An Overview of Treatment Challenges and the role of Herbal Antioxidants in Diabetes Mellitus

 

Krishna Ravi¹, Rosmi Jose, Sumitha SK, Teena Johny, Krishnaveni K^2*,

Shanmuga Sundaram R³, Sambath Kumar R⁴

¹Post Graduate, J.K.K. Nattraja College of Pharmacy, Komarapalayam-638183, Tamil Nadu

²Assistant Professor, J.K.K. Nattraja College of Pharmacy, Komarapalayam-638183, Tamil Nadu

³Professor, J.K.K. Nattraja College of Pharmacy, Komarapalayam-638183, Tamil Nadu

^1,2Department of Pharmacy Practice, J.K.K. Nattraja College of Pharmacy, Komarapalayam-638183, Tamil Nadu

³Department of Pharmacology, J.K.K. Nattraja College of Pharmacy, Komarapalayam-638183, Tamil Nadu

⁴Department of Pharmaceutics, J.K.K. Nattraja College of Pharmacy, Komarapalayam-638183, Tamil Nadu

 

ABSTRACT:

WHO predicts that the diabetes mellitus (DM), a global health crisis, currently affects almost 300 million people worldwide. India is host to the largest diabetes population in the world, with an estimated 35 million people, accounting approximately about 10% of the adult population. Synthetic oral hypoglycemics used in the treatment of Type 2 DM have been reported to possess prominent side effects and fail to manage DM complications. Such challenges forms the basis for better treatment regimens and finding alternative therapies. Traditionally, DM is treated with diet, physical exercise and herbal remedies. Herbal drugs can be quite acceptable as these are believed to cause less adverse effects, more effective and cost less. In this review, we have focused on comparison of conventional antidiabetics with some of the herbal extracts shown to have both antioxidant and antidiabetic activity. Since one of the etiologic factors implicated in the development of DM and its complications is the damage induced by free radicals and, hence an antidiabetic compound with an excellent antioxidant property would be more beneficial. Further, plenty of research needs to be carried out to evaluate the possible mechanism of action of such herbs.

 

 

 

INTRODUCTION:

Diabetes mellitus (DM) is a complex chronic metabolic disorder that is a major source of ill health worldwide. It is characterized by hyperglycemia and disturbances of carbohydrate, protein and fat metabolisms, secondary to an absolute or relative lack of insulin hormone. ¹

 

The prevalence of diabetes has risen from 2.4% to 6.4% in the last 15 years.²Diabetes related deaths are more common in the low and middle-income countries where more than 80% deaths occur.³ The World Health Organization (WHO) projects that DM will be the 7th leading cause of death in 2030.⁴The cost of health care associated with diabetes continues to grow and is a huge economic burden for afflicted patients and countries.

 

It is a silent epidemic that directly affects glucose catabolism leading to energy yielding changes. The chronic effects include blindness (2%); visual handicap (10%); diabetic retinopathy and neuropathy; sensory loss and damage to limbs.⁵ In India, the difference in number of cases being affected in urban population with respect to rural is 8% because of changes in lifestyle and consumption patterns.⁶ Globally type I diabetes, an autoimmune disorder in which beta cells are not functional, affects 10% of diabetic population while 90% cases falls into category of type II wherein down regulation of receptors leads to insulin non-responsiveness.⁷ type II diabetes produces mild symptoms like fatigue, increased thirst and hunger, weight loss, blurred vision, frequent urination and slow healing of wounds or sores, and can be controlled with a healthy diet, exercise and weight loss. There are more than 1000 plants which are used in antidiabetic herbal formulations and among them about 100 plants have been scientifically validated.⁸

 

However, no single approved herbal drug is available till date for mass usage. It is essentially due to lack of standardization methodologies adopted prior to development of drug. The present review focuses on the herbal standardization models that can be useful for development of evidence based holistic natural plant products with a special case study on ‘management of diabetes’. It provides an in depth analysis of limitations of treatment methodologies; available herbal alternatives; contraindications vs. complications criterion and novel models for standardization of herbal drugs.

 

Oxidative stress is produced during normal metabolic process in the body as well as a variety of environmental factors and chemical substances. Oxidative stress has been shown to have a significant effect in the causation of diabetes mellitus as well as diabetes related completions in human beings.⁹ Oxidative stress in diabetes mellitus has been shown to coexist with a reduction in the antioxidant status and glycation of proteins, inactivation of enzymes, and alteration in structural functions of collagen basement membrane.¹⁰

 

Oxidative stress is reported to be increased in patients with diabetes mellitus.¹¹ Accumulating evidence suggests that oxidative cellular injury caused by free radicals contributes to the development of diabetes mellitus.¹² Reactive oxygen species generated in the cells are scavenged by antioxidant enzymes.¹³ Moreover, diabetes also induces changes in the tissue content and activity of the antioxidant enzymes.^14,15

 

