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Diabetes & Obesity International Journal Research Article 22 min read

The KATP Channel is a Potential Target for Natural Plant Products in Type 2 Diabetes Mellitus

AL Kury L.T* and Abdoh A*
* Corresponding author
ISSN: 2574-7770  10.23880/doij-16000219  Received: December 12, 2019  Published: January 16, 2020
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Keywords
Diabetes Mellitus Natural Plant Products KATP channels
Abstract

Diabetes mellitus (DM) is a chronic metabolic disorder affecting a vast number of people all around the world. Diabetes is mainly characterized by chronic hyperglycemia, resulting from defects in insulin secretion or insulin action, or both. To date, several glucose-lowering drugs have been used clinically. These drugs exert their anti-diabetic effect by stimulating insulin secretion, increasing peripheral absorption of glucose, delaying the absorption of carbohydrates from the intestine and reducing hepatic gluconeogenesis. The concern over effectiveness and side effects of currently available therapies in the treatment of Type 2 DM (T2DM) has promoted interest in discovery and development of natural antidiabetic drugs. Plants used in folk medicine to treat DM represent a viable alternative for the control of this disease. Several plants with antidiabetic properties exert their effects by inhibiting ATP-sensitive potassium (KATP) channels in the β-cell plasma membrane, resulting in membrane depolarization and stimulation of insulin release from insulin stores by exocytosis. In this article, we examined the results of earlier studies on the actions of natural compounds on pancreatic KATP channels. It is likely that these natural compounds can be employed as lead structures for the synthesis of therapeutic agents to treat T2DM in future clinical studies.

Introduction

Diabetes mellitus is a chronic metabolic disorder affecting a vast number of people worldwide. It is The KATP Channel is a Potential Target for Natural Plant Products in Type 2 Diabetes Mellitus expected that the total number of people with diabetes will rise from 171 million in 2000 to 366 million in 2030 [1]. Diabetes is mainly characterized by chronic hyperglycemia, resulting from defects in insulin secretion or insulin action, or both. Diabetes is classified into two main types: Type I Diabetes Mellitus (T1DM) and Type II Diabetes Mellitus (T2DM) with T2DM comprising about 85% of diabetes cases. In T1DM, there is a decreased in insulin secretion due to the damage in β- Diabetes Obes Int J

cells of the pancreas, resulting in individuals with this condition relying essentially on exogenous insulin administration for survival [2]. In contrast, T2DM is characterized by decreased peripheral resistance to insulin, resulting in reduced insulin sensitivity to the skeletal muscles, adipose tissues and liver. The major complications associated with diabetes mellitus are classified as microvascular (including retinopathy, neuropathy and nephropathy) and macrovascular (including cardiovascular myopathy and cerebrovascular diseases) [2, 3]. Hyperglycemia plays an important role in the onset and development of these complications, mainly by generating reactive oxygen species (ROS) which causes lipid peroxidation and membrane damage. Furthermore, hyperglycemia results in excessive non-enzymatic glycation of proteins and formation of advanced glycation end products (AGE). The glycation modifications can further deteriorate the pathology of diabetes [4, 5].

Currently, there are a number of effective medications for the treatment of T2DM; however, many of these medications are associated with side effects. In addition, long term medication is very costly. Therefore, natural products can be a good alternative to replace or at least supplement the use of conventional drugs.

Current Pharmacological Agents in the
Treatment of T2DM
(biguanides).
family, is		For example, metformin, from the biguanide
family,a potent antihyperglycemic agent now
recommended as the first line oral therapy for T2DM. The
generally accepted mechanism for metformin action is the
inhibition of hepatic gluconeogenesis [6]. The main effect
of this drug is to acutely decrease hepatic glucose
production, mostly through a mild and transient
inhibition of the mitochondrial respiratory-chain complex
1 [7]. As a consequence, the resulting transient decrease
in cellular energy status promotes activation of AMP-
activated protein kinase(AMPK), a well-known cellular
energetic sensor. Consequently, metformin-induced
AMPK activation is believed to promote transcriptional
inhibition of hepatic gluconeogenic program [8].
Sulphonylurea drugs have been used for over 60 years to

AL Kury L.T and Abdoh A. The KATP Channel is a Potential Target for Natural Plant Products in Type 2 Diabetes Mellitus. Obes Int J 2020, 5(1): 000219.

treat T2DM [9] and they are commonly used as a second line class of antidiabetic drugs [10]. Sulphonylureas stimulate insulin secretion from pancreatic β-cells primarily by closing ATP-sensitive potassium (KATP) channels in the β-cell plasma membrane [11, 12]. As direct inhibitors of channel activity, sulphonylureas act only as partial antagonists at therapeutic concentrations. However, they also exert an additional indirect inhibitory effect via modulation of nucleotide-dependent channel gating [13]. Sulphonylureas are largely used due to their potency, fewer drug interactions and less severe adverse reactions. However, sulfonylureas lose their effectiveness after 6 years of treatment in 44% of patients [14].

