Nanotechnological approaches in diabetes treatment: A new horizon

Abstract

Diabetes is a chronic metabolic disorder that affects millions of people worldwide and takes a heavy toll on human life. Treatment of diabetics often poses a problem in selection of the proper drug, its dose and unwanted side effects. Therefore, newer drugs with the least side effects but with highest efficiency are being relentlessly searched for. In recent years, nanotechnology has given new hope for the formulation of various drugs against a myriad of diseases, including diabetes. This review tries to give an overview of the advantages of various new drugs being used, including a wide range of nanoformulations of orthodox as well complementary and alternative medicines. Several studies and research reports based on nanotechnological approaches in the formulation of anti-diabetic drugs have pointed out the fact that research in the formulation of nanodrugs improved strategies for combating diabetes based on the plausible molecular mechanism of action of the drugs. Furthermore, attempts have also been made to delineate the optimum drug concentration and time of exposure in order to recommend a scientifically validated drug dose response in developing different therapeutic strategies. Thus, to a considerable extent, recent studies have contributed towards improving the life expectancy and quality of life of diabetics, through both targeted orthodox medicine and complementary medicine, particularly those obtained from natural resources.

Key Words: Diabetes; Complementary and orthodox medicine(s); Orthodox anti-diabetic medicines; Nanotechnology and nanomedicine; Nanoformulation

Core tip: This review on diabetes aims to provide information available on research carried out on both traditional and modern medicine practices, highlighting some recent ones including use of nanomedicines that would hopefully be able to give patients a better quality of longer life. This review also focuses on some unresolved issues and concerns about the benefits of using plant products and nanoformulations in reducing side effects and provides convincing evidence of their ameliorative properties.

INTRODUCTION

The onset of diabetes mellitus (DM) is marked initially by an impaired glucose tolerance that sometimes can produce severe symptoms needing immediate medical attention. Diabetes is mainly caused by dysfunction of the β cells of the pancreas. This in turn leads to decreased production of the hormone insulin and/or increased resistance to the action of insulin in the peripheral tissues[1].

Diabetes can be categorized into two types: type 1 and type 2. Type 1 diabetes, or juvenile-onset diabetes, develops when the body’s errant immune system attacks itself and damages and destroys the pancreatic β cells that produce the blood glucose regulating hormone insulin. To survive, people with type 1 diabetes must have an exogenous delivery of insulin hormone. This form of diabetes usually strikes children and young adults, although the onset of the disease may occur at any age[2]. In adults, type 1 diabetes accounts for about 5% of all diagnosed cases of diabetes. Risk factors for type 1 diabetes may be autoimmune, genetic or environmental. No known way to prevent type 1 diabetes exists. Several clinical trials for preventing type 1 diabetes are currently in progress or being planned[3].

Type 2 diabetes (non-insulin-dependent diabetes mellitus; NIDDM) or adult-onset diabetes usually begins as an initial phase of progressive insulin resistance/insensitiveness, with an ensuing reduction in the ability of the pancreatic hormone to promote peripheral glucose disposal and to suppress hepatic glucose output[4]. To compensate, the pancreas pumps out increasing amounts of insulin to normalize blood glucose levels. Over time, as long as a decade, this ever increasing production becomes unsustainable and the pancreas’ ability to produce insulin declines. As a result, the blood glucose level rises and, because it is unable to enter the body’s cells, it begins to appear in the urine and causes increased urination. Established risk factors for type 2 diabetes include older age, obesity, physical inactivity, stress, family history and genetic polymorphism[5]. Type 2 DM patients need to follow a diet and exercise program to control their blood glucose levels. If this first line treatment does not control blood sugar levels effectively, an oral medication can be added to the treatment plan. In certain circumstances, patients with type 2 diabetes may also need insulin injections. Many patients also need to control their blood pressure and cholesterol levels. Type 2 diabetes accounts for about 90% to 95% of all diagnosed cases of diabetes. African Americans, Hispanic/Latino Americans, American Indians and some Asian Americans are at particularly high risk for type 2 diabetes, along with its complications, and are also being diagnosed, although still rare, as children and adolescents[3].

