diabetes mellitus: treatment challenges and the …...degradation and dpp-iv inhibitors...

Middle-East Journal of Scientific Research 20 (7): 786-798, 2014ISSN 1990-9233© IDOSI Publications, 2014DOI: 10.5829/idosi.mejsr.2014.20.07.82226

Corresponding Author: Rajalingham Sakthiswary,Department of Medicine,Faculty of Medicine Universiti Kebangsaan MalaysiaMedical Centre Jalan Yaacob Latif, Bandar Tun Razak 56000, Cheras, Kuala Lumpur, Malaysia.Tel: +6-03-91456097.

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Diabetes Mellitus: Treatment Challengesand the Role of Some Herbal Therapies

Rajalingham Sakthiswary, Zaiton Zakaria and Srijit Das1 2 3

Department of Medicine, Universiti Kebangsaan Malaysia Medical Centre,1

56000, Cheras, Kuala Lumpur, MalaysiaDepartment of Physiology, Universiti Kebangsaan Malaysia,2

50300, Kuala Lumpur, MalaysiaDepartment of Anatomy, Universiti Kebangsaan Malaysia,3

50300, Kuala Lumpur, Malaysia

Abstract: Diabetes mellitus (DM) is a chronic metabolic disorder with devastating complications affectingmillions of individuals across the world. Alarmingly, the incidence of DM continues to rise steadily. Hence, itis not surprising that both modern and traditional medicine researchers have been consistently experimentingantidiabetic agents for the treatment of DM and its complications. Despite the promises and convincingscientific evidence that lie beneath the prescription of drugs, a significant number of DM patients opt for herbalpreparations. The popularity of herbal supplements for treating DM and its complications is attributed to thecost effectiveness and lesser side effects. The three main domains of complementary and alternativemedicine i.e. western herbalism, Chinese and Ayurvedic medicine have been tried for the effective treatmentof DM. The main aim of the present review is to highlight the advances of the used herbal antidiabeticpreparations. Besides, we have discussed the various macrovascular and microvascular complications occurringin DM with the potential role of herbal supplements in this regard. For the purpose of this review, we haveretrieved some related articles from Pubmed, Ebsco and ScienceDirect published between the years 1980 and2013.

Key words: Diabetes Mellitus Antidiabetic Drugs Treatment Herbs Antioxidants

INTRODUCTION diabetic retinopathy, diabetic nephropathy and diabetic

The Global Burden of Diabetes Mellitus: Diabetes steadily grown to an alarming figure of 285 million in 2010mellitus (DM) is an endocrine disorder resulting in based on the estimation by the World Health Organizationhyperglycaemia due to insulin deficiency, insulin (WHO). The number is still expected to increase by almostresistance or both. This heterogeneous disease which two fold to over 400 million by 2030 [2].runs an insidious course may result from a complex The vast majority of cases of DM hail from the low tointerplay of metabolism, environmental and genetic middle income countries. India ranks first in thisfactors [1]. DM can be further subdivided into type 1 DM, aspect, accounting with the highest number of DM cases.type 2 DM and gestational DM. Complications of this China is rated as the second nation with regard to thecondition are far too many affecting almost any organ incidence [2, 3]. The rising trend in prevalence of DM overfrom head to toes. The major macrovascular complications the years are attributable to the modern diet and lifestyleare coronary artery disease, stroke and peripheral vascular and more effective screening methods. This disease posesdisease whereas the microvascular sequela include an enormous economic burden to many nations in the

neuropathy. The number of diabetics worldwide has

Middle-East J. Sci. Res., 20 (7): 786-798, 2014

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Fig. 1: Schematic diagram showing the main classes of oral antidiabetic agents used in clinical practice.

east and west [3-9]. In England, it has been reported that At a cellular level, more recently, dysfunction of thethe cost of treatment of DM escalated from £458.6 millionin 2004/5 to £649.2 million in 2009-2010 [10]. It isreasonable to expect a parallel rise in morbidity andmortality secondary to the cardiovascular disease.The DM epidemic has set off alarms and calls for a globalinitiative ideally involving practitioners of modern andalternative medicine.