Abbreviations: DM:Diabetes Mellitus; SUR:
Sulfonylurea Receptor 1; DCM;Dichloromethane; GK:
Goto-Kakizaki; ROS:Reactive Oxygen Species; AGE:
Advanced Glycation End.

Role of Pancreatic KATP

Pancreatic β-cells express ATP-sensitive potassium
(K ) channels that are needed for normal insulin
ATP
secretion and are considered as a potential target for the
development of drugs for the treatment of diabetes.
Pancreatic K is a metabolic sensor that is influenced by
ATP
the metabolic state of the cell and responsible for
initiating the ionic events that precede insulin exocytosis
by converting the intracellular ATP/ADP ratio into
membrane excitability in pancreatic β cells [15,16]. The
intracellular ATP formed by oxidative phosphorylation
inhibits K channels, reducing K+ efflux. This causes
ATP
membrane depolarization of β-cells resulting in Ca2+
influx through voltage- dependent L-type calcium
channels and stimulation of insulin release from insulin
stores by exocytosis [17]. In addition to this pathway,
otherK channels
ATP		-independent pathway involves
second messengers such as cyclic AMP (cAMP) and
diacylglycerol, and exerts its stimulatory effect on insulin
exocytosis [18,19].

The KATP channel is composed of hetero-octameric protein complex of four inward-rectifying potassium channel 6 (Kir6) pore-forming subunits and four sulfonylurea receptor 1 (SUR) regulatory subunits. Specifically, pancreatic KATP channels consist of Kir6.2 and SUR1 subunits, which have high-affinity binding sites for inhibitory sulfonylureas and glinides [15]. KATP channels have a rich and diverse pharmacology with a number of agents acting as specific inhibitors and activators.

Effect of Natural Products on Pancreatic KATP Channel

Nearly 60-80% of the world’s population uses traditional medicines derived from medicinal plants for Copyright© AL Kury L.T and Abdoh A.

various diseases including diabetes [20]. The concern over effectiveness and side effects of currently available therapies in the treatment of T2DM has promoted interest in discovery and development of natural antidiabetic drugs. Plants used in folk medicine to treat diabetes mellitus represent a viable alternative for the control of this disease. Several herbs with antidiabetic properties exert their effects by stimulating insulin secretion, decreasing intestinal glucose absorption, increasing glucose uptake by adipose and skeletal muscle tissues, increasing glycogenesis or inhibiting hepatic glucose glycogenolysis [21, 22, 23]. Plants containing natural antioxidants such as tannins, flavonoids, vitamin C and E can preserve β-cell function by free radical scavenging and prevention of diabetes-induced ROS formation [24]. Several plants exert their antidiabetic effects by inhibiting ATP-sensitive potassium (KATP) channels in the β-cells of the pancreas, resulting in increased insulin secretion. The plants mentioned below have been commonly used in traditional medicine and were examined for their hypoglycemic effects in earlier studies.

Enicostemma Littorale

Enicostemma littorale Blume, a small herb of family Gentianaceae, is commonly used in India for its anti- cancer [25] and anti-inflammatory effects [26]. Experimentally, the herb has also been reported for its blood-glucose lowering potential in alloxan-induced diabetic rats [27, 28]. Maroo, et al. [28] has shown that a single dose of aqueous extract of E. littorale (15 g dry plant equivalent extract per kg) causes a significant increase in the serum insulin levels in alloxan-induced diabetic rats at 8 hours, whereas glybenclamide showed increase in serum insulin levels both at 4 and 8 hours. Using rat pancreatic islets, the extract enhanced glucose- induced insulin release and was partially able to reverse the effect of diazoxide (KATP channel opener). Incubation with Ca2+ chelator (EGTA) and Ca2+ channel blocker (nimodipine) did not affect the glucose-induced insulin release augmented by the extract. Therefore, the results suggested that the glucose lowering effect of the aqueous extract of E. littorale is associated with potentiation of glucose-induced insulin release through the KATP channel- dependent pathway, but did not require Ca2+ influx [28].