Gestational diabetes is a form of glucose intolerance diagnosed during pregnancy, is more common among obese women and women with a family history of diabetes, and requires treatment to optimize maternal blood glucose levels to lessen the risk of complications in the infant[6,7]. Other types of diabetes result from specific genetic conditions, such as maturity-onset diabetes of youth, surgery, medications, infections, pancreatic disease and other illnesses. Such types of diabetes account for 1% to 5% of all diagnosed cases.

The present review is based on several studies and research reports on possible side effects emanating from the use of orthodox medicines that justifies the search for measures to eliminate these unwanted toxic effects. These efforts have culminated in the experimental approach towards formulation and use of nanotechnologically synthesized anti-diabetic drugs and evaluation of their adaptability and acceptability in the medical fraternity. To achieve this goal, a primary extensive literature search was made and all information related to this research area was procured through search engines like SCOPUS, PUBMED, MEDLINE, GOOGLE, etc., with proper key words. Relevant information from the year 1973 through 2013 in the area of nanotechnology based design on anti-diabetic drugs were covered and incorporated briefly in this review.

Tables are provided which include some prominent study reports highlighting the bioactive constituents/major bioactive compounds found in potent anti-diabetic phytomedicines (CAMs) which could potentially be used for nanoformulations of anti-diabetic drugs in future. As this is a review work, raw data could not be provided from the original papers as such, but the source from where original data can be procured from the actual papers has been cited. This review has been divided into several subheadings for discussion of certain important aspects for ease of the readers.

ORTHODOX MEDICINAL REGIMEN

The first line treatment for diabetes is usually diet and exercise and sometimes these measures alone are sufficient to bring blood glucose levels back to the normal range. If these measures do not effectively control blood glucose levels, one or a combination of medications may be necessary to control hyperglycemia. The medications for diabetes are from various classes; each class contains one or more specific drugs. Some of these drugs are taken orally and others must be injected. Various diabetes drugs work in different ways to lower blood sugar. A drug may work by: (1) stimulating the pancreas to produce and release more insulin; (2) inhibiting the production and release of glucose from the liver; or (3) blocking the action of gastric enzymes for carbohydrate catabolism or making tissues more sensitive to insulin.

MOST FREQUENTLY USED ANTI-DIABETIC DRUGS

Several anti-diabetic drugs are being used but they often have side effects (Figure 1[8-16]). The side effects of these drugs often preclude their use in many diabetic patients with an extremely high blood glucose level.

Figure 1 Frequently used anti-diabetic drugs and their side effects.

Insulin: The most prominent biological molecule associated with diabetes

Insulin is one such therapeutic agent that is extensively used for the treatment of both type 1 and type 2 diabetes patients.

Physiologically, insulin hormone is secreted by the islet β cells of the pancreas to lower blood glucose by stimulating the uptake of glucose into skeletal muscle and fat balance, thereby regulating the blood glucose level. Insulin resistance can result from mutations or post-translational modifications of the insulin receptor or insulin peptide itself or any of its downstream effector molecules[17]. Preproinsulin, the initial precursor of insulin, at the time of its synthesis generally gets cleaved at the posttranslational process to form proinsulin which further cleaves to form insulin. Therefore, even a mild depletion in the level of secretion of insulin or mutation in the insulin molecule or its receptor system leads to the initiation and progression of hyperglycemia. Exogenous supplemental insulin administration thus is one of the therapeutic remedies for diabetes. Insulin is classified according to how it works in the body: (1) depending on the time of onset, that is, how soon it starts working; (2) depending on the peak, that is, when it is working most effectively; and (3) depending on the duration, that is, how long it lasts in the body. For example, insulin glargine (http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0010728/) and insulin detemir (http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0000962/) are examples of long acting insulin that works slowly over a period of about 24 h. On the other hand, insulin lispro (http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0000957/), marketed by Eli Lilly and Company as “Humalog”, is a fast acting insulin analogue. It was first approved for use in the United States in 1996, making it the first insulin analogue to enter the market. A literature survey also suggests that insulin aspart protamine and insulin aspart are combinations of fast-acting insulin and an intermediate-acting type of human insulin (http://en.wikipedia.org/wiki/Insulin_aspart). Diagrammatic representation of the insulin activity profile is shown in Figure 2.