The Evolving Concepts of Pathogenesis of DM: Variouscomplex mechanisms with multifactorial pathwaysultimately lead to DM. The pathogenesis of DM hasevolved to a great extent ever since it was initiallydiscovered. Although much is known about themechanisms involved, there are still questions which needto be answered. The severity of the disease and theoccurence of complications may vary from oneindividual to another despite similar levels ofendogenous insulin. The interplay of genes, lifestyle,environment and oxidative stress may determine thecourse of the illness. The key mechanisms involved inDM are insulin resistance and beta-cell dysfunction.Excessive ectopic fat accumulation especially visceralfat increases the risk of insulin resistance. In therecent decades, there has been a paradigm shift in theunderstanding of DM with newer concepts oninsulin resistance which have emerged and beenestablished. It is now believed that it involves cytokineproduction by activated white blood cells as part of animmune response [11-14]. Besides, oxidative stress,especially involving reactive oxygen species (ROS) canresult in auto-oxidation of glucose and impairment ofantioxidant defense enzyme activities [15-17]. The incretinhormones secreted by the intestine i.e. glucagon-likepeptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP)enhance insulin production postprandially andaccumulating evidence assigns a blunted GLP-1secretionin DM [18].

mitochondria and endoplasmic reticulum (ER) werediscovered to be partially responsible for the -celldysfunction and insulin resistance. ER stress can triggermitochondrial dysfunction with subsequent apoptosissignaling via Ca2+- and reactive oxygen speciesdependent mechanisms. The interaction betweenmitochondrial dysfunction and ER stress is a rapidlygrowing area of research interest. Dissection of theprocesses involved in DM will pave the way for moretargeted therapies [19-21].

The Conventional Therapies in DM: The standardinternational practice now is to adopt an aggressiveglucose-lowering approach from the very beginning of thedisease process in order to effectively overcome themacrovascular risk. It is strongly recommended to usecombination of drugs with a complementary mode ofaction to achieve an HbA1c level of below 7% [22].The two broad categories of pharmacological approach toDM are insulin therapy and oral hypoglycaemic agents(OHA). More efficacious therapies are constantly beingsought by researchers to achieve optimal glycaemiccontrol and improve outcomes. Today, clinicians have theluxury of an extensive range of OHA. The main classes areheterogeneous in their pharmacodynamics andpharmacokinetics. The older OHAs are sulphonylurea,alpha-glucosidase inhibitors and biguanides while thenewer agents are incretin-based therapies, drugsinhibiting kidney glucose reabsorption (SGLT2 inhibitors)and glucokinase activators (Fig. 1). Patients withsuboptimal diabetic control while on OHA, severehyperglycaemia and type 1 DM are some of thecandidates for insulin therapy. Oral anti-diabetic agentshave variety of ways to exert therapeutic effects. Theseinclude stimulation of insulin secretion, reduction ofhepatic glucose production, inhibition of absorption ofintestinal carbohydrate or enhancement of peripheralinsulin sensitivity [23, 24].


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Insulin sensitizers namely biguanides and glucagon receptor, inhibitors of glycogen phosphorylasethiazolidinediones (TZDs) address the key mechanism and fructose-1,6-biphosphatase). Glucokinase activatorsinvolved in Type II diabetes which is insulin resistance. (GKA) lower glucose levels by increasing insulinBiguanides reduce hepatic glucose production and secretion and hepatic glucose metabolism [36, 37]. A newincrease peripheral utilisation of glucose. This class of promising treatment strategy which is awaiting Food andOHA has emerged as the most widely prescribed agent in Drug Administration (FDA) approval; targets the sodium-type 2 DM. Metformin has been around since the 1960s glucose co-transporter 2 (SGLT2). SGLT2 inhibitorsand is usually the first line OHA [25, 26]. TZDs, on the regulate glucose through interference of glucoseother hand, binding to PPAR , a type of nuclear reabsorption in the proximal tubules of the kidneysregulatory protein is involved in transcription of genes resulting in increased urinary glucose excretion.involved in glucose homeostasis. These PPARs act on Compared to the other antidiabetic agents, SGLT2peroxysome proliferator responsive elements (PPRE [1]) inhibitors have a rather unique mode of action which isto enhance production of mRNAs of insulin-dependent insulin independent [38] (Fig. 2). Interleukin-1 receptorenzyme resulting in improved glucose utilization. antagonist (IL-1Ra) is a novel anti-inflammatoryExamples of TZDs are rosiglitazone (Avandia), therapeutic strategy in DM, which has already beenpioglitazone (Actos) and troglitazone (Rezulin). The approved by FDA [39].ADOPT study and DREAM trial had results in favor ofTZDs with demonstrable retardation of disease The Drawbacks ofConventional Therapies and the Unmetprogression among the subjects [27, 28]. Needs in DM: Despite the promises of the wide range of

