h) [60], and that 7.6 g of guar gum per meal attenuate insulinemia in diabetic patients
by increasing hepatic extraction of insulin [61]. More recently, den Besten et al. [62] demonstrated in both humans and rodents that this beneficial effect of guar gum
was mediated by the short-chain fatty acids produced by colonic fermentation. These
short-chain fatty acids stimulate GLP-1 release, increasing peripheral glucose clearance.
Another type of dietary fiber, soluble fiber from Plantago indica L. (syn: Plantago psyllium L., Plantaginaceae) was studied by Karhunen et al. [63] in humans obtaining similar results. Fiber-enriched meals decreased glycemia and
insulinemia in healthy young adults by strongly modifying postprandial signals arising
from the gastrointestinal tract. Postprandial GLP-1 concentrations increased for 20 min
after the white wheat bread, low-fiber, and low-protein meals, and then the concentrations
returned gradually toward the baseline. In contrast, the GLP-1 concentration after
the fiber and protein-rich meal decreased below the baseline for the entire experimental
period.
Other products with high interest are those containing phenolic compounds, such as
coffee and its main phenolic, chlorogenic acid. It is largely known that dietary phenolics
have positive effects on the pattern of glucose uptake in the small intestine. In
this sense, Johnston et al. [64] observed the effects of caffeine and chlorogenic acid from coffee on glycemia, insulinemia,
and GIP and GLP-1 secretion, modifying intestinal glucose absorption. Other authors
established that a supplement of chlorogenic acid (e.g., as green decaffeinated coffee)
lowers the glycemic index of meals and increase GLP-1, reducing the risk for diabetes
[65]. However, Esatbeyoglu et al. [66] studied different phenolic derivatives from deep purple carrots [Daucus carota subsp. sativus (Hoffm.) Arcang. var. atrorubens Alef., Apiaceae], such as the anthocyanin fraction, primarily phenolic acids and
chlorogenic acid, but none of them affected GLP-1 secretion and DPP-4 activity. Overall,
the phenolic fraction exhibited an inhibitory effect on α-amylase and α-glucosidase activity and on cellular glucose uptake, indicating potential antidiabetic
properties.
Sweet potato [Ipomoea batatas (L.) Lam., Convolvulaceae] leaves contain polyphenols such as caffeoylquinic acid
derivatives. Nagamine et al. [67] studied the effect of sweet potato leaf extract powder on hyperglycemia in type
2 diabetic mice and observed that, after five weeks, the extract lowered glycemia.
When testing both the sweet potato leaf extract powder and its caffeoylquinic acid
derivatives in vitro, they found enhanced GLP-1 secretion, demonstrating that the effect of sweet potato
leaf extract powder is mediated by the caffeoylquinic acid derivatives, which attenuate
postprandial hyperglycemia through the enhancement of GLP-1.
Potentiality of Medicinal Plants as Incretin Modulators
Potentiality of Medicinal Plants as Incretin Modulators
Aside from food, medicinal plants have been used as a potential source of antidiabetic
agents, and many of them are of interest as modulators of incretins. There are complete
and good reviews, such as the revision of Hung et al. [68] and Eddouks et al. [69], on the discovery of plant-derived antidiabetic natural products, which cover the
years from 2005 to 2010 and until 2013, respectively, but no references on incretins
were included. However, some articles describing this activity during this period
were published [60], [61], [70]. Ribnicky et al. [70] analyzed the effect of Tarralin, an ethanolic extract of Russian tarragon (Artemisia dracunculus L., Compositae), as a potential antihyperglycemic drug in genetically diabetic KK-A
γ
mice and nondiabetic animals. Oral administration of this extract (500 mg/kg/d for
1 week) decreased blood glucose levels by 24% in respect to the negative control,
whereas positive controls troglitazone (30 mg/kg/d) and metformin (300 mg/kg/d) lowered
glycemia by 28 and 41%, respectively. Insulinemia was also reduced in diabetic mice
by 33% with the extract, whereas its combination with troglitazone or metformin reduced
it by 48 and 52%, respectively. The authors hypothesized a possible mechanism of action
and what the active principles would be, but these were not tested. Moreover, the
extract decreased PEPCK mRNA expression in streptozotocin-induced diabetic rats, but
PEPCK expression was not affected in nondiabetic rats. In fact, it did not modify
glycemia or insulinemia in nondiabetic rats, but it did increase the binding of GLP-1
to its receptor in vitro. For this reason, the authors proposed the potential use of Tarralin as a supplement
for the management of glycemia and insulin resistance in diabetic patients [70]. Other authors, such as the Park et al. [71], investigated the effects of different medicinal plants used in Chinese medicine
with interesting results; however, they used mixtures of crude drugs and it is not
easy to establish the potentiality of each of them.
It is known that yerba mate (Ilex paraguariensis A. St.-Hil., Aquifoliaceae) has antidiabetic properties [34]. In this sense, Hussein et al. [72] investigated an aqueous extract of mate on diabetes and metabolic syndrome effects
in a mouse model. The extract (50, 100 mg/kg) was administered orally for 3 weeks
and a significant increase in GLP-1 was observed. Moreover, acute administration of
the principal constituents of mate, dicaffeoyl quinic acids and matesaponins, also
produced a significant increase in GLP-1 levels, suggesting that yerba mate exerts
anorexic effects by direct induction of satiety and by stimulation of GLP-1 secretion,
as well as by modulating leptin levels. As mentioned earlier, these same compounds,
caffeoylquinic acid derivatives, were also described as the active principles of sweet
potato leaves [67].