Figure 2 Diagrammatic representation of insulin activity profile.

Biosynthetic “human” insulin is now manufactured for widespread clinical use exploring genetic engineering techniques and using recombinant DNA technology, which the manufacturers claim reduces the presence of many impurities. Eli Lilly marketed the first such insulin, Humulin, in 1982. Humulin was the first medication produced using modern genetic engineering techniques in which actual human DNA is inserted into a host cell (E. coli in this case). The host cells are then allowed to grow and reproduce normally and, due to the inserted human DNA, they produce a synthetic version of human insulin.

Problems in using insulin

In spite of the extensive use of artificial insulin, several problems gradually develop with insulin as a long-term clinical treatment for diabetes. These may be the mode of administration, selecting the “right” dose and timing, selecting an appropriate insulin preparation (typically on “speed of onset and duration of action” grounds), adjusting dosage and timing to fit food intake, amounts and types, adjusting dosage and timing to fit exercise undertaken, for instance during the increased stress of illness, variability in absorption into the bloodstream via subcutaneous delivery, etc. In fact, the dosage is non-physiological in that a subcutaneous bolus dose of insulin alone is administered instead of a combination of insulin and C-peptide being released gradually and directly into the portal vein. It is simply a nuisance for patients to inject whenever they eat carbohydrate or have a high blood glucose reading. Furthermore, it is dangerous in the case of a mistake, most especially injecting an increased dosage of insulin causing hypoglycemia, which causes a dangerous fall in blood glucose level, even threatening life.

The most common modes of application of exogenous insulin are subcutaneous injection and an insulin pump. More recently, various other modes of insulin administration include inhalation (Food and Drug Administration approved the use of Exubera, the first inhalable insulin), transdermal and intranasal (Nasulin). Oral insulin capsules have even been formulated in recent years by a biotechnology company (Oramed Pharmaceuticals Inc., Kafer Hi-Tech, based in Jerusalem, Israel), which is currently conducting Phase 2B clinical trials of its oral insulin capsule, ORMD-0801, on 30 patients diagnosed with type 2 diabetes. The technology is based on two components: (1) a chemical make-up that protects insulin during passage through the gastrointestinal tract; and (2) absorption enhancers so that insulin could be absorbed by the intestine.

A combination therapy of insulin and other anti-diabetic drugs appears to be most beneficial in diabetic patients who still have a residual insulin secretory capacity. A combination of insulin therapy and sulphonylurea is more effective than insulin alone in treating patients with type 2 diabetes after secondary failure of oral drugs, leading to better glucose profiles and/or decreased insulin needs. The mechanisms by which insulin-sulfonylurea therapy improves glycemic regulation and decreases insulin requirements involve an increase in endogenous insulin secretion and possibly some extra-pancreatic actions of the sulfonylureas on muscle and liver[18]. However, this combination is not widely used now for curing diabetic patients.

Use of complementary and alternative medicines in diabetes therapy

In view of undesirable side effects of orthodox therapies, a search is on to find ways to avoid some of these by using drugs that are equally effective but with no or little side effects. The results of the preclinical study could prove useful for phase 2 clinical trials in which the morbidity and mortality of DM complicated by the side effects of drug-induced hypoglycemia may be reduced by the practice of integrated medicine (CAM). Several compounds that constitute the major sources of chemical diversity, in a purified or structurally identified form with biological activities, are broadly defined as “natural products”. The products derived from these natural sources, e.g., plants, animals and microorganisms, are often used in crude therapeutic formulations and serve the regimen of CAM[19,20].

