Article Citation:
Waleed M. Al-Shaqha.
Anti-Diabetic potential of herbal remedies on the glucose transport gene (GLUT) in liver and skeletal muscles.
Journal of Research in Biology (2015) 5(8):1885-1895
Journal of Research in Biology
Anti-Diabetic potential of herbal remedies on the glucose transport gene (GLUT) in liver and skeletal muscles
Keywords:
Herbal Remedies, Glucose Transporter (GLUT), mRNA.
ABSTRACT:
For a long time, several herbal medicines have been used for the treatment of diabetes in the form of compound drugs. Moreover, after the references made by researchers on diabetes mellitus, investigations on the hypoglycemic activity of compound drugs from medicinal plants have been more important.Although, the molecular mechanisms behind this effect is not much explored yet. There are various approaches to reduce the diabetes effect and its secondary complications, and herbal drugs are more preferred due to its less side effects and low cost.One of the major factors in the development of diabetes and its complications is the damage induced by free radicals. Therefore antidiabetic compounds with antioxidant properties would be -cell function of herbal remedies might add to glucose uptake through improvement in the expression of genes of the glucose transporter (GLUT) family in liver and skeletal muscles. Here we selected some plants with the ability to control blood glucose aswell as to modulate some of the mechanisms-cell function, glucose transport (GLUT) gene and incretin relatedpathways. Therefore, plants remedies may be appealing as an alternative and adjunctive treatment for diabetes mellitus.
1885-1895 | JRB | 2015 | Vol 5 | No 8
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Authors:
Waleed M. Al-Shaqha
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Al-Imam Muhammad Ibn Saud Islamic University (IMSIU), Riyadh-13317-7544, Kingdom of Saudi Arabia (KSA).
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Waleed M. Al-Shaqha
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Dates:
Received: 01 July 2015 Accepted: 03 December 2015 Published: 26 December 2015
Journal of Research in Biology
An International Scientific Research Journal
Original Research
ISSN No: Print: 2231 –6280; Online: 2231- 6299
INTRODUCTION
Through ages people have utilized natural resources especially plants to maintain good health and fighting against infections, pain and diseases. In the past 200 years we have seen an increased extinction of plant species due to industrialization and a decline in knowledge of traditional medicinal which relies heavily on plants. World Health Organization (WHO) identifies 21,000 plant species with medicinal value from different parts of the world. Though, traditional medicine has been replaced by modern medicine almost everywhere, we are becoming increasingly aware of its many shortcomings, and chief among them are its ineffectiveness against many conditions and diseases, harmful side effects and increasing cost of treatment. The present review is an attempt to discuss the role of herbal drugs preparations and plants used in the treatment of diabetes and effect of herbal drug on the Glucose Transporters (GLUTs) genes. All eukaryotic cells rely chiefly on glucose for energy production which is transported across the membrane via Glucose transporters. GLUTs are expressed in all cell types in humans where they are primarily responsible for sugar uptake destined for metabolic pathways (Augustin, 2010; Thorens and Mueckler, 2010).
Diabetes and significance
Among lifestyle diseases diabetes mellitus is emerging as a life threatening condition right behind cancer and cardiovascular disease. It is a chronic metabolic disease with high prevalence, morbidity and mortality rate (Kannel et al., 1979; King et al., 1998). Diabetes mellitus doesn’t have any geographical specificity with nearly 4% of world’s population affected by this deadly disease and the death toll is likely to increase by 5.4% in the year 2025 (Kim et al., 2006). Additionally diabetes is known to be a risk factor for other diseases as well. The International Diabetes Federation (IDF) estimates that 285 million people, 6.4% of the world population, suffered from diabetes in 2010 and this prevalence will increase to 439 million people, 7.7% of the world population by the year 2030 (Shaw et al., 2010). Over 90% of patients are diagnosed with type 2 diabetes mellitus (T2DM) (Boyle et al., 1999; Attele et al., 2002). The cost of health care associated in diabetes continues to grow and becoming a big economic burden for diabetic patients and countries. Nearly US$ 174 billion were spent in the year 2007 alonein the United States treating 17.5 million adults (Cashen et al., 2008).