Kubow et al. [73] tested a phenolic-rich potato (Solanum tuberosum L., Solanaceae) extract (final concentration: 1.93 or 3.5%, w/w) in C57BL/6 J mice
with a high-fat diet for 10 weeks. This extract attenuated weight gain by 63% in both
male and female mice, an effect associated with a reduction in adiposity, but sex
differences were observed in GIP as well as other metabolic indicators (insulin, ghrelin,
leptin, and resistin). These differences were not observed in other experiments with
phenolics. Previously, Raasmaja et al. [74] demonstrated a decrease in circulating GLP-1 in genetically obese Zucker rats fed
with a high-fat/high-cholesterol diet after the administration of a 70% ethanol extract
(obtained from a water extract) of Citrus maxima (Burm.) Merr. [syn: Citrus grandis (L.) Osbeck, Rutaceae] at 300, 600, and 1200 mg/kg, which could be related with an
increase in glucagon and glucose levels, as well as a decrease in the insulin level.
Bitter melon (Momordica charantia L., Cucurbitaceae) has been reported as an antidiabetic fruit, but similar properties
have also been demonstrated for other parts of this plant [34]. Several metabolites, such as α-eleostearic acid or a Zn-free protein, and mechanisms have been described; however,
the implication of GLP-1 was not analyzed. In this way, Bhat et al. [75] recently studied the effect of an aqueous extract (300 mg/kg/d for 28 d) of bitter
melon on both normal and diabetic Wistar rats, demonstrating that this extract increased
insulinemia and GLP-1 in normal (nonsignificant) and in diabetic Wistar rats (significant,
p < 0.01). This effect was associated to elevated β-cell proliferation and insulin secretion.
The main medicinal plants and some of their relevant fractions are compiled in [Table 1], including plant material investigated, extracts used, concentration, protocols
employed, and effects obtained in the experiments.
Table 1 Medicinal plants as incretin modulators.
|
Plant
|
Extract
|
Concentration
|
Protocol
|
Effects
|
Ref
|
|
DPP-4 = dipeptidyl peptidase-4, GIP = glucose-dependent insulinotropic polypeptide,
GLP-1 = glucagon-like peptide-1
|
|
Artemisia dracunculus
|
Tarralin (commercial)
|
Ethanolic extract
500 mg/kg/d
|
Diabetic KK-Aγ mice
and diabetic rats
|
Reduces glycemia and insulinemia, and PEPCK mRNA expression
|
[70], [71]
|
|
Citrus maxima
|
Dried fruits
|
70% Ethanol extract obtained from a water extract
300, 600, and 1200 mg/kg
|
Genetically obese Zucker rats
|
Decrease of circulating GLP-1
|
[74]
|
|
Coffea arabica
|
Green decaffeinated coffee
|
400 mL Decaffeinated coffee (equivalent to 2.5 mmol chlorogenic acid/L)
|
Healthy fasted volunteers
|
Lowers the glycemic index of meals and increase GLP-1
|
[65]
|
|
Cyamopsis tetragonoloba
|
Guar gum
|
20 and 40 mg/kg
|
Human – diet
|
Reduces glucose absorption, and insulin and GIP secretion
|
[60]
|
|
Cyamopsis tetragonoloba
|
Guar gum
|
7.6 g per meal
|
Diabetic patients
|
Attenuates insulinemia by increasing the hepatic extraction of insulin
|
[61]
|
|
Cyamopsis tetragonoloba
|
Guar gum
|
High-fat diet supplemented with 10% guar gum/12 weeks
|
C57Bl/6 J mice
|
Short-chain fatty acids produced by colonic fermentation stimulate GLP-1 release,
increasing peripheral glucose clearance
|
[62]
|
|
Daucus carota subsp. sativus var. atrorubens
|
Anthocyanin fractions
|
Anthocianidins (50 µg/mL) and
chlorogenic acid (17.7 µg/mL)
|
GLUTag cells
|
Inhibitory effect on α-amylase and α-glucosidase activity, but no effect on GLP-1 secretion and DPP-4 activity
|
[66]
|
|
Gentiana scabra
|
Whole plant
|
Water extract in vitro EC50 113.3 µg/mL
in vivo 100 and 300 mg/kg
|
NCI-H716 cells
Lepr−/−
(db/db) mice
|
Stimulates GLP-1 secretion
|
[88]
|
|
Ilex paraguariensis
|
Leaves
|
Water extract
50 and 100 mg/kg
|
Male ddY mice
|
Stimulates GLP-1 secretion
|
[72]
|
|
Ipomoea batatas
|
Leaf extract and quinic acid derivatives
|
Extract 10 mg/mL
Compounds 10 mM
|
Diabetic mice
GLUTag cells
|
Lowers glycemia and enhances GLP-1 secretion
|
[67]
|
|
Momordica charantia
|
Fruits
|
Water extract (300 mg/kg/d for 28 d)
|
Diabetic Wistar rats
|
Increases insulinemia and GLP-1
|
[75]
|
|
Plantago indica
|
Fiber-enriched meals
|
23 g per meal
|
Healthy young adults
|
Decreases glycemia and insulinemia, and increases postprandial GLP-1
|
[63]
|
|
Solanum tuberosum
|
Potato
|
Polyphenolic-rich extracts 1.93 and 3.5% (w/w)/diet
|
C57BL/6 J mice
|
Reduction in adiposity and GIP secretion
|
[73]
|
Medicinal Plants and Natural Products as Inhibitors of Dipeptidyl Peptidase-4
Medicinal Plants and Natural Products as Inhibitors of Dipeptidyl Peptidase-4
Ríos et al. [34] reviewed the medicinal plants as enhancers of insulin secretion and pancreatic β-cell proliferation and cited different plants as possible activators of GLP-1 and
GIP or inhibitors of DPP-4. For example, different inulin-type fructans, such as those
obtained from Cichorium intybus L. (Compositae) and Agave tequilana F. A. C.Weber (Asparagaceae), enhance colon production of GLP-1, whereas Pterocarpus marsupium Roxb. (Leguminosae) and Syzygium cumini (L.) Skeels (syn: Eugenia jambolana Lam., Myrtaceae) inhibited DPP-4. Indeed, because DPP-4 is an enzyme that inactivates
incretins, its inhibition could increase their level. Searching for this effect, Kosaraju
et al. [76] studied in vitro and in vivo the potential DPP-4 inhibition of three medicinal plants, Pterocarpus marsupium, Syzygium cumini, and Gymnema sylvestre (Retz.) R.Br. ex Sm. (Apocynaceae). Two of them, P. marsupium and S. cumini, inhibited DPP-4 (IC50 of 274 and 279 µg/mL, respectively), whereas G. sylvestre had an IC50 of 773 µg/mL. The three species had a long duration as enzyme inhibitors, with half-lives
of 462.3, 317.2, and 153.8 min, respectively. In conclusion, the extracts increased
GLP-1 levels, and maximum peaks of GLP-1 were appreciated at 2 h for P. marsupium and S. cumini, and at 1.5 h for G. sylvestre. In a parallel analysis with P. marsupium and S. cumini (200 and 400 mg/kg, orally) on streptozotocin-treated Wistar rats, an increase in
GLP-1 levels was observed [77].