There is growing awareness of the role and practice of integrated medicine in the field of metabolic disorders, particularly in oncology[21-25] and diabetes[26-33], to give patients a better quality of life by alleviating some of their sufferings. This is based in part on a flood of reported scientific data about medicinal plants, including those with anti-diabetic potential, and partly on the support provided for its practice by governmental agencies and the WHO. Several ethanolic plant extracts are now used in Ayurvedic or homeopathic formulations. The principal difference between these two modes of treatment lies primarily in the use of a lesser amount of drug in the case of homeopathy. The use of plant extract as an ingredient or component among a mixture of several other substances with medicinal properties is well accepted, even by the orthodox mode of treatment (allopathy) and also in other CAM modes. Several CAMs could interact with a wide variety of proteins and other biological targets for specific purposes, i.e., they bind to a variety of protein domains and folding motifs that lead to modulating or inhibiting protein-protein interaction, thereby making these molecules behave as effective modulators of cellular processes such as immune responses, signal transduction, mitosis, apoptosis, inhibitors of apoptosis and potential anti-oxidants[34,35]. Some of the phytochemicals have already been established as mainstream drug(s) with identified and characterized chemical ingredients for marked public use now to combat diabetes and its complications. They share high chemical diversity, biochemical specificity, molecular mass, number of chiral centers, molecular flexibility and distribution of heavy metals suitable for therapeutic applications[36]. A list of such phytochemicals with identified biological active components is given in Table 1[37-66]. In addition to several mechanisms to ameliorate diabetic complications, these phytochemicals also render potential antioxidant activities which impart an extra advantage to their diabetes attenuative properties, like increasing insulin secretion, insulin receptors in RBCs, repair and regeneration of pancreatic islets, increasing glycogen synthesis, regulating action of insulin signaling proteins, etc.[33,40,42,45,54,55,65]. The therapeutic potentials and efficiency of biologically active molecules are essentially dependent on the identification of their bio-target and active sites. Interestingly, some of the phytomedicines have been found to interact with double-stranded DNA, which provides us with useful information concerning the drug-nucleotide interaction; this would bear testimony to the fact that the DNA acts as the molecular target of those drugs[33,67,68]. However, one important question remains about the exactness of the dose of a few herbal formulations and the exact and optimum drug doses to be administered during different forms of diabetes which still need to be validated, calling for further research.

Table 1 Bio-active constituents/ major bioactive compounds found in potent anti-diabetic phytomedicines.