It is a complex metabolic disorder resulting due to the lack of insulin or inability of cells to respond to insulin. Insulin insufficiency due to the lack of functional beta cells results in type 1 diabetes mellitus (T1DM, insulin dependent) while patients with T2DM(insulin dependent) are unable to respond despite producing normal amounts of insulin. Patients with type 1 insulin are totally dependent on external sources of Insulin however, patients with type 2 insulin can be managed with dietary changes, medications and exercise. Nearly 90% of cases are of T2DM and it is the most common form of diabetes. General symptoms of diabetes includes: high levels of sugar in the blood, unusual thirst, frequent urination, extreme hunger and loss of weight, blurred vision, nausea, vomiting, tiredness, extreme weakness, irritability, and mood changes.
Pathophysiology of diabetes
A complete pathophysiological profile of diabetes remains to be ascertained, however, mounting evidence points towards the crucial role of free radicals in the pathogenesis and development of diabetic complications. (Oberlay et al., 1988; Baynes et al., 1997; Lipinski et al., 2001). T1DM is a catabolic disorder in -cell fail to respond to all insulin secretory stimuli.
Free radicals are extremely reactive species produced as a byproduct of cellular metabolism and damages cellular molecules like nucleic acid, proteins and lipids leading to altered cellular function. Many studies show the role of antioxidants that could
neutralize free radicals, in reducing the effects of aging and cancer (Kubish et al., 1997; Naziroglu et al., 2001). These antioxidants also have the ability to prevent experimentally induced diabetes in mouse models and reduce diabetic complications. (Lipinski et al., 2001). Mounting evidence from epidemiological studies suggests that genetic and environmental factors are most -cell function that result in impairment in insulin action, insulin production, or both.
Nearly 5% of western population is affected by T2DM that is the most common endocrine disorder (Zimmet et al., 2001; Shaw et al., 2010; Centers for Disease Control and Prevention, US, 2011). Insulin is a very important protein hormone that regulates the metabolism of fat, glucose and protein in cells. Patients with T2DM suffer from both reduced insulin secretion and inability to respond to insulin (Naziroglu et al., 2001). Insulin resistance has been attributed to elevated levels of free fatty acids in plasma, (Zimmet et al., 2001) leads to decreased glucose transport into muscle cells, elevated, increased breakdown of fat and hepatic glucose production. Insulin is solely produced by pancreatic beta cells and any defects in its production or mode of action results in grave metabolic consequences. Increased cardiovascular risk starts to appear much before the development of hyperglycemia. Targeting beta cells early in the disease progression has resulted in a new approach to treat T2DM. (Boden et al., 1996). During the induction of insulin resistance, such as is seen after steroid administration, high-calorie diet, or physical inactivity, increased glucagon levels and increased Glucose-dependent Insulinotropic Polypeptide (GIP) levels accompany glucose intolerance; however, postprandial Glucagonlike Peptide-1 (GLP-1) response is unaltered (Tourrel et al., 2001). Several growth factors, cell cycle mediators and nuclear factors regulate beta cell homeostasis and maintaining and enhancing beta cells function has the ability to stabilize and reverse the detrimental effect of T2DM (Leahy et al., 2010; Ackermann et al., 2007).
Role of glucose transport gene (glut)
Glucose is transported across the cell membrane by a family of integral membrane protein GLUT proteins that catalyzes facilitated diffusion of pentose and hexose sugar molecules down a concentration gradient. GLUT protein contains 500 amino acids and share 25-68% sequence identity with one another (Thorens and Mueckler, 2010).Nearly all the mammalian cells express GLUTs and some of them help in the transport of dehydroascorbate, urate or myoinositol apart from glucose. Most cells express one isoform of GLUTs that helps in the transport of major monosaccharide unit while other 13 isoforms are expressed at a lower level. Inhibition of GLUT-1-mediated sugar transport in human red cells by specific inhibitors reduces glucose permeability by five orders of magnitude (Naftalin et al., 1977). The GLUTs, therefore, provide a pathway for cellular sugar import across the cell membrane which is otherwise a very effective barrier to trans-membrane flow of monosaccharaides. In most cells it is the glucose import which is the most important function because it is a source of metabolic fuel, however, in some cells (liver, kidney and gastrointestinal tissues) export is required.