Ocimum Sanctum

Ocimum sanctum Linn. (Labiatae), commonly known as holy basil, is a herbaceous plant found throughout the South Asian region and is widely used as an anti-stress medication and to treat conditions such as bronchitis, skin diseases, chronic fever, and hemorrhage. O. sanctum AL Kury L.T and Abdoh A. The KATP Channel is a Potential Target for Natural Plant Products in Type 2 Diabetes Mellitus. Obes Int J 2020, 5(1): 000219.

leaves were found to possess hypoglycemic effects in experimental animals [29, 30]. For example, the ethanol extract of O. sanctum leaves has been shown to cause a significant reduction in blood glucose levels in normal, glucose-fed hyperglycemic and streptozotocin-treated diabetic rats. Furthermore, a diet containing leaf powder fed to normal and diabetic rats for 1 month significantly reduced fasting blood glucose [30]. In a randomized, placebo-controlled, crossover, single blind clinical trial, leaf extract of O. sanctum caused a significant decrease in fasting and post-prandial glucose [31]. A more recent study on alloxan-treated diabetic rats has also shown that an ethanol extract of O. sanctum reduces hyperglycemia in both acute and long-term feeding studies [32]. In an attempt to understand the mechanism of hypoglycemic effect of O. sanctum leaves, ethanol extracts and partition fractions of O. sanctum leaves were evaluated for their effects on insulin secretion using isolated perfused rat pancreas, isolated islets and clonal BRIN-BD11 cells [33]. In all of the three preparations, ethanol extract and partition fractions were able to stimulate insulin secretion in a concentration-dependent manner. Involvement of the KATP channel in the stimulatory action of O. sanctum was evident in β -cells. Diazoxide inhibited the insulin- releasing effects of the extract, suggesting that the closure of KATP channels participates in the overall mechanism of action of O. sanctum [33].

Psacalium Decompositum

An earlier study has investigated the mechanism of the hypoglycemic effect of root and rhizome aqueous decoctions of the medicinal herb Psacalium decompositum (Asteraceae) [34, 35]. P. decompositum, commonly known as “matarique”, is a widely used remedy in folk medicine in Mexico for the treatment of diabetes, ulcers, pain, rheumatic disorders, hepatic and renal colic, and neuralgia. The study has identified three hypoglycemic sesquiterpenoids; cacalol, cacalone epimer mixture, and cacalol acetate. All compounds were able to block KATP channels in aortic smooth muscle rings in a similar way to glibenclamide. However, the sesquiterpenoids were less effective than glibenclamide in lowering plasma glucose levels, suggesting that they may display a higher affinity to SUR2 subunit of KATP channels in aortic smooth muscle than to SUR1 subunit in pancreatic beta-cells [34].

Teucrium Polium

One of the medicinal plants that has been used in folk medicine for the treatment of diabetes in Iran is Teucrium Copyright© AL Kury L.T and Abdoh A.

polium L. Studies have reported a number of therapeutic effects for this plant including antioxidant [36], anti- inflammatory, [37] and hypolipidemic [38] effects. Mirghazanfari, et al. [39] tested the effect of a T. polium extract on insulin secretion in isolated rat pancreas. Interestingly, only the Methanolic extract but not the aqueous extract of T. polium caused a significant increase in insulin release. Furthermore, diazoxide (KATP channel opener) and verapamil (Cav channel blocker) were used to assess the mechanism of insulin secretion by T. polium. The results of this study showed T. polium extract had an insulinotropic effect that was inhibited by both diazoxide and verapamil. These findings indicate that the extract- stimulated insulin secretion is mediated through the inhibition of KATP channels, activation of Cav channels, or both. Furthermore, it was concluded that the insulinotropic effect of T. polium extract can be attributed to the presence of the compound apigenin only in methanolic extract but not in aqueous extract [39].