CAMs	Bioactive ingredient(s)	Functions	Ref.
Ficus carica, Ficus religiosa	Ficain, Sitosterol-d-glucoside leucocyandin 3-O-beta-d-galactosyl cellobioside, leucopelargonidin-3-O-alpha-L rhamnoside	Protease enzyme antioxidant	http://www.ficain.com/ Bnouham et al[37], Ayodhya et al[38]
Nigella sativa	Thymoquinone	Reduces appetite, glucose absorption, hepatic gluconeogenesis, cholesterol, triglycerides, body weight, simulates glucose induced secretion of insulin	Mathur et al[39]
Trigonella foenum-graecum	Fenugreekine, 4- hydroxyisoleucine, galactomannan	Liver detoxifier, increase insulin receptors in RBC, improve glucose utilization in peripheral tissues, stimulate insulin secretion	http://diabetes-drugsandcure.blogspot.in/2013/03/fenugreek-for-diabetes_13.html, Madar et al[40]
Cinnamomum cassia, Cinnamomum zeylanicum	Cinnamaldehyde, methylhydroxy chalcone polymer	Lower blood glucose, triglyceride, cholesterol, elevate plasma insulin	Jarvill-Taylor et al[41]
Euonymus alatus Kalanchoe pinnata, Eucommia utmoides	Quercetine	Stimulate insulin for glucose uptake, regeneration of pancreatic islet	Fang et al[42]
Gynura procumbens, Euonymus alatus	Kaemferol	Hypoglycemic effect	Fang et al[42]
Ecklonia cava	Dieckol	Inhibitor for α-glucosidase and α-amylase	Lee et al[43]
Tinospora cispa	Apigenin	Increase plasma insulin level	Noor[44]
Bumelia sartorum	Bassic acid	Increase insulin secretion and glycogen synthesis	Kerry et al[45]
Gymnema sylvestre	Gymnemic acid	Increase generation of β-cells	Ahmed et al[46]
Olea europaea	Hydroxytyrosol, oleuropein	Anti-oxidant, slow digestion and absorption	Al-Azzawie et al[47], Jemai et al[48]
Momordica, Charantia	Momordins, oleanolic acid, glycosides	Prevent absorption of sugar	Mitra[49]
Panax ginseng	Ginsenoside 20(S)-Rg(3)	Anti-oxidant, lowers triglycerides and cholesterol	Kang et al[50]
Syzygium jambolanum	Morroniside	Anti-oxidant, regeneration of β cells, drug-DNA interaction, regulates signal proteins	Samadder et al[33]
Eugenia jambolana	1-0-galloyl castalagin, casuarinin, alkaloid jambosine, glycoside jamboline, quercetin, betulinic acid, b- sitosterol, eugenin, ellagic, gallic acid, bergenin	Slow down diastatic conversion of starch into sugar, increase insulin secretion, inhibit insulin depletion	Ayyanar[51], Morton[52]
Pterocarpus marsupium	(−)Epicatechin	Enhance insulin release and conversion of proinsulin to insulin, strengthen and activate insulin signaling proteins, regulates glucose production through AKT and AMPK modulation	Ahmad et al[53], Rizvi et al[54], Cordero-Herrera et al[55]
Allium sativum	Allicin, n- acetylcysteine, Acetylcysteine	Antioxidant, enhance serum insulin by combining with cysteine and sparing it from SH group reactions	Mathew et al[56], Jain et al[57]
Cassia fistule	Catechin	Glucose oxidizing and insulin mimetic activities	Daisy et al[58], Kamiyama et al[59]
Curcuma longa	Curcumin	Prevention and treatment of diabetic encephalopathy	Kuhad et al[60]
Leandra lacunosa	Ursolic acid	Inhibit blood glucose level	Cunha et al[61]
Hemionitis arifolia	Coumarin	Stimulate β-cells to secrete insulin	Nair et al[62], da Cunha et al[63]
Ajuga iva	Naringenin	Anti-oxidant, reduce lipid peroxidation	Taleb-Senouci et al[64]
Anoectochilus roxburghii	Kinsenoside	Repair β-cell in pancreatic islet injury	Li et al[65]
Coprinus comatus	Comatin	Maintain low level of glucose, improve glucose tolerance	Ding et al[66]

CAMs: Compounds found in potent anti-diabetic phytomedicines.