The major family of glucose transporters is the GLUT gene family. The principal insulin-sensitive glucose transporter in the liver and muscle is insulin-sensitive glucose transport gene (GLUT). Among the large super family of transport facilitators GLUT genes form a subset and includes 12 SLC2A genes numbered 1-12 encoding 12 GLUT proteins. GLUT1 is expressed highly in erythrocytes and brain and GLUT2 is associated with Fanconi-Bickel syndrome. GLUT3 is responsible for glucose transport across neuronal plasma membrane. Insulin regulated glucose transport in adipose tissues, heart muscles and skeletal muscles are carried out by GLUT4. Skeletal muscles that are primary site for
dietary glucose disposal, metabolizes glucose via glycolysis and glycogen synthesis (Ikemoto et al., 1995). GLUT4 regulation is also involved in obesity-induced insulin resistance characterize by increased blood glucose and plasma insulin levels. GLUT4 mRNA and protein expression are reduced during adipose tissue expansion which is another major site for dietary glucose disposal and might represent an adaptive response in order to prevent brain against hypoglycemia (Garvey et al., 1991; Fronzo et al., 1985). GLUT5 is highly expressed in intestine, testis, kidney, and GLUT7 expression is currently unknown. GLUT5 and GLUT7 are present contiguously on chromosome 1p36.2 with a high degree of sequence similarity (58% identical amino acids). GLUT5 is expressed in brain microglia though its function remains unclear (Kern et al., 1990; Slentz et al., 1992). Many studies indicate that glucose transport response to insulin in liver and skeletal muscle is heavily influenced by GLUTs. In fact one of the major reasons of hyperglycemia is the decrease in glucose transport gene levels. Glucose unresponsiveness with GLUT gene impairment is a hallmark of T2DM and restoring GLUT levels would enhance uptake of glucose in liver and help combat hyperglycemia (Thorens et al., 1992).
Herbal therapy for diabetes
Throughout the human history people have relied on natural products, particularly on plants. Medicinalplants were applied to treat a wide range of diseasecategories (Basch et al., 2003) and maintain good health. Past 200 years have witnessed not only an acceleration in the rate of extinction of plant species but also in erosion of traditional knowledge related to the medicinal properties and uses of herbal plants. Although herbal medicine systems are sometimesmisinterpreted as being unscientific and anachronistic but theirlong-term existence proved that they are able to compete withmodern medicine at some level. Therefore, use of medicinal plants, mainly to distinguish the ancient and culture-bound health care practices, which existed before the application of science to health care in official modern scientific medicine or allopathic. An anti-diabetic herb with many phytochemicalsmay have multiple benefits by targeting several metabolicpathways. One study demonstrated that a combination therapy of modern medicine and herbalmedicine exhibited a better (synergistic) effect than eithermedicine alone (Kaur et al., 2012).Therefore, herbal medicines can be a complementof modern therapy in T2DMand provide hope for a cure. In our pervious study we observed antidiabetic effect of catharanthus roseus on STZ induced diabetes and comparison with Metformin, treatment with c. roseus in diabetic wistar rats, the contents of glucose transport gene mRNA were restored to near normal values (Waleed et al., 2015).
All traditional medicines have their roots in medicinal values and household remedies and playa prominent role in human health care. WHO has listed 20,000 medicinal plants used in different parts of the world, and among them, 1200 plants have been claimed to be anti-diabetes remedies (Marles and Farnsworth 1995; Habeck 2003). Over 400 plants and 700 recipes compoundshave been scientifically evaluated for T2DM treatment (Singh et al. 2011).Metformin was developed based on a biguanide compoundfrom anti-diabetic herbs, French lilac, and is now a first linedrug for T2DM (Oubre et al., 1997).
Selected medicinal herbs for diabetes
More than 400 herbals and their compounds have shown anti-diabeticactivities. Instead of listing400 herbals and their compounds, here, we selected some plants with the ability to control blood glucose aswell as to modulate some of the mechanisms-cell function, glucose transport (GLUT) gene and incretinrelatedpathways.
Acacia arabica
Acacia arabica is a popular ornamental and medicinal tree. Use of A. arabica for the prevention and treatment of various health ailments has been in practice
for hundreds of years. Theplant extract acts as an anti-diabetic agent by acting assecretagouge to release insulin. It contains chiefly arabin which is the mixture of calcium, magnesium and potassium salts of arabic acid. It induces hypoglycemia incontrol rats but not in alloxanized animals. Powder of Acacia arabica, when administered (2,3 and 4 g/kg bodyweight) to normal rabbits, induced a hypoglycemic effect by-cell (Wadood et al., 1989).
Aegle marmelos
Aegle marmelos leaves (family of Rutaceae), which is also called as 61/va in ancient Sanskrit, has been used as herbal drug in the Indian subcontinent for over 5000 years. The hepatoprotective effect of A. marmelos in al-cohol-induced liver injury was evaluated for biochemical parameters. Many studies have validated the ethnomedicinal uses and indicated that the fruit possesses broad range of therapeutic effects like antioxidant, inhibition of lipid peroxidation, antibacterial, antiviral, gastroprotective, anti-diarrheal, hepatoprotective and anti-diabetic effects. The aqueous extract of leaves of A. marmelos has reported to improvesdigestion and reduces blood sugar and urea, serum cholesterolin alloxanized rats. Instead of exhibiting hypoglycemic activity, the extract also prevented blood sugar level at 1h in oral glucose tolerance test (Karunanayake et al., 1984).