In recent years, more interest has been paid to protect human beings against oxidative damage caused by free radicals which leads to ageing and human diseases like diabetes and cancer. One possible solution is to explore the potential antioxidant and anticancer properties of herbal or polyherbal extracts.¹⁶ Antioxidants, which can scavenge free radicals against damage and decay, have an important role in biological system and may be helpful in the prevention of cancer, diabetes mellitus and heart diseases.¹⁷Since long back plants are being used for treatment of different ailments including diabetes and other cardiovascular disease under traditional system. Very few of the antidiabetic herbals have received proper scientific or medicinal scrutiny recommendations by WHO. In developing countries, 70-95% of the population relies on herbal medicines for primary care mainly due to cost imperatives or unavailability of conventional drugs. In India, in spite of over 80% of the population dependent upon herbal drugs; it occupies less than 2.5% of the global market share.^18,19

 

Pathophysiology:

Increasing evidences have suggested that oxidative stress plays a major role in the pathogenesis of DM. Oxidative stress also appears to be the pathogenic factor in underlying diabetic complications. Reactive oxygen species (ROS) are generated by environmental factors, such as ionizing radiation and chemical carcinogens, and also by endogenous processes, including energy metabolism in mitochondria. ROS produced either endogenously or exogenously can attack lipids, proteins and nucleic acids simultaneously in living cells.

 

ROS are being reported to be formed in different tissues in diabetes by various sources such as the non-enzymatic glycosylation reaction, the electron transport chain in mitochondria and membrane-bound NADPH oxidase. ROS are also involved in the progression of insulin resistance as well as pancreatic β-cell dysfunction.^20-26Also, advanced glycation end products (AGEs) are produced by non-enzymatic glycosylation of proteins, which tends to mount up on long-lived molecules in tissues creating abnormalities in cell and tissue functions.^27,28 AGEs also play a role in improved vascular permeability in both micro- and macro-vascular structures by sticking to specific macrophage receptors, which leads to free radical production and endothelial dysfunction. AGEs, produced on nucleic acids, may also lead to altered gene expression and mutation.

 

There are many potential mechanisms whereby excess glucose metabolites travelling along these pathways might promote the development of DM complication and cause pancreatic β cell damage. However, all these pathways have in common the formation of ROS, which in excess and over time cause chronic oxidative stress, which in turn causes defective insulin gene expression and insulin secretion as well as increased apoptosis. Free radicals are proficient enough of damaging cellular molecules, proteins, lipids and DNA, leading to alternation of cell functions. In fact, the abnormalities in lipids and proteins are one of the key reasons for the development of diabetic complications.

 

Figure 1: Pathways for responses and signals during oxidative stress.²⁹

 