Nelumbo Nucifera

Nelumbo nucifera is an aquatic perennial and national flower of India and Vietnam. Its leaves, rhizomes, and seeds are all used in Asian cuisine. In addition, the plant has been used in traditional Vietnamese medicine to treat diabetes. Nguyen, et al. [40] found that Nuciferine, extracted from N. nucifera, stimulated insulin secretion in isolated islets and in INS-1E cells at both 3.3 and 16.7 mM glucose concentrations. Nuciferine acted primarily by closing KATP channels. In addition, the effect of nuciferine was abolished by diazoxide, nimodipine, protein kinase A, and protein kinase C inhibition. Nuciferine had a weaker affinity for binding to the sulfonylurea receptor, a stronger effect on insulin secretion, and less cytotoxicity than glibenclamide [40].

Kalanchoe Pinnata

Kalanchoe pinnata Lam. (Crassulaceae) is used as a traditional medicine worldwide to treat several illnesses. The major reported pharmacological effects are immunosuppression [41], hepatoprotection [42], antitumor [43], and hypoglycemic activity [44]. Patil, et al. [45] evaluated Kalanchoe pinnata Lam. (Crassulaceae) for its antihyperglycemic and insulin secretagogue potential through in vivo and in vitro studies. The dichloromethane (DCM) fraction of the plant demonstrated glucose- independent insulin secretagogue action similar to the currently used drug glibenclamide. In streptozotocin- induced diabetic rats, fasting blood glucose values were significantly reduced on treatment with 10mg/kg body weight of DCM fraction. In addition, the insulin level and AL Kury L.T and Abdoh A. The KATP Channel is a Potential Target for Natural Plant Products in Type 2 Diabetes Mellitus. Obes Int J 2020, 5(1): 000219.

lipid profile values were close to normal values. Glycated hemoglobin was also improved to 8.4% compared with 12.9% in diabetic controls. In vitro studies demonstrated a dose-dependent insulin secretagogue action. Insulin secretion was 3.29-fold higher compared to the positive control. Most importantly, the insulin secretagogue activity was found to be KATP channel-dependent [45]. Similarly, another species of Kalanchoe, K. crenata (Crassulaceae), was also shown in an earlier study to possess antihyperglycemic activity. Its antihyperglycemic mechanism was proposed to be due to modulation in insulin sensitivity [46].

Leonurus Sibiricus

The plant Leonurus sibiricus L. has been used to treat T2DM in traditional medicine of many Asian countries. Many pharmacological effects of L. sibiricus were reported in the literature. For example, the plant was shown to exert an anti-inflammatory activity in rats [47] and humans [48] and to possess a potent antioxidant activity [49]. Treatment with a L. sibiricus herb extract has been shown to affect the atherogenic process in animals. For example, C57BL/6 mice displayed decreased plasma cholesterol levels, reduced plasma triglyceride levels, and an increased HDL-cholesterol concentration when given atherogenic diet supplemented with a L. sibiricus herb extract compared to animals receiving the atherogenic diet alone [49]. The effect of extracts from the plant L. sibiricus on insulin secretion, electrophysiological properties, intracellular calcium concentration and cell proliferation of INS-1E insulinoma cells were investigated by Schmidt, et al. [50]. Insulin secretion of rat INS-1E cells was significantly increased in the presence of aqueous and methanolic L. sibiricus extracts. Acute application of the aqueous extract resulted in KATP inhibition, membrane depolarization, and an increase in intracellular Ca2+ concentration. Interestingly, the electrophysiological effects were comparable to those of tolbutamide. Furthermore, treatment with the aqueous extract stimulated INS 1-E cell proliferation. The findings of this study support the use of L. sibiricus in the treatment of DM and related disorders in traditional medicine [50]. A more recent study investigated the short- and long-term effects of the flavonoid quercetin and its glycoside rutin, which are constituents of L. sibiricus extract, on beta cells. Although both constituents are known to exert insulinotropic properties in vivo and in vitro, rutin did not alter insulin secretion or the electrophysiological behavior of rat INS-1 cells. In contrast, quercetin acutely stimulated insulin release, presumably by transient KATP channel inhibition and intracellular Ca2+ stimulation.

Copyright© AL Kury L.T and Abdoh A.

Diazoxide caused a significant hyperpolarization and completely prevented quercetin and tolbutamide - induced membrane depolarization, suggesting that KATP channels are direct targets of quercetin. Long term application of quercetin inhibited cell proliferation and induced apoptosis, most likely due to the inhibition of PI3K/Akt signaling [51].