Allium cepa
Allium species are among the oldest cultivated crops. Diverse representations in Egyptian artifacts dating to 2700 BC suggested that onions had been cultivated and in wide use by that time. Many ether soluble fractions and insoluble fractionsof dried Allium powder show anti-hyperglycemic activity inthe diabetic rabbits. Allium cepa is also known to have antioxidantand hypolipidaemic activity. Sulfur containing amino acid from Allium cepa, S-methylcysteine sulphoxide induced diabetic rats significantly controlled bloodglucose and lipids in serum and normalized the activities of liver hexokinase and glucose 6-phosphatase (Roman et al., 1995; Kumari et al., 1995). Scientific and pharmacological studies have found evidence that Allium cepa or their derived compounds have antimicrobial and antifungal properties, and may also be of benefit in preventing or treating heart disease and diabetes.
Allium sativum
Allium sativum is a strongly aromatic crop plant that has been cultivated for thousands of years, belonging to the liliaceace. It has been used as a medicinal agent for thousands of years and is renowned throughout the world for its distinctive flavor and health-giving properties. Allium sativum contains phosphorus, iron and copper, which have multiple beneficial effects like antimicrobial, antithrombotic, hypolipidemic, anti-arthritic, antitumor and anti-diabetic effects (Sheela et al., 1992). It also contains allyl propyl disulphide, diallyl disulphide and alliin, which increase hepatic metabolism and insulin release from-cell and/or insulin sparing effect (Bever et al., 1979).
Active compound allyl propyl and diallyl sulfide have played a role in decrease blood glucose levels. The aqueous homogenate orally administered to rabbits significantly increased hepatic glycogen, freeamino acid content, decreased fasting blood glucose, andtriglyceride levels in serum (Zacharias et al., 1980).
Aloe vera and Aloe barbadensis
Aloe vera belong to Aloaceae family, has been used for medicinal purpose from a very long time. Many studies worldwide indicated that aloe is a general tonic for the immune system and helps in fighting of all kind illness. Aloe has an important role to play in managing diabetes. Some studies have found that two tablespoons of aloe decreased blood sugar levels. Extracts of aloe effectively increased glucose tolerance in normal anddiabetic rats (Shibib et al., 1993).Aloe vera reduced hyperglycemia and hypercholesterolemia in diabetic patients. Active compound of Aloe vera,
-glucosidase activity and intestinal glucose absorption. Single andchronic doses of Aloe vera showed hypoglycemic effect in diabetic rats. Aloe vera-cell (Vats et al., 2002). Aloe vera-glucosidase (gut glucose absorption) and insulin resistance. Aloe vera also has an anti-inflammatory activity and improved wound healing indiabetic mice (Rai et al., 1997).
Azadirachta indica
Azadirachta indica belongs to Meliaceae family contains glycerides of saturated and unseturated fatty acid. The main fatty acids are oleic and stearic acids and 2% are sulpher containing compounds like nimbidin, nimbin, nimbinin, nimbidol. Hydroalcoholic extracts of A. indica showed antihyperglycemicactivity in diabetic rats and thiseffect is due to increase in glucose uptake and glycogendeposition in isolated rat hemidiaphragm (Chattopadhyay et al., 1987). Apart fromhaving anti-diabetic activity, A. indica also has anti-bacterial,ant-imalarial, anti-fertility, hepatoprotective and antioxidantactivities (Biswas et al., 2002). Leaves extract of A. indica may be helpful in controlling the development of hyperlipidemia and atherosclerosis in diabetic subjects in view of its antihyperlipidemic activity.A. indica has been used extensively by humankind to treat various ailments since prehistoric times.