Nanotechnology: A new platform for formulating anti-diabetic drugs

Keeping pace with the discovery of modern nanosciences, where improved and advanced drugs are being tested on biological systems, it has become necessary to seek an outlook at designing a more cell/tissue specific drug with better efficacy in a minimum dosage. Recently, considerable progress has been made in developing biodegradable nanoparticles as effective vehicles for the delivery of proteins and peptides[69]. These polymer drug delivery systems offer many advantages as they can carry and deliver the drug to a target site, have the ability to deliver proteins, peptides and genes, increase the therapeutic benefits and minimize the side effects of the drug[70,71]. The poly (lactide-co-glycolide) polymers (PLGA), being biocompatible, have been used as controlled release delivery systems for parenteral and implantable applications[72]. A successful PLGA nanoparticulate system, as shown in Figure 3, has a high drug loading capacity as it allows a small quantity of the carrier during a single administration. This approach of PLGA encapsulation has been used to encapsulate a wide variety of hydrophobic drugs, including natural products curcumin[73,74], coumarin[75-77], plant extracts used as homeopathic mother tinctures[25,78,79], coenzyme Q10[80], estradiol[81], protein[82,83] and others. A brief step wise procedure of PLGA encapsulation of any drug is demonstrated in Figure 1. PLGA, a biodegradable polymer, is approved for human use by the United States Food and Drug Administration and the polymer readily decomposes without any induction of inflammation or immune reactions[84]. Nanoparticles made of PLGA conjugated with glyco-heptapeptides was also shown to cross the blood brain barrier (BBB) after in vivo administration[76,82,85].

Figure 3 Steps involved during the formulation of [poly (lactide-co-glycolide)] polymers encapsulated nanoparticles. PLGA: [Poly (lactide-co-glycolide)] polymers.

Beneficial role of nano insulin in diabetes therapy

Insulin is the most effective drug in the treatment of advanced stage diabetes. Despite the significant advancement in the field of pharmaceutical research, development of a proper insulin delivery system remains a challenge[86].

In this respect, biodegradable nanoparticulate delivery systems have been proposed for the safe and controlled parenteral administration of peptides[87]. The biodegradable and biocompatible PLGA polymers possess various unique properties for the design of a sustained release drug delivery application[88-90].

Formulations of PLGA encapsulated micro and/or nano insulin (Table 1) have been tested in recent years using various stabilizers via several administered routes of entry[82,83]. Overall results of these studies open up the possibility of using nano insulin as an effective new anti-diabetic strategy that may target any of the several mechanisms that are involved in the development of diabetes; these may be done by adopting the proper correctional measures to bring the regulatory events back to the right track. The major targets of nano insulin are mainly focussed on the various glucose transporters (GLUTs) present in the pancreas, muscle, brain, etc., which are primarily involved in the influx of glucose into several organs to maintain glucose homeostasis in the body. Samadder et al[82,83] observed that nano insulin could modulate expression levels of several GLUTs better than that by unencapsulated insulin in a diabetic condition and could bring their expression level near to normal values. Even the mitochondrial signaling pathway that is normally affected in diabetic conditions could be favorably affected by the administration of nano insulin compared to that by the unencapsulated insulin. However, more work on other animal models is needed prior to conducting pre-clinical human trials for evaluating its actual efficacy and beneficial use in diabetic patients.

The need for an increasing dose of insulin administration is frequently observed with the lapse of time and progress of the disease for effective control. Increase in dose also increases the risk of developing hypoglycemia suddenly. Therefore, the dose of insulin is often a great concern in effective management of the disease. One of the primary goals of using nano insulin is to reduce the dose of insulin and help in suspended release of insulin from its nanocapsule to make the best use of its optimum efficacy. A suspended release of insulin was observed in diabetic mice when this nano insulin was subjected to i.p injection. Moreover, it was possible to obtain similar results at a dose of nano insulin several folds (10 fold or so) less than that of the unencapsulated form of insulin, as reported by Samadder et al[82,83] in experimental diabetic mice. Thus, in certain arsenic contaminated areas where diabetes predominantly occurs at a large scale, nano insulin may be found to be particularly helpful in reducing the cost and for better management of the disease. Furthermore, a non toxic PLGA coating more readily degrades and increases the bioavailability to a great extent and can prove to be an effective agent of targeted drug delivery with the desirable suspended release.