Peptides from oat (Avena sativa L., Poaceae), buckwheat (Fagopyrum esculentum Moench, Polygonaceae), and highland barley [Hordeum aegiceras Nees ex Royle, syn: Hordeum vulgare var. trifurcatum (Schltdl.) Alef., Poaceae] were also studied for their capacity to inhibit DPP-4.
All of them showed in vitro DPP-4 inhibitory activity, with IC50 values ranging from 0.13 to 8.15 mg/mL. In total, more than 35 peptides were identified
in the tryptic hydrolysates of oat globulin [78].
Fagonia cretica L. (Zygophyllaceae) and Hedera nepalensis K.Koch (Araliaceae) are used in folk medicine for the treatment of diabetes. To clarify
the effect on this illness and its mechanism of action, Saleem et al. [79] analyzed in vitro the inhibitory effect on DPP-4 of both plants using a crude extract obtained by maceration
with chloroform-methanol (1 : 1) during 7 days, and also tested five isolated compounds.
Of them, the crude extract of H. nepalensis had the best activity (IC50 of 17.2 µg/mL), whereas the activity of F. cretica was lower (IC50 of 38.1 µg/mL). However, when the extracts were fractioned and purified, the activity
did not improve. As an example, the ethyl acetate of H. nepalensis gave an IC50 of 34.4 µg/mL and the n-hexane fraction, an IC50 of 34.2 µg/mL. Regarding the isolated compounds, the inhibitory activities on DPP-4
did not improve the activity of the original extracts, so the IC50 values were as follows: quinovic acid 30.7 µM, quinovic acid-3β-O-β-D-glycopyranoside 57.9 µM, quinovic acid-3β-O-β-D-glucopyranosyl-(28 → 1)-β-D-glucopyranosyl ester 23.5 µM ([Fig. 2]), and stigmasterol > 100 µM, all of them from F. cretica. The triterpene lupeol from H. nepalensis was tested and showed an IC50 of 31.6 µM. Taking together these results, F. cretica and H. nepalensis could be considered as antidiabetic agents with potential significant DPP-4 inhibitory
activity [79].
Fig. 2 Chemical structure of quinovic acid, quinovic acid-3β-O-β-D-glycopyranoside, and quinovic acid-3β-O-β-D-glucopyranosyl-(28 → 1)-β-D-glucopyranosyl ester.
González-Abuín et al. [80] described that grape-seed procyanidin extract prevented a decrease in DPP-4 activity
and modulated the gene expression of GLP-1 and its receptor in the hypothalamus, inferring
that procyanidins can abrogate the effects of the cafeteria diet on intestinal GLP-1
production and DPP-4 activity. The administration of the enriched extract to healthy
Wistar female rats induced a plasmatic increase in GLP-1, and a decrease in glycemia.
They also assayed if this inhibition occurred in inner intestinal tissues close to
GLP-1-producing cells, such as the endothelium of the capillaries, and tested the
effects of the main compounds, such as catechin, epicatechin, B2 dimer, and gallic
acid, demonstrating that they inhibit DPP-4 activity in endothelial HUVEC cells in
an additive way. They concluded that procyanidins improve glycemia via GLP-1 secretion
caused by the inhibition of the inner intestinal DPP-4 activity, increasing active
GLP-1 levels, and, in consequence, affecting insulin release [81]. Sulaiman [82] also investigated the potential role of standardized grape-seed proanthocyanidin
(50 mg/kg) on incretin effects as a response to the glucose load in healthy rats,
both oral and i. p., and the results were compared with the values obtained with sitagliptin
(40 mg/kg) and the negative control (vehicle). Both the treated group and the positive
control improved hyperglycemia induced by oral glucose. The mechanism of proanthocyanidin
was associated with an enhancement of the incretin effect of gut peptides, and the
authors concluded that the possible action of proanthocyanidin is via DPP-4 inhibition.