Insulin secretagogues can be further subdivided options of prescription medications, these drugs areinto sulfonylurea and nonsulfonylurea secretagogues. associated with numerous side effects which areThis category of OHAs trigger insulin release by acting intolerable for many patients. Table 1 summarized theon the potassium channels of the pancreatic beta cells. mechanisms of action and the side effects of the mainSulfonylureas were the earliest most widely prescribed classes of antidiabetic agents. Sulfonylureas are known toOHAs. The first generation of sulphonylureas include cause weight gain and hypoglycemia. Biguanides carry atolbutamide, tolazamide, chlorpropamide whereas low risk of lactic acidosis especially among the elderly andglipizide, glibenclamide, glimepiride and glyclazide are in the presence of hepatic, liver or renal failure. The moresome of the second generation drugs [29, 30]. common side effects of metformin involve theNonsulfonylurea secretagogues refer to meglitinides gastrointestinal tract, with nausea, cramps and diarrhea.(repaglinide and nateglinide) which are also known as Up to 30% of patients experience these symptoms while"short-acting secretagogues [31]. on metformin; the most widely prescribed OHA [40].

Alpha-glucosidase inhibitors for e.g. acarbose and Vitamin B deficiency has been reported in approximatelyvoglibose act on the small intestine to slow the digestion 7% of patients on metformin following 1 year of treatmentof starch for a more gradual rise in the plasma glucose [41]. Alpha-glucosidase inhibitors, on the other hand,levels postprandially. This group of OHA is less popular cause flatulence. This is due to gas formation followingin the United States but is still widely prescribed in other the digestion of undigested carbohydrate by colonicregions of the world like Asia and Europe [32, 33]. bacteria in the large bowel. The most feared side effect of

In the recent years, strong emphasis has been placed this agent is hepatic necrosis high serum a-glucosidaseon GLP-1. It is proven to increase beta-cell mass in murine level especially in the presence of renal decompensationstudies. GLP-1. However, it is rapidly degraded by [42].dipeptidylpeptidase IV (DPPIV) which limits its Since 2007, rosiglitazone, a thiazolidinedione, hastherapeutic potential. To tackle this problem, GLP-1 raised a lot of concerns and controversies pertaining toanalogs (exenatide) which are more resistant to the increased risk of myocardial infarction anddegradation and DPP-IV inhibitors (sitagliptin) were cardiovascular mortality. A meta-analysis published indeveloped [34, 35]. Biological therapies are being 2010 concluded that this agent had an unfavorable benefitincreasingly experimented with encouraging results. to risk ratio. The other major problem with this class ofThe pharmacodynamics of these agents are very diverse drugs is fluid retention due to excess production ofand consist of insulin sensitization (11beta-HSD-1 vascular endothelial growth factor (VEGF) andinhibitors and antagonists of glucocorticoids receptor), overstimulation of the peroxisome proliferator-activatedreduction in hepatic glucose output (antagonist of receptor (PPAR) gamma receptors [43].

12


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Fig. 2: Schematic diagram of sites and mechanisms of action of oral antidiabetic SGLT2: Sodium-glucose co-transporter 2, TZD : thiazolidinediones, DPP-IV : dipeptidylpeptidase IV

Table 1: The mechanism of actions and side effects of antidiabetic agents

Antidiabetic agents Mechanism of action Adverse effects

-binds to an ATP-dependent potassium channel on the cell Hypoglycaemia,weight gain,

membrane of pancreatic beta cells. abdominal pain, hypersensitivity reactions,

Sulfonylurea -sensitizes ?-cells which limits hepatic gluconeogenesis, lipolysis teratogenic,

and clearance of insulin by the liver. increased risk of cardiovascular death (FDA warning)