PLGA is composed of biodegradable, biocompatible and non-toxic polymers and has satisfactory nanoencapsulation potentials with smaller size and uniform spatial planar frequency, giving it the ability to enter cells and act faster, and provides an alternative approach for encapsulation of insulin for an optimized cost-effective use in the control of diabetes because the quantity of the drug entering the body is reduced[82,83]. Nanoparticles possess the potential to modulate several biomarkers by different amounts, depending on their amount taken for the encapsulation (20 mg insulin in this case) and the final yield after formulations of the encapsulated form (approximately 200 mg nano insulin). Hence, the actual amount of the original drug substance in PLGA-encapsulated nano insulin is minimized by about 10-fold (approximately in this case) but nonetheless provides similar efficacy as that of their unencapsulated counterpart[82,83].

Several other formulations of insulin nanoparticles were also administered to check if they can render protection to the drug carried through gastric acid and if they are able to get through the intestinal wall to enter into the liver and ultimately to the bloodstream[91,92].

Transdermal delivery of nano insulin is also an attractive alternative therapy as it can control release of the drug and avoid possible drug degradation resulting from gastrointestinal tract (GIT) of first-pass liver effects. Although the mechanisms of action of PLGA encapsulated nano insulin in several forms of diabetes are not known and still need proper investigation, some Indian researchers believe that people with diabetes may soon take a pill of insulin-loaded nanoparticles instead of having to give themselves painful injections[92]. The pills, coated with tiny nanoparticles, protect insulin as it enters the stomach and keep blood sugar levels stable for 10 h. The minute nanoparticles are smaller than 100 nanometres across, attract water on the inside and are water-repelling on the outside. When they reach the bloodstream, they break down in response to the pH of blood and then release the insulin. The animal experiments demonstrated that the nanoparticles enter the bloodstream and end up in organs such as the liver and kidney. In diabetic pigs, the pill containing the nanoparticles led to control of blood glucose after eating[67]. The size and distribution profile of the nanoparticles, smaller than 100 nanometers, has been characterized by the use of atomic force microscopy and dynamic light scattering. Some experts opine that while the research is promising, it will be some time before such a pill can be tried on humans (Available from: URL: http://www.news-medical.net/news/2009/01/27/45264.aspx).

The latest advance in this field of research is the nano insulin pump. A small capsule the size of a tiny silicon chip containing pancreatic cells has been created for this purpose. It has micro pores which allow the squamous red blood cells and other small molecules in and out of the capsule. It restricts larger cells such as phagocytes, antibodies and other immunoresponsive cells and proteins to enter; hence, it keeps the pancreatic cells inside safe from danger but also provides nutrients and allows them to release insulin according to the amount of glucose in the blood at that particular moment. The tiny pump needs to be mounted on a disposable skin patch or underneath the skin to provide continuous insulin infusion to diabetic patients. This new technology will help diabetics so that they can be completely free from dietary regulations and the restrictive systematic regime. They will no longer be dependent on insulin injections and their blood glucose levels will be adjusted according to their glucose level at that moment of time. This would enable them to lead a normal life. The benefits would be especially useful for the young who are always active, allowing them to feel like a person without diabetes. The unhappiness diabetics feel with fluctuating weight gain, especially during teenage years, would be diminished and help them feel more mentally secure and confident amongst their peers.

Use of nanoencapsulated CAM medicines in diabetes treatment

In addition to the wide therapeutic arsenals of modern medicine in combating diabetes, it is necessary to develop a traditionally adapted but more advanced complementary and alternative drug formulation to treat several symptoms of diabetes and its complications[2] in order to improve the validation and dose selection strategies of several phytochemicals which are already in use. There are several drugs of plant origin containing substantial amounts of alkaloids, glycosides and flavonoids with strong antioxidant properties for the treatment of diabetes which are described in ancient literature. However, these drugs prove to be mostly effective in long-term treatment and so often lose their importance when compared to the faster onset of action of orthodox medicines. Therefore, efforts are needed to enhance their action and increase their bioavailability to targeted organs/organ systems.

Among the wide range of alternative therapies that manifest potential anti-diabetic properties, PLGA nanoencapsulated forms of Syzygium jambolanum[93] (SJ) and Gymnema sylvestre[94] (GS) have been tested and shown to have relatively more anti-hyperglycemic effects than their unencapsulated counterparts in various experimental models.