Kozuka et al. [83] tested the juice of aronia berries (Aronia sp., Rosaceae) as DPP-4 inhibitors. Enzymatic activity was determined by fluorometry
(excitation 380 nm and emission 440 nm), and DPP-4 inhibition was performed using
L-proline 4-methyl-coumaryl-7-amide (Pro-MCA) as the substrate in Tris-HCl (pH 9.0).
The results demonstrated that the juice of aronia berries inhibited DPP-4 indirectly,
increasing GIP and GLP-1. Cyanidin 3,5-diglucoside ([Fig. 3]) was identified as the main active principle and studied as a DPP-4 inhibitor. Although
there are previous researches that identified cyanidin and cyanidin 3-glucoside as
inhibitors of DPP-4, in the present study, the greater potency of cyanidin 3,5-diglucoside
was demonstrated, giving an IC50 of 5.5 µM.
Fig. 3 Chemical structure of cyanidin 3,5-diglucoside and delphinidin 3-rutinoside.
Relevant medicinal plants, their extracts, and concentrations are summarized in [Table 2], including their effects on DPP-4.
Table 2 Medicinal plants and natural products as inhibitors of DPP-4.
|
Plant
|
Extract
|
Concentration
|
Protocol
|
Effects
|
Ref
|
|
AMC = amido-4-methylcoumarin, DPP-4 = dipeptidyl peptidase-4, GIP = glucose-dependent
insulinotropic polypeptide, GLP-1 = glucagon-like peptide-1, MCA = methyl-coumaryl-7-amide,
pNA = p-nitroanilide, STZ = streptozotocin
|
|
Aronia sp.
|
Juice fruits
|
No declared
|
In vitro
DPP-4 + Gly-Pro-MCA
|
DPP-4 inhibition and increase in GLP-1 and GIP levels
|
[83]
|
|
Avena sativa
|
Extracts of seed
proteins
|
IC50 0.99 mg/mL
|
In vitro DPP-4 + Gly Pro-pNA and peptide
|
Inhibition of DPP-4
|
[78]
|
|
Fagonia cretica
|
Aerial parts CHCl3-MeOH (1 : 1)
|
IC50 38.1 µg/mL
|
In vitro
DPP-4 + Gly Pro-AMC
|
Inhibition of DPP-4
|
[79]
|
|
Fagopyrum esculentum
|
Extracts of seed
proteins
|
IC50 1.98 mg/mL
|
In vitro
DPP-4 + Gly Pro-pNA and peptide
|
Inhibition of DPP-4
|
[78]
|
|
Gymnema sylvestre
|
Leaves
100% ethanol
|
IC50 773 µg/mL
|
In vitro DPP-4 inhibitor screening assay kit
|
Inhibition of DPP-4
|
[76]
|
|
Hedera nepalensis
|
Aerial parts
|
IC50 17.2 µg/mL
|
In vitro
DPP-4 + Gly Pro-AMC
|
Inhibition of DPP-4
|
[79]
|
|
Hordeum aegiceras
|
Extracts of seed
proteins
|
IC50 3.91 mg/mL
|
In vitro
DPP-4 + Gly Pro-pNA and peptide
|
Inhibition of DPP-4
|
[78]
|
|
Pterocarpus marsupium
|
Heart wood 100% ethanol
|
IC50 274 µg/mL 200 and 400 mg/kg
|
In vitro DPP-4 inhibitor screening assay kit
STZ-treated Wistar rats
|
DPP-4 inhibition and increase in GLP-1 levels
|
[76], [77]
|
|
Syzygium cumini
|
Fruits
100% ethanol
|
IC50 279 µg/mL
200 and 400 mg/kg
|
In vitro: DPP-4 inhibitor screening assay kit In vivo: STZ-treated Wistar rats
|
DPP-4 inhibition and increase in GLP-1 levels
|
[76], [77]
|
|
Vitis vinifera
|
Grape-seed procyanidin extract
|
1 mg/kg
|
Healthy Wistar rats
|
Increase of GLP-1, and a decrease in glycemia
|
[81]
|
|
Vitis vinifera
|
Standardized grape-seed proanthocyanidin
|
50 mg/kg
|
Healthy Wistar rats
|
DPP-4 inhibition and increase in GLP-1 levels
|
[82]
|
Natural Products as Stimulants of GLP-1 and GIP Secretion
Natural Products as Stimulants of GLP-1 and GIP Secretion
Jafri et al. [84] studied GLP-1 and GIP secretory activity of isolated compounds from Fagonia cretica in pGIP/neo STC-1 cells, which secrete both GLP-1 and GIP, and are potentially a
very useful model for studying the secretory responses of both incretin hormones.
Incretins were detected by GLP-1 and GIP ELISA kits. Intracellular levels of incretin
hormones and their gene expression were also determined by the same protocol. The
fresh aerial parts were extracted with chloroform/methanol (1 : 1) and the crude extract,
as well as its n-hexane, ethyl acetate, and aqueous fractions (125 and 250 µg/mL), stimulated both
GLP-1 (3- to 55-fold) and GIP (1.6- to 2.2-fold) secretion. Gene expression of GIP
was also increased (6.2- to 12.3-fold). Purified compounds from the ethyl acetate
extract were identified as quinovic acid and its derivatives, 3β-O-β-D-glycopyranoside and 3β-O-β-D-glucopyranosyl-(28 → 1)-β-D-glucopyranosyl ester ([Fig. 2]). These three compounds significantly stimulated GLP-1 secretion in pGIP/neo STC-1
cells without triggering GIP secretion, but 3β-O-β-D-glucopyranosyl-(28 → 1)-β-D-glucopyranosyl ester was the most active as secretagogue (at 25 µM it increased
GIP secretion 1.6-fold; at 50 µM it increased the GLP-1 secretory response by 16.9-fold).