Metformin -suppresses hepatic gluconeogenesis diarrhea,abdominal cramps, nausea and vomiting increased

-activates AMP-activated protein kinase (AMPK), an enzyme that flatulence lactic acidosis

plays an important role in insulin signaling and glucose metabolism

-increases insulin sensitivity, enhances peripheral glucose uptake (by

phosphorylating GLUT-4 enhancer factor), increases fatty acid

oxidation, and decreases absorption of glucose from the

gastrointestinal tract

Alpha-glucosidase - inhibits pancreatic alpha-amylase and reduces glucose flatulence, diarrhea, Pneumatosis cystoides intestinalis

inhibitor absorption from carbohydrates

Thiazolidinediones -activates PPARs (peroxisome proliferator-activated receptors Increases cardiovascular risk, Oedema,

leading to decreased insulin resistance, modification of adipocyte Weight gain, Worsens congestive cardiac failure

differentiation, decreased leptin levels and increased adiponectin

levels

Dipeptidyl Peptidase- -increases blood concentration of the incretin GLP-1 by inhibiting Increased risk for infection, headache

4 Inhibitors its degradation by dipeptidyl peptidase-4.

Injectable Glucagon-like -binds to a membrane GLP receptor decreased gastric motility causing nausea

peptide (GLP) analogs

and agonists


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Antidiabetic agents especially insulin therapy cause progressive nature of DM [47]. Regardless of the initialfluctuations in the plasma glucose levels. Hypoglycaemic choice of OHA, the good glycaemic control achieved isattacks are common and potentially life threatening. not sustained over a prolonged period requiring eitherInsulin secretagogues are also notorious in this sense. combination therapy or switches between drug classes. In a recent study in South Central England, 4081 Besides, the currently available drugs, with theemergency calls over a 1 year period were coded as exception of insulin, only result in modest lowering ofhypoglycaemia. The vast majority of the patients were glycated hemoglobin (HbA1c) by approximately 1%-2%.diabetics. In the United kingdom, the estimated annual This response is inadequate for the long-standingcost for emergency services related to hypoglycaemia was diabetics and for those with HbA1c which is way above13.6 million pounds [44]. the recommended targets.

The safety profile and tolerability of the newer Patients on antidiabetic agents are required to haveantidiabetic drugs are questionable and require further a battery of regular blood tests to screen forrobust evidence before they are deemed safe. complications related to the disease and the medications.Unfortunately, certain serious side effects are not For instance, following the commencement of TZDs, thediscovered until years elapse after the drugs official liver function test has to be checked every few months.approval. Many antidiabetic agents have been withdrawn It is most inconvenient for patients on insulin therapyfrom the market due to safety issues. Rezulin, for example, who may have to self-monitor their glucose levels bya form of TZD, was banned following reports of serious performing the fingertip glucose measurements on a dailyliver toxicity [45]. Recently, the majority of the FDA basis. Routine blood check while incurring extra costs arepanelists voted against the approval of the SGLT2 often troublesome and a problem for many patients.inhibitor due to the potential hazard of developing bladderand breast cancer [46]. Evidence Based Herbal Therapies for DM and its

Patients’ compliance with medication is strongly Complications: We have performed a random search ofaffected by the troublesome side effects. On the flip side, the Pubmed, Scopus and Science Direct databases for thecompliance is bound to be fair in the setting of a good or herbal extracts which were reported to possesstolerable side effect profile. Non compliance accelerates antidiabetic properties. A selected number of thethe development of both macro and microvascular aforementioned agents are described in this review.complications of DM due to chronic hyperglycaemia.The poor patients are often in a dilemma to choose Gingko: Ginkgo belongs to the Gingko Biloba species,between the clinical manifestations of DM and the side also known as EGb 761 in the scientific literature; waseffects of the medications. Apart from unfavorable patient coined by W. Schwabe Company, Karlsruhe, Germanyoutcomes, non compliance translates to unproductive and it is one of the most popular over-the-counter herbalpublic expenditure. dietary supplement in the United States and Europe [48].