Ravichandran[94] reported that gymnemic acids, the main phytoconstituents of GS, possess potential natural pharmacological activities like suppression of taste sensitivity to sweetness, inhibition of intestinal glucose absorption and lowering plasma glucose levels. Nanonization of active drug components are shown to improve their physiological action. In this study, nanoparticulate formulations of gymnemic acids were studied for their pharmacokinetic and pharmacodynamic behaviors compared with that of some marketed products. The nanoformulation exhibited significantly enhanced anti-diabetic activity compared to marketed products[94].

Although the study on nano-GS was only undertaken on a “glucose level” content parameter, another study conducted by our own group, Samadder et al[93], conducted both in vitro (in L6 cells) and in vivo (in mice) experiments to assess the relative efficacy of nano SJ against its unencapsulated counterpart. The physicochemical characterization of the formulated nano-SJ was undertaken by several standard protocols. Bio-markers and signal proteins associated with stress and hyperglycemia were also critically analyzed to determine the relative efficacy of nano-SJ against SJ. Nano-SJ was also found to have localized in the brain tissue of mice, suggesting that it could efficiently cross the blood brain barrier. Brain, specially the hypothalamic region, has been proposed to be the glucose sensor region which plays a critical role in initiating the counter regulatory response to glucose homeostasis. Transport of glucose across the brain capillary and into neurons in this region is mediated by a different glucose transporter (GLUT) gene family. BBB participates in brain sensing of blood glucose concentration. Under normal physiological conditions, glucose is the major metabolic fuel in the brain and therefore adequate insulin mediated glucose supply is essential for the maintenance of cerebral energy production[95]. The ability of nano-SJ to cross the BBB therefore has great implications in terms of its potentiality to maintain insulin supply leading to optimum glucose homeostasis. Therefore, the overall results suggest that nano-SJ had a greater potential than that of SJ, indicating the possibility of using NSJ in the future drug design and management of hyperglycemia and stress.

Can nanotechnology bring relief to diabetics?

Several instances of earlier studies reported many possibilities of nanotechnology to implement new ways of treating diabetes. As the world population increases, greater resources are needed to sustain society. An alternative to this issue is to be highly efficient and this could be achieved through nanotechnology. With this new technology, diabetics may become completely free from dietary regulations and the restrictive systematic regime. Some devices are so adjustable that diabetics will no longer be dependent on insulin injections and their blood glucose levels will be adjusted according to their glucose level at that moment in time. This would enable them to lead a normal life, especially the young who are always active. It helps the patient to feel more mentally secure/better and confident, as well as being cost-effective in other aspects as it requires fewer resources with a much more effective outcome. Efficiency is essential as the world population increases and therefore economical efficiency is the most stable way of supporting the billions of patients with diabetes.

Nanotechnology: Scope of future research

A survey of the literature suggests that a lot of work has been undertaken to establish the anti-diabetic potentials of several drugs, ranging from traditional (homeopathy and Ayurvedic) to formulated nanomedicines, but the field of nanotechnology or nanomedicine needs special attention. In this context, there is an open area of research to establish standard nanodrugs, explore more advanced insulin therapy, their nanoformulations, delivery and the pathway through which they act. Finding the truth of which drugs are really capable of bringing about corrective modulations of some parameters (maybe genes) and are scientifically acceptable with protocols/methodologies adopted that can be repeated by others is absolutely necessary. Exploring this area of research will not only bring a new dimension in the regimen of treatment to diabetic patients, but could also be a step forward towards building a platform for development of newer scientifically tested drugs by following an advanced procedure of drug designing.

The discovery and development of potent anti-diabetic drugs has been greatly hampered due to a lack of a suitable preclinical model with respect to the optimum dose of the drugs to check the efficacy of candidate agents. To bridge