Other derivatives with potential as GLP-1 secretagogues are marnieranosides A and
B ([Fig. 4]), isolated from Cynanchum marnierianum Rauh (Apocynaceae). These pregnanes (100 µM) increased the release of GLP-1 in STC-1
cells by 130 and 133%, respectively. Isolated marnieranosides showed similar effects
as compound P57, a pregnane analogue responsible for the activity of Hoodia gordonii (Masson) Sweet ex Decne. (Apocynaceae), used as a positive control [85]. These same authors isolated five new pregnane-type steroidal glycosides, menarandrosides
A – E, together with three known compounds, from the aerial parts of Cynanchum menarandrense Jum. & H.Perrier (Apocynaceae) and studied them for their potential to stimulate
GLP-1 secretion in intestinal STC-1 cells. Although the pregnane-rich fraction led
to a 2-fold stimulation of GLP-1 secretion vs. blank cells, none of the pure compounds
had any influence, and the fraction enriched in pregnanes exhibited a significant
activity, suggesting a possible synergistic effect [86].
Fig. 4 Chemical structure of marnieranosides A and B.
Spergularia marina (L.) Besser (Caryophyllaceae) is an edible plant and it is also used as a medicinal
plant in Korea for the treatment of diabetes. To analyze this activity, a hydroethanolic
extract (100, 200, and 500 µg/mL) was tested on GLP-1 release from enteroendocrine
NCI-H716 cells. Treatment of these cells with the extract increased GLP-1 secretion
together with iCa2+ and cAMP levels in a dose-dependent manner. Transfection of cells with TGR5-specific
small interference RNA inhibited all these effects, which demonstrated that S. marina-stimulated GLP-1 secretion involved TGR5 activation and is a possible candidate for
antidiabetic purposes [87].
The roots of Gentiana scabra Bunge (Gentianaceae) are used in traditional Korean medicine for treatment of T2D,
and its properties were associated with the intestinal bitter taste sensation, which
stimulates GLP-1 secretion. The aqueous extract stimulated GLP-1 secretion in a dose-dependent
manner on human enteroendocrine NCI-H716 cells (1 – 1000 µg/mL, EC50 of 113.3 µg/mL). In addition, treated Lepr
−/− (db/db) mice (100 and 300 mg/kg) decreased glycemia due to the GLP-1 secretion. After chemical
analysis, the authors hypothesized that loganic acid ([Fig. 5]) could be the responsible part of GLP-1 secretion [88].
Fig. 5 Chemical structures of loganic acid, geniposide, and shanzhiside methylester.
One group of high interest as a source of antidiabetic compounds is procyanidins from
grape seed (Vitis vinifera L., Vitaceae). Since cellular membrane depolarization is determinant for several
nutrient-induced hormone secretions, González-Abuín et al. [89] employed an in vitro experimental approach to evaluate whether a procyanidin extract from grape-seeds
modulates cellular membrane potential in intestinal endocrine cells (STC-1) and if
these changes influence GLP-1 secretion. They observed that the grape extract induced
opposite effects depending on the dose, depolarization at low concentrations (0.05 mg/L)
and hyperpolarization at high concentrations (50 mg/L). The high concentration was
effective in reducing GLP-1 secretion, even under nutrient-stimulated conditions [89].
The proanthocyanidins from grape seed also modulate several parameters involved in
metabolic syndrome through changes in the microbiota and enterohormone secretion.
Indeed, it was observed that the ratio of Firmicutes : Bacteroidetes was lower in
the microbiota of rats treated with proanthocyanidins (500 mg/kg, 8 d) versus the
control, but the extract also increased plasma GLP-1. For this reason, these kinds
of phenolics could be of interest as potential antidiabetics [90].
Other anthocyanins of interest are those present in blackcurrant (Ribes nigrum L., Grossulariaceae), which increases GLP-1 secretion in an enteroendocrine L cell
line (GLUTag cells). The authors administrated 5 mg of fruits/kg, with a content of
1 mg delphinidin 3-rutinoside/kg, and observed that the enriched extract significantly
improved glucose tolerance by stimulating GLP-1 and insulin secretion, while GLP-1
secretion was stimulated by delphinidin 3-rutinoside ([Fig. 3]), but not by its major degradation products, gallic acid and phlorogucinol aldehyde
[91].
Black soybean [Glycine max (L.) Merr., Leguminosae] is a type of soybean with a black seed coat. Previous studies
identified anthocyanins and procyanidins as the two main types of polyphenols and
described their antidiabetic effects. Qiu et al. [92] demonstrated that the phenolic-enriched crude extract increased the concentrations
of serum insulin and GLP-1 in streptozotocin-induced diabetic rats after 8 weeks of
treatment. However, they did not identify any specific compound in the extract.