Despite all the elegant clinical studies and trials, there This herb has been used mainly to treat age-associatedare several unmet needs with the conventional treatment memory impairments and cerebral insufficiency [49].strategies of DM. The earlier discussed medications Researches have revealed that ingestion of 120 mg of EGbaddressed the effect of the disease which is 761 as a single dose for 3 months, produced an increasehyperglycemia rather than tackling the culprit causative in pancreatic beta cell function and reduction in collagenprocesses like declining function of pancreatic beta cells. and arachidonic mediated platelet aggregation [50]. It isAntidiabetic agents are not disease-modifying, reasonable to assume that any agent which enhances betaallowing relentless progression of the disease over years. cell function will be beneficial in type 2 DM. The popularThe ADA/EASD consensus guidelines have clearly consumption of EGb 761 in the United States of Americahighlighted that even among patients who initially proves its role as an effective supplement.succeed in achieving glycemic goals with only metforminmonotherapy, may eventually require combination Momordica Charantia: Momordica charantia (MC) ortreatment, with or without insulin. Furthermore, the results bitter gourd which belongs to the Cucurbitaceae familyof the U.K.’s Prospective Diabetes study showed that has been proven to be an effective antihyperglycemicdespite successful initial lowering of fasting blood vegetable. Experiments conducted on animals as well asglucose and HbA1c with intensive monotherapy, these in humans showed the potential hypoglycaemic action ofparameters steadily increased with time due to the MC in DM [51, 52]. In our earlier experiments, we


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observed the potential therapeutic effects of MC in DM Cordyceps: A parasitic fungus i.e. Cordyceps sp, alsowound healing [53]. Moreover, administration of MC known as ‘‘winter-worm and summer-grass’’ is a popularextract reversed the damages caused in the liver and Chinese herb which has been used effectively for thekidneys of experimental Sprague-Dawley rats induced treatment of various household disorders. Researcheswith diabetes [54, 55]. have showed that polysaccharides extracted from cultured

MC has been reported to reduce the fructosamine mycelium of Cordyceps, when administeredlevel [56]. Research studies have shown that intraperitoneally exhibited potent hypoglycemic activityhypoglycaemic properties of MC are attributed to its in diabetic mice [66]. The plausible mechanism involvedinsulin-like properties [57], increased insulin secretion the presence of the high content of the fibres. It cannot be[58], peripheral tissue uptake of glucose [59], liver and forgotten that a delay in glucose absorption or reductionmuscle glycogen storage [60] and suppression of hepatic in glucose absorption may help stabilise plasma glucosegluconeogenesis [61]. levels in DM. The fibres have an effect on glucose

Cuminum Cyminum L: The English name Cumin isderived from the Latin name Cuminum. It belongs to the Eggplant (Solanum melongena): Eggplant (Solanumfamily Cuminum Cyminum. Cuminum cyminum L is usedto improve the taste and flavour of various foodpreparations. Earlier research reports have shown that theCuminum cyminum L which belongs to the family ofApiaceae exhibited potential hypoglycaemic effects inexperimental animals [62]. The authors explained that thehypoglycaemic effects of Cuminum cyminum L wasprobably due to insulin-like action or increasedproduction of insulin by the pancreatic islets [62].Interestingly, it was shown that C. cyminum normalisedthe total haemoglobin and HbA1C in the experimentaldiabetic rats, by reducing the plasma glucose levels [61].5.4 Fruits of Emblica officinalis and Terminaliabellerica

The fruits of Phyllanthus emblica also known asEmblica officinalis (EB) or Indian gooseberry andTerminalia bellerica (TB) or also known as Gaertn, possesspotent antibacterial, antiviral and anti-inflammatoryactivity. EB and TB have been reported to possess goodantioxidant and free radical scavenging activity [62].It cannot be refuted that DM is a disease that involvesoxidative stress and production of reactive oxygenspecies (ROS) is responsible for multiorgan damage.The EB and TB extract have also been reported to show

-amylase and -glucosidase inhibitory potential alongwith antiglycation activity which may be helpful intreatment of DM [63]. Interestingly, past researchersreported that EB extract reduced the lipid profile inexperimental diabetic animals [64]. There are reports of TBsuppressing the absorption of triacylglycerol andexhibiting a strong inhibitory effect on pancreatic lipaseactivity [65]. The authors of the same study [65] had theopinion that gallic acid was the component which wasresponsible for the inhibition of the pancreatic lipaseactivity.