Caesalpinia bonducella
Caesalpinia bonducella is widely distributed throughoutthe coastal region of India and widely used for controlling blood sugar by the tribalpeople of India. C. bonducella has been used in different system of traditional medication for the treatment of diseases. C. bonducella contained various alkaloids, glycosides, terpenoids and saponins. C. bonducella has been reported as anti-diabetic, anti-asthmatic, anti-bacterial, anti-inflammatory, anti-oxidant, hypoglycemic, anti-tumor and immunomodulatory. Aqueousand ethanolic extracts showed potent hypoglycemic activityin chronic T2DM models and alsoincreased glycogenesis thereby increasing liver glycogencontent (Chakrabarti et al., 2003). Aqueousand ethanolic (50% each) extracts of C. bonducella seedsshowed antihyperglycemic and hypolipidemic activities indiabetic rats (Sharma et al., 1997). The antihyperglycemicaction of the extracted seed is due to theblocking of glucose absorption. C. bonducella has the potential toact as anti-diabetic and anti-hyperlipidemic (Kannur et al., 2012).
Coccinia indica
Coccinia indica, an herb grows abundantly in India, has been used in traditional treatment of diabetes. C. indica is also known by the scientific names Coccinia indica and Coccinia cordifolia. C. indica has been used as an anti-diabetic drug in Ayurveda since ancient times and also used as a vegetable. Leaves of C. cordifolia have a potential hypoglycemic agent in healthy individuals thus it has been used for the treatment of patients with mild diabetes independent of energy/food intake or weight loss. An aqueous alcoholic extract of C. cordifolia, has been reported on the blood glucose levels of newly detected T2DM patients requiring only dietary or lifestyle treatment (Kamble et al., 1996).
Ocimum sanctum
It is commonly known as Tulsi, an herbaceous plant found throughout the south Asian region. The plant widely cultivated in homes and temple gardens wild in India. Since ancient times, thisplant is known for its medicinal properties. The aqueousextracted leaves of O. sanctum showed significantefficiency in reduction of blood sugar level in both normal and diabetic rats (Vats et al., 2002). Significant reduction of fastingblood glucose, uronic acid, cholesterol, amino acid, triglyceride and lipid indicated the hypoglycemic andhypolipidemic effects of O. sanctum in diabetic rats (Rai et al., 1997). The ethanolic extract of O. sanctum leaves has been reported in significant reduction of blood glucose in normal, glucose-fed hyperglycaemic and streptozotocin-
treated diabetic rats. Also, renal glycogen increased 10 fold whileskeletal muscle and hepatic glycogen levels decreased by 68and 75% respectively in diabetic rats with compared to control rats (Vats and Yadav 2004). O. sanctum has also shown antibacterial,antifungal, antiviral, antiasthemitic, antitumor, antistress, antioxidant, antimutagenic and immunostimulantactivities.
CONCLUSION
Prevalence of diabetes is increasing in all over the world, especially in developing country like India, at an alarming rate. Various factors, contribute to increase prevalence of diabetes include genetic factors that determine body fat distribution, glucose transport (GLUT) gene which is responsible for glucose transport, rapid changes in eating habits and lifestyles that are increasingly sedentary. Hypoglycemic effect in T2DM through stimulating or regenerating effects on β-cells. Diabetic stress and some other biological changes in tissue reduce by antioxidants in body (Sabu and Kuttan, 2013). Therefore, appropriate interventions in the form of weight reduction, changes in dietary habits, and increased physical activity could help in preventing the diabetes.
The insulin-responsive facilitative glucose transporter, GLUT gene, plays an extremely important physiologic role in the partitioning of glucose among peripheral tissues. In the normal cycle of fasting and refeeding, insulin is the key regulator of GLUT4 redistribution to the cell surface leading to increased glucose flux, yet the fate of glucose transported by GLUT4 is not completely understood. Restoration of GLUT gene levels enhance the uptake of glucose in liver and help to combat hyperglycemic conditions (Thorens et al., 1992). A second important role of glucose transport (GLUT) gene is to provide a mechanism of enhanced glucose uptake in working skeletal muscle, and also in adaptation of skeletal muscle to increased metabolic demand during periods of prolonged muscle contraction. Glucagon also raises blood glucose by stimulating gluconeogenesis, glycogenolysis and inhibiting glucose uptake by hepatic and muscle tissues. Diazoxide may be helpful as a daily treatment to raise the interprandial blood glucose.
Literature on the synthetic drugs for treatment of diabetes mellitus proved that mostly drugs have several side effects. Therefore, scientists are working to find out some safe and natural anti-diabetic agents that can cure the diabetes without side effects. Also, WHO has recommended the development of herbal medicine for the treatment of diabetes (Schmincke, 2003). Thus many different plants or their extracts have been used individually or informulations as potential therapeutic agents in the treatment of diabetes and its complications. Traditional health care systems including herbal medicine are widely spread in developing countries, and the care of diabetic patients has been influenced by a growing interest in complementary and alternative medicines.
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