Chlorogenic acids are ubiquitous phenolic compounds present in different medicinal
plants as well as food and beverages, such as coffee. These kind of phenolics are
responsible for different pharmacological activities, including antidiabetic [64], [65]. To demonstrate the mechanism of these isomers, Tunnicliffe et al. [93] administered 120 mg/kg of chlorogenic acids to male Sprague-Dawley rats and measured
the incretins GLP-1 and GIP. GLP-1 response was also analyzed using the human colon
cell line NCI-H716. Results showed that the plasma GIP response was blunted in rats
fed chlorogenic acids ([Fig. 6]), and there were no changes in GLP-1 secretion in vivo or in vitro, concluding that treatment with chlorogenic acids modifies GIP concentrations and
reduces glycemia, justifying the potential antidiabetic effect of chlorogenic acids
and coffee. Chlorogenic acids increase the production of GLP-1, and this incretin
hormone acts on β-cells to promote the synthesis and activity of the transcription factor IDX-1, which
is crucial for maintaining the responsiveness of β-cells to an increase in plasma glucose. In addition, chlorogenic acids have a putative
impact on glucose absorption, and this delay may itself protect β-cells [65]. As mentioned above, the principal compounds studied in this chemical group were
3-caffeoylquinic acid, 3,4-dicaffeoylquinic acid, 3,5-dicaffeoylquinic acid, 4,5-dicaffeoylquinic
acid, and 3,4,5-tricaffeoylquinic acid ([Fig. 6]) [67].
Fig. 6 Chemical structures of caffeoylquinic derivatives from I. batatas leaves [67].
Previous papers described Salvia fruticosa Mill. (Lamiaceae) as a possible source of antidiabetic compounds [94]. Azevedo et al. [95] studied more recently the effects of an infusion from this species (2.8 mg dry extract
per mL, “ad libitum”) and its principal constituent rosmarinic acid ([Fig. 7]) in drinking water (577 µg/mL) “ad libitum”. They studied different effects, including those on GLP-1 using streptozotocin-treated
rats. Although the plasmatic levels of GLP-1 and the number of GLP-1-expressing cells
per cm of villus was smaller in diabetic animals compared with healthy controls, none
of the treatments caused any changes.
Fig. 7 Chemical structures of rosmarinic acid, berberine, trans-resveratrol, puerarin, allantoin, and [6]-gingerol.
The effect of berberine ([Fig. 7]) on glucose metabolism in diabetic rats was studied by Zhang et al. [96], who used two doses of the compound (120 and 240 mg/kg, during 8 weeks) and found
that it significantly decreased fasting blood glucose levels and, in parallel, increased
plasma postprandial GLP-1 levels. In addition, they verified that the GLP-1 receptor
was significantly upregulated, suggesting that berberine can improve blood glucose
levels in diabetic rats through a mechanism in which GLP-1 is implicated.
Puerarin ([Fig. 7]) is a common isoflavone present in different vegetables, including medicinal plants
such as Pueraria montana var. lobata (Willd.) Sanjappa & Pradeep [syn: Pueraria lobata (Willd.) Ohwi, Leguminosae]. This compound was evaluated by Yang et al. [97] for its possible effects on β-cell survival, and the GLP-1R pathway in db/db diabetic mice and isolated mouse islets treated with high glucose. They observed
that the circulating level of GLP-1 in mice was unaffected, but puerarin enhanced
GLP-1R expression. The protective effect of puerarin was suppressed by an antagonist
of GLP-1R, concluding that puerarin protects β-cell survival by mechanisms that involve the activation of GLP-1R signaling and downstream
targets.
Different positive effects of iridoid geniposide ([Fig. 5]) on insulin secretion and glucose concentration were reported by Guo et al. [98]. In their experiments with rat INS-1 cells, geniposide (0.01 – 100 µM) increased
insulin secretion in a concentration-dependent manner, and at 10 µM, it enhanced acute
insulin secretion in response to both low and moderately high levels of glucose. The
blockade of GLP-1R with an antagonist (exendin, 200 nM) or the knock-down of GLP-1R
with shRNA interference in cells decreased the effect of geniposide (10 µM) on insulin
secretion stimulated by glucose (5.5 mmol/L). Therefore, the authors concluded that
geniposide increases insulin secretion through GLP-1 receptors in rat INS-1 insulinoma
cells.
Shanzhiside methylester ([Fig. 5]) is an iridoid present in Phlomoides rotata (Benth. ex Hook.f.) Mathiesen [Syn: Lamiophlomis rotata (Benth. ex Hook.f.) Kudô, Lamiaceae]. The anti-allodynia effect of this monoterpene-glycoside
is abolished by the selective GLP-1 receptor antagonist exendin (9 – 39). This fact
made the authors consider this iridoid as a receptor agonist, however, it was not
studied as a potential antidiabetic compound. Since it is a geniposide analogue, shanzhiside
methylester could have similar effects on insulin secretion [99].
Crude powder of yam (Dioscorea polystachya Turcz., syn: Dioscorea batatas Decne., Discoreaceae), its water extract, and its active constituent allantoin ([Fig. 7]) were analyzed in a rat model of streptozotocin-induced diabetes. All of them produced
a significant increase in GLP-1, with allantoin inducing an increment of 162% (2 mg/kg,
i. v.). The results indicate that yam and allantoin have antidiabetic effects through
the modulation of antioxidant mechanisms and by promoting the release of GLP-1, thereby
improving β-cell function, and maintaining normal insulin and glucose levels [100].
Hu et al. [101] studied the effects of ginger (Zingiber officinale Roscoe, Zingiberaceae) on gastric motility and emptying, abdominal symptoms, and
hormones that influence motility in dyspepsia, including GLP-1 values, and they observed
that the serum concentration of this incretin was modified. In the same line, Samad
et al. [102] recently reported that GLP-1 mediates the insulinotropic activity of [6]-gingerol
([Fig. 7]), the major component of ginger. Treatment of Leprdb/db
type 2 diabetic mice with this compound increased the activity of glycogen synthase
1 and enhanced the cell surface presentation of GLUT-4, facilitating glucose disposal
in skeletal muscles.
[Table 3] compiles the principal compounds from medicinal plants and their effects on GLP-1
and GIP secretion. It includes active compounds, medicinal plants, concentration,
experimental protocols and their effects.