absorption [66].

melongena), a type of tropane alkaloids, is also known topossess glycosidase inhibitory activity [67]. Phenolicphytochemicals present in this plant can help inscavenging the free radicals and combat oxidative damageto the organs in DM. It was shown that the phenolicingredients of eggplant could cause intestinal -glucosidase inhibition [67] which reduceshyperglycaemia.Enicostemma Littorale Blume: Enicostemma littoraleBlume, is a small herb which hails from the familyGentianaceae and it has been widely used in India.The herb has shown hypoglycaemic effect on alloxantreated rats [68]. It was found experimentally that the herbpossessed insulinotropic effect at 10 mins and 60 mins,thereby suggesting that the extract caused the release ofinsulin from the secretory as well as the reserve pool [68].Interestingly, the Enicostemma littorale Blume possiblyworks through activating another secondary messenger,which may be responsible for increasing the intracellularCa ions from another source and cause insulin2+

exocytosis [69].

Ginseng: Ginseng (Panax) is a plant from theAraliaceae family and it is widely used in Chinesemedicine. The usage of the herb is also gaining popularityall over the world. The active constituent of the herbs isginsenocide, a group of steroidal saponins. The extract ofthe herb acts on the intestinal absorption of glucose andregulates the secretion of insulin [70].

Panax ginseng CA Meyer has been used effectivelyas a supplement in many parts of Asia, over the last 2000years [71]. Fresh Ginseng is steamed and dried to yield thered ginseng. During such process, the ginsenocide issubjected to various chemical changes which result inimportant physiological properties [71]. Clinical trials have


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shown that ginseng induces a reduction in plasma -glucosidase inhibitory activity compared to that ofglucose as well as HbA1c levels in T2DM patients [72]. -amylase and this is the reason why the soyabeanTreatment with red ginseng improves insulin phenolic extracts are considered to be better than othersensitivity [71]. Research reports reveal that activation of anti-diabetic drugs available in the market with little or noadenosine monophosphate–activated protein kinase side effects [79].(AMPK) increases fatty acid oxidation and glucoseuptake by the skeletal muscles of the body [73]. The herb Kudzu Root: Kudzu root (Pueraria lobata) belonging toregulates the glucose metabolism by the above mentioned the family Fabaceae, has been traditionally used bypathway. Chinese population in Asia. It is also used in the United

Piper Sarmentosum (PS) and Piper Betle (PB): PS and root was included in the Japanese pharmacopoeia [80].PB belong to the Piperaceae family. The leaves are Puerarin, the major isoflavone isolated from kudzu root,chewed in many parts of Asia. Researches have shown has been reported to possess anti-that oral administration of PB for 30 days reduced the hypercholesterolaemic, anti-platelet, anti-inflammatory,blood glucose level, glycosylated haemoglobin and anti-arrhythmic, anti-oxidant, anti-ischaemic, anti-decreased the activities of liver glucose-6-phosphatase apoptotic, hypoglycaemic and neuro-protective propertiesand fructose-1,6-bisphosphatase [74]. The results of [81]. Puerarin can induce adipogenesis through PPARrprevious studies showed that PB is effective in pathway [81]. The pathological changes occurring as ainfluencing the glucose metabolism. result of DM was reversed by Kudzu root. Peroxisome

In our earlier studies, we documented the protective proliferator-activated receptor gamma (PPAR ) iseffect of PB on DM. The damage to the cardiac muscle responsible for regulating glucose homeostasis,and proximal aorta was reversed when the experimental adipocyte differentiation, lipid metabolism anddiabetic animals were treated with PS extract [75]. inflammation [82]. PPAR is a regulator of lipid