Table 1: Details about Antioxidant herbals used in DM

Sl.No	Scientific Name/Family	Local Name	Parts Used	Extraction	Constituents	Mechanism of action
1.	Acanthopanox senticosus (Araliaceae)	Ginseng	Whole Plant	Aqueous	Polysaccharide	Alloxan/polysaccharides of this plant decreased the blood glucose and it also increase the body weight, liver glycogen formation, and anti-oxidant enzyme (SOD and GPX) levels as compared with those of diabetic control group.
2.	Afzeliaafricana (Fabaceae)	African mahogany	Leaves	Alcoholic	Alkaloid, terpenoids, steroids, tannins and phenol	Improvement in glucose tolerance, restoration of liver glycogen and antioxidant activityto reduce the risk of secondary complication associated withdiabetes.
			Fruit	Methanol	Bioactive triterpenes such as oleanolic acid and ursolic acid. Bioactive phenolic acids, vitamin and flavonoids.	Inhibition of glucose transporter, α-glycosidase, α-amylase, lipase and strong antioxidant potential
3.	Allium cepa (Liliaceae)	Onion	Bulb	Aqueous	Protein, carbohydrate, vitamin A,B,C, allyl propyldisulphide	Allium cepahave antioxidant and hypolipidemic activity. Administration of a sulfur containing amino acid, S-methyl cysteine sulphoxide (SMCS) (200 mg/kg for 45 days) to alloxan induced diabetic rats significantly controlled bloodglucose as well as lipids in serum and tissues
4.	Phyllanthus emblica (Phyllanthaceae)	Amla	Fruit	Aqueous	Hydrolysable tannins possessing like vitamin C	The antioxidant activity of Amla extract is associated with the presence of hydrolyasable tannins possessing vitamin c can be concluded that Amla plays a role in reducing oxidative stress and improving glucose metabolism in type-2 diabetes
5.	Azadirachta indica (Meliaceae)	Neem	Whole parts	Aqueous, Alcohol	nimbin, nimbinin, nimbidinin, nimbolide, nimbilic acid. Gedunin obtained from neem’s seed. It also contain mahmoodin, Azadirachtin, some tannins like, Gallic acid, Margolonon and Polysaccharide	Azadirachta Indica extracts may actually help to repair or regenerate the pancreas's beta cells, which play a crucial role in the production and secretion of insulin
6.	Asystasia gangetica (Acanthaceae )	Chinese violet	Leaf extract	Ethanol	Flavanoids	Levels of the protective antioxidant enzymes like SOD, CAT and GSH were increased along with decrease in the LPO levels.
7.	Aegle marmelos (Rutaceae)	Wood Apple	Fruits and Leaves	Ethanol	Tannins, active principle (marmelosin), alkaloids (aegelin and aegelinin), coumarin (marmesin).	A. marmelos might be increase the release of insulin from the existing β –cells of pancreas.
8.	Basella rubra (Basellaceae)	Malabar spinach	Young seedlings Leaves and ground whole parts	Aqueous	Vitamin A and C, Calcium, Iron.	A significant decrease in blood sugar level and increased level of liver enzymatic (Super Oxide Dismutase (SOD), Catalase (CAT), Glutathione peroxidase (GPx)) and non enzymatic antioxidants (vitamin C, E and reduced glutathione). These results indicate that Basella rubra extract effectively reduced the oxidative stress and diabetic complications.
9.	Ocimum sanctum (Labiatae)	Tulasi	Leaves	Aqueous	V.oil, phenol, aldehyde, fixed oil, alkaloid, tannin, ascorbic acid	Reduces blood sugar level and have antioxidant activity. Presence of eugenol and fibre content leads to hypoglycaemic effect.
10.	Panax ginseng (Araliaceae)	Pannag	Root	Ethanol	Glycans, panaxans I, J, K and Lginsenosides.	Increases peroxisome proliferator-activated receptor gamma expression and adenosine monophosphate-activated protein kinase phosphorylation in liver and muscle.
11.	Allium sativum (Lilliaceae)	Garlic	Ripe bulbs	Aqueous	Allicin, Carbohydrates, Protein, Saponins, Phytic acid, Lipids.	S-allyl cystein sulfoxide (SACS), the precursor of Allicin and garlic oil, is a sulfur containing amino acid, which controlled lipid peroxidation. It also exhibits antimicrobial anticancer and cardioprotective activities.
12.	Musa sapientum (Musaceae)	Banana	Seed, Fruit, leaves	Methanol	Carbohydrate Proteins, Calcium, Sodium, Iron,	It seems possible that the anti-diabetic properties in the leaf extract of Musa sapientum and its fractions maybe due to the inhibition of α-amylase, increased storage of glucose as glycogen in the liver and/or reduced breakdown of liver glycogen stores
13.	Mangifera indica (Anacardiaceae)	Mango	Leaves, Seed kernel.	Aqueous	Mangiferin, vitamins (A,B6, C, D, E and K), carotenoids, essential elements (K and Cu) and amino acids. Peel and pulp contain antioxidants, carotenoids, polyphenols, omega-3 and omega-6 polyunsaturated fatty acids, provitaminA, carotene lutein, polyphenols (quercetin, kaempferol, gallic acid, caffeic acid, catechins, and tannins), which counteract free radicals in various disease.	Reduction of intestinal absorption of glucose. A significant decline in free radical generation, thus showing normalized SOD, GSH and lipid peroxidation levels depending on administration duration.

 

Table 2: Conventional oral hypoglycemics currently in use.

Medications	Mechanism of action	Side Effects	Contraindications
Sulfonylureas Glyburide (Diabeta) Chlorpropamide (Diabinase)	Stimulate release of endogenous insulin	Hypoglycemia Nausea GI discomfort	Hepatic or renal Impairment
Meglitinides Repaglinide (Gluconorm)	Stimulate release of endogenous insulin (rapid acting, better post-prandial glucose control)	Hypoglycemia (less frequent than with sulfonylureas)	Hypersensitivity, Diabetic acidosis (DKA)
Biguanides Metformin (Glucophage)	Reduce gluconeogenesis, increase glucose utilization	Lactic acidosis, anorexia, nausea, diarrhoea, GI discomfort	Hepatic or renal impairment, alcoholism,    advanced age
Thiazolidinedioes Rosiglitazone (Avandia) Pioglitazone (Actos)	Increase peripheral insulin sensitivity, reduce gluconeogenesis	Increased TG, weight gain, hepatotoxicity, anaemia	Liver disease, congestive heart failure (CHF)
Glucosidase Inhibitors Acarbose (Prandase)	Decrease the absorption of carbohydrates (thus decreasing postprandial rise of glucose)	Flatulence, abnormal cramping, diarrhoea	Hypersensitivity, DKA, inflammatory bowel disease (IBD)

 

CONCLUSION:

The mission of the WHO Diabetes Programme is to prevent diabetes whenever possible and, where not possible, to minimize complications and maximize quality of life. Our core functions are to set norms and standards, promote surveillance, encourage prevention, raise awareness and strengthen prevention and control.

The review establish the use of plants, plant parts or extract in curing DM. Scientific evidence reveals that antioxidant property of herbal drugs reduce the risk of DM. It may be difficult to find the exact mechanism and active components responsible for the hypoglycemic effect.

 

CONFLICT OF INTEREST:

Authors declare no conflict of interest.

 

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Accepted on 30.06.2017           © RJPT All right reserved