Table 3 Natural products as stimulants of GLP-1 and GIP secretion.
|
Compound
|
Plant
|
Concentration
|
Protocol
|
Effects
|
Ref
|
|
DPP-4 = dipeptidyl peptidase-4, GIP = glucose-dependent insulinotropic polypeptide,
GLP-1 = glucagon-like peptide-1, GLP-1R = glucagon-like peptide 1 receptor, MCA =
methyl-coumaryl-7-amide, STZ = streptozotocin
|
|
Allantoin
|
Dioscorea polystachya
|
2 mg/kg, i. v.
|
STZ-treated Sprague–Dawley rats
|
Increases release of GLP-1
|
[100]
|
|
Berberine
|
Coptis chinensis
|
120 and 240 mg/kg
|
STZ-treated Sprague–Dawley rats
|
Increases GLP-1 levels
|
[96]
|
|
Chlorogenic acids
|
Coffea arabica
|
120 mg/kg
|
Sprague-Dawley rats
NCI-H716 cells
|
Increases GIP concentrations and GLP-1 production
|
[93]
|
|
Cyanidin 3,5-diglucoside
|
Aronia sp.
|
IC50 of 5.5 µM
|
In vitro
DPP-4 + Gly-Pro-MCA
|
DPP-4 inhibition and increases GLP-1 and GIP levels
|
[83]
|
|
Delphinidin 3-rutinoside
|
Ribes nigrum
|
Fruits 5 mg/kg with 1 mg/kg delphinidin 3-rutinoside
|
GLUTag cells
|
Stimulates GLP-1 and insulin secretion
|
[91]
|
|
Geniposide
|
Gardenia jasminoides
|
10 µM
|
INS-1 cells
|
Increases insulin secretion through GLP-1
|
[98]
|
|
[6]-Gingerol
|
Zingiber officinale
|
200 mg/kg
|
Leprdb/db
diabetic mice
|
Activates GLP-1-mediated insulin secretion
|
[102]
|
|
Marnieranoside A
|
Cynanchum marnierianum
|
100 µM
|
STC-1 cells
|
Increases release of GLP-1 by 130%
|
[86]
|
|
Marnieranoside B
|
Cynanchum marnierianum
|
100 µM
|
STC-1 cells
|
Increases release of GLP-1 by 133%
|
[86]
|
|
Procyanidins
|
Vitis vinifera
|
0.05 and 50 mg/L
|
STC-1 cells
|
Suppression of GLP-1 secretion!
|
[89]
|
|
Procyanidins
|
Vitis vinifera
|
500 mg/kg
|
Wistar rats
|
Increases plasma GLP-1
|
[90]
|
|
Puerarin
|
Pueraria montana var. lobata
|
150 and 300 mg/kg
|
db/db diabetic mice
|
Enhances GLP-1R expression
|
[97]
|
|
Quinovic acid-3β-O-β-D-glucopyranosyl-(28 → 1)-β-D-glucopyranosyl ester
|
Fagonia cretica
|
25 µM and 50 µM
|
pGIP/neo STC-1 cells GLP-1 and GIP ELISA kits
|
Increases GIP secretion 1.6-fold (25 µM)
Increases GLP-1 secretion 16.9-fold (50 µM)
|
[84]
|
|
Rosmarinic acid
|
Salvia fruticosa
|
577 µg/mL, in water “ad libitum”
|
STZ-treated Wistar rats
|
No changes in GLP-1
|
[95]
|
|
Shanzhiside methylester
|
Phlomoides rotata
|
10, 30, 100, and 300 µg intrathecal
|
Wistar rats, allodynia test
|
GLP-1 receptor agonist
|
[99]
|
Clinical Trials
The number of clinical trials focusing on the effects of medicinal plant extracts
or natural products is quite scarce, and demonstrated limited effects. Andersson et
al. [103] tested an extract (40 g for 6 weeks) of rose hip fruit (Rosa canina L., Rosaceae) in a randomized, double-blind, crossover study with a total of 31 obese
individuals with normal or impaired glucose tolerance, but the extract had no effect
on incretins.
Although Vallianou et al. [104] cited the antidiabetic potential of trans-resveratrol ([Fig. 7]), clinical trials conducted by Brasnyó et al. [105] did not associate this property with incretins. Indeed, in a study with 19 patients
with T2D, only small changes were detected between the groups treated with resveratrol
(5 mg × each day during 4 weeks) versus placebo, but they were not significant. However,
these results must be taken with caution due to the small number of patients employed.
More promising results were found by Törrönen et al. [106], who evaluated the effects of different berries on postprandial glucose, insulin,
and GLP-1 responses, comparing them with a similar sucrose load without berries. The
study was a randomized, single-blinded, placebo-controlled, crossover study and enrolled
12 healthy subjects. The participants had two meals on separate days based on 150 g
of a puree made with bilberries (Vaccinium myrtillus L., Ericaceae), cranberries (Vaccinium macrocarpon Aiton), blackcurrants (Ribes nigrum), and strawberries [Fragaria × ananassa (Duchesne ex Weston) Duchesne ex Rozier, Rosaceae] and 35 g of added sucrose (placebo
group received an equivalent dose of sucrose). The glycemia, insulinemia, and GLP-1
concentrations were monitored during 15 to 120 min after taking the meal. Glucose
and insulin concentrations were reduced in the group taking the berry-based meal,
although only a modest effect on the GLP-1 response (p = 0.05) was observed.