Goshajinkigan: Goshajinkigan (GJG) is a traditional herb insulin sensitive tissues [83].that has been widely used to treat diabetic neuropathy.Interestingly, research studies found that GJG was better Salacia: The Salacia (S) species which belongs to thethan mecobalamin in the treatment of diabetic neuropathy family Celastraceae and it is found in many parts of India,[76]. The GJG had a remarkable effect on the vibratory Sri Lanka and South-East Asia. The plant extract has beenthreshold. Thus, GJG improved the sense of vibration in used traditionally to treat gonnorhea, pruritus, rheumatismdiabetics. Few authors have opined that the GJG may act and asthma [84]. The extract was reported to enhanceto correct the abnormal steps of the insulin signal PPAR- -mediated lipogenic gene expression [PPAR-pathway in the skeletal muscle [77]. The same study mRNA and protein, carnitine palmitoyltransferase-1showed that decreased insulin receptor substrate-1 (CPT-1) [85]. According to previous research, Salacia has(IRS-1) protein content was significantly improved by PPAR-alpha activator, which provides a potentialtreatment with GJG [77]. mechanism for checking the postprandial hyperlipidemic

Soybeans (Glycine Max (L.) Merrill): Soybeans (Glycine and obesity [86].max (L.) Merrill) is one of the dietary legumes and formsthe major source of protein in the food. Soybean has been Green Tea: Green tea is made from the leaves of Camelliareported to act against cancer, osteoporosis and coronary sinensis. Green tea is a popular drink consumedheart disease [78]. Experiments showed that bound worldwide. Research studies have shown that green teaphenolic extract caused higher -amylase and ACE reduces the level of the blood glucose, improvesinhibition than the free phenolic extract [79]. It was sensitivity to insulin and enhances antioxidant defencesreported that inhibition of amylase by the soybean [87]. It was found that green tea reduced the collagenbound phenolic extract involves direct interaction with content in the tendon of the rat tail and also reduced thethe antioxidants with the disulfide bridges [79]. It was extent of advanced glycation and its end products (AGE)also found that free phenolic extract had a higher [87].

States of America and Australia. Interestingly, the Kudzu

metabolism and it can reduce lipid accumulation in various

state and hepatic steatosis, in conditions such as diabetes


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Gynura Procumbens: Gynura procumbens is a herb which Poria Cocos (Polyporaceae): P.cocos, a rotten treecontains flavonoids and alkaloids. Specifically, fungus has been commonly used in Chinese medicine.flavanoids and alkaloids are responsible for inhibition of According to research reports, dehydrotrametenolic acid,the -amylase and -glucosidase [88]. Synergistic effect one triterpene constituent of P. cocos, was reported toby all active constituents in the herb extracts is exhibit hyperglycemic effects in db/db mice [96].responsible for ACE inhibition [88]. Interestingly, researches also showed that

Aloe Arborescens: Aloe arborescens has been reported constituents present in the crude extract of P.cocos butto exhibit hypoglycaemic action. Aloe as dietary the glucose lowering effect of dehydrotrametenolic acidsupplements have been tried to treat DM [89]. and pachymic acid was more pronounced than theHistological findings also revealed that the extract was dehydrotumulosic acid [97].able to combat the pancreatic cell damage and inhibitintestinal glucose absorption [89]. CONCLUSION

Ginger: Ginger (Zingiber officinale Roscoe Type 1 DM is known to affect at least 10 millionZingiberaceae) is commonly used as a spice all over individuals worldwide. Insulin is the only reportedthe world. It is known for its anti-inflammatory and medication and the side effects are many. Over theantioxidant properties. Recent research studies had years the incidence of DM and its complications hasshown that ginger extract at a dose of 100- 800 been on the rise. Many herbal and vegetablemg/Kg, was able to reduce 24-53% of blood glucose products have been tried as effective supplements.in STZ-type 1 diabetic rat models [90]. Another All the actions of the herbal supplements can beresearch study showed that ginger was able to prevent better understood if the possible mechanisms arethe 5-Hydroxytryptamine (5 HT) induced acute defined clearly. There are not many documentedhyperglycemia by acting on the 5 HT receptors [91]. side effects for the majority of the herbal extractsBesides, there is evidence that ginger could influence the consumed. This is because of less side effects, easykey enzymes which control the carbohydrate metabolism availability, cost effectiveness and patient complianceand also increase insulin release/sensitivity which lead to factors. Further research is advised to gain newthe increase in glucose uptake by the peripheral fat insights into the herbal alternatives for DM. This wouldtissues and skeletal muscles [92]. In fact, the lipid reduce the sufferings of patients and ease the worldlowering property of ginger overall improves insulin economic burden caused by DM; one of the world’s mostresistance [92]. deadly diseases.

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