Gynostemma Pentaphyllum

The pharmacological effects of the herbal plant Gynostemma pentaphyllum, commonly known as Jiaogulan, have been proven in many studies. The plant was previously reported to have high radical scavenging capacity [52], anti- inflammatory [53], hypoglycemic [54] and anticancer effects [55]. Earlier study has investigated the mechanism of antidiabetic effect of G. pentaphyllum water extract on blood glucose and serum insulin levels in Goto-Kakizaki (GK) rat, an animal model T2DM [56]. The results of this study have shown that G. pentaphyllum extract improved glucose tolerance, increased plasma insulin levels, and increased insulin secretion from islets isolated from the treated rats. In vitro results show that the G. pentaphyllum extract stimulated insulin release from the isolated rat islets at high glucose only. In addition, extract-induced insulin release was partly mediated via KATP, L-type Ca2+ channels, and protein kinase A system, and partly dependent on pertussis toxin sensitive Ge-protein at high glucose [56].

Lupinus Mutabilis

Lupinus mutabilis, commonly named Tarwi [57], is a legume usually consumed as cooked seeds , and is traditionally used to reduce glycemia after the meal [58]. Clinical trials showed that L. mutabilis reduces blood sugar in slightly hyperglycemic subjects, and cooked L. mutabilis seeds reduce glycemia in patients with type 2 diabetes, an effect related to its alkaloid content [58, 59]. A recent study evaluated the anti-diabetic effect of L. mutabilis in the spontaneously diabetic Goto-Kakizaki (GK). The mechanism of insulin release was tested in pancreatic islets isolated from both GK and Wistar rats as healthy controls. The hydroethanolic extract of L. mutabilis seeds improved glucose tolerance in both GK and Wistar rats by enhancing insulin release. This effect was mainly mediated by L‐type calcium channel, the PKC and PKA systems and G protein‐coupled insulin exocytosis and partially mediated by KATP channels of the beta cells [60].

AL Kury L.T and Abdoh A. The KATP Channel is a Potential Target for Natural Plant Products in Type 2 Diabetes Mellitus. Obes Int J 2020, 5(1): 000219.

Swietenia Humilis

Recently, some active components from the seeds of Swietenia humilis, commonly used to treat T2DM in Mexico, were isolated and identified; these compounds were tetranortriterpenoids of the mexicanolide class and exhibited not only antidiabetic but also antihyperalgesic effects in hyperglycemic mice [61, 62]. In an attempt to evaluate the mechanism of antihyperglycemic effect of S. humilis, Ovalle-Magallanes, et al. [63] tested the effects of selected mexicanoloides in vivo (Using streptozotocin- treated mice) and in vitro (using INSE1, H4IIE and C2C12 cells). The findings of this study showed that S. humilis mexicanolides interact with multiple pharmacological targets including pancreas (KATP channels), liver (glucose-6-phosphatase), and skeletal muscle (mitochondria and possibly glucose transporters) to modulate glucose homeostasis, indicating that these compounds could be a promising resource to treat T2DM [63].

Conclusion

DM is a chronic metabolic disorder affecting a vast number of people worldwide. Although conventional antidiabetic drugs are effective in treating DM; nonetheless, they are associated with unavoidable side effects. On the other hand, medicinal plants may act as an alternative source of antidiabetic agents. However, lack of understanding of the precise mechanism impedes their use. KATP channels are metabolic sensors needed for normal insulin secretion and are considered a potential target for the development of drugs for the treatment of DM. It is likely that natural compounds can be employed as lead structures for the synthesis of therapeutic agents that target KATP channels to treat T2DM in future clinical studies.

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@article{al2020,
  title   = {The KATP Channel is a Potential Target for Natural Plant
Products in Type 2 Diabetes Mellitus},
  author  = {AL Kury L.T* and Abdoh A},
  journal = {Diabetes & Obesity International Journal},
  year    = {2020},
  volume  = {5},
  number  = {1},
  doi     = {10.23880/doij-16000219}
}
AL Kury L.T* and Abdoh A (2020). The KATP Channel is a Potential Target for Natural Plant
Products in Type 2 Diabetes Mellitus. Diabetes & Obesity International Journal, 5(1). https://doi.org/10.23880/doij-16000219
TY  - JOUR
TI  - The KATP Channel is a Potential Target for Natural Plant
Products in Type 2 Diabetes Mellitus
AU  - AL Kury L.T* and Abdoh A
JO  - Diabetes & Obesity International Journal
PY  - 2020
VL  - 5
IS  - 1
DO  - 10.23880/doij-16000219
ER  -