Regarding worldwide consumed stimulating beverages, such as coffee and tea, two interesting
clinical trials were performed. Johnston et al. [64] carried out a randomized, crossover study with 9 healthy fasted volunteers who were
given 25 g of glucose in either 400 mL of water (control) or 400 mL of caffeinated
or decaffeinated coffee (equivalent to 2.5 mM chlorogenic acid). GIP secretion decreased,
whereas GLP-1 secretion increased (0 – 120 min, postprandial) after decaffeinated
coffee consumption compared with the control and caffeinated coffee. These results
confirmed the known metabolic effects of caffeine. The gastrointestinal hormonal profiles
were consistent with delayed intestinal glucose absorption, suggesting that chlorogenic
acid might have an antagonistic effect on glucose transport, attenuating intestinal
glucose absorption and shifting its absorption to more distal parts of the intestine.
Green tea (Camellia sinensis), which has a similar phenolic compound profile, was also tested in another clinical
trial with 92 patients with T2D. Thirty-nine of them drank 500 mg of green tea extract,
three times a day. After 16 weeks, the green tea extract caused a significant increase
in GLP-1 versus placebo and significantly improved insulin resistance [107].
More recently, Castro-Acosta et al. [108] published the results of a randomized, controlled, double-blinded, crossover trial
conducted in healthy volunteers to investigate if enriched polyphenol drinks based
on apple [Malus sylvestris (L.) Mill., Rosaceae] and blackcurrant (Ribes nigrum L.) could affect postprandial blood glucose concentrations. They analyzed different
parameters, including GIP secretion, in 20 men (age average: 26 years old) and 5 postmenopausal
women (age average: 57 years old) who consumed two polyphenol-rich drinks containing
fruit extracts or placebo. Doses administered were 1200 mg of apple polyphenols, or
apple polyphenols (600 mg) + blackcurrant anthocyanins (600 mg). Postprandial insulin
and GIP concentrations were significantly reduced compared to placebo, but postprandial
glycemia decreased, probably due to the inhibition of GLUT-2 and SGLT1-mediated intestinal
glucose transport.
Finally, in this last year, two clinical trials dealing with dietary supplements have
been published. Boix-Castejón et al. [109] analyzed a dietary supplement based on a combination of two phenolic extracts from
Aloysia citriodora Palau [syn: Lippia citriodora (Palau) Kunth, Verbenaceae] and Hibiscus sabdariffa L. (Malvaceae). They studied 54 overweight subjects in a double-blind, placebo-controlled
intervention, monitoring different vital parameters during 60 days. Patients taking
the phenolic extracts had an increase in anorexigenic hormones (GLP-1), whereas the
orexigenic hormones (ghrelin) decreased. Zanzer et al. [110] evaluated the effect of a black pepper-based (Piper nigrum L., Piperaceae) beverage containing gallic acid equivalent (20 mg) in a randomized,
crossover intervention in 16 healthy subjects (10 men and 6 women, average age: 26
years old). In this case, they only noticed some evidence in appetite modulation,
but they did not observe changes in glycemia or gut hormone levels (including GLP-1).
Future Perspectives and Conclusions
Future Perspectives and Conclusions
Although this review shows several compounds of interest for the treatment of T2D
that modify glycemia via the modulation of incretin activity, either by direct activation
or by repression of its inhibitor, there is not a clear structural relationship among
them. The terpenic derivatives of ursane-type structure stand out, with the glycosylated
bidesmosidic derivative being the most active (IC50 of 23.5 µM) as an inhibitor of the DPP-4 enzyme; among the phenolic derivatives,
cyanidin 3,5-diglucoside, with an IC50 of 5.5 µM, stands out. Considering the compounds that stimulate GLP-1 secretion,
triterpenic derivatives are likewise worth mentioning, since they are also bidesmosidic
derivatives and marnieranosides pregnane derivatives, especially with compounds A
and B (bi- and triglycoside, respectively) being the most active. Even more interesting
are the iridoids (monoterpene-glucosides), such as geniposide and shanzhiside methylester,
which act as GLP-1 receptor agonists. Other compounds, such as caffeoylquinic acid
derivatives, rosmarinic acid, trans-resveratrol, puerarin, and the alkaloid berberine, could also be of interest.
Among the results obtained experimentally as well as the previous data referred to
in food or clinical trials, it is reasonable to hypothesize that the inhibition of
DPP-4 could be a valid alternative to deepen these type of studies. However, the limited
number of clinical trials and the small number of patients means that definitive conclusions
cannot be drawn for these compounds. Therefore, it is recommended to increase the
number of trials, putting emphasis on the importance of unifying the protocols, as
well as increasing the number of patients to follow. Regarding the tests with experimental
animals, it is worth highlighting some compounds whose mechanism is related to the
activation of GLP-1R, especially the iridoid derivatives, which could be valid as
leads for a series of studies with structural analogues. Derivatives of cyanidin,
especially diglycosylated ones, may also be valid, since they can be an interesting
source of DPP-4 inhibitory molecules and therefore indirectly give rise to the active
form of incretins.
In view of the small number of clinical trials, it is only possible to postulate the
complementary use of these medicinal plants and their active compounds together with
standard drugs (e.g., metformin) in the treatment of patients diagnosed with T2D or
in prediabetes phases. In cases of foods studied as potential antidiabetics via incretins,
no clear results have been obtained, with only those which, in practice, can be considered
active substances of medicinal plants being effective, such as guar gum or phenolic
derivatives from different sources. In conclusion, the use of medicinal plants or
active compounds should be considered only as complementary therapy and not as a substitution
treatment. On the other hand, there are some active principles that could be investigated
as potential leads for future treatments of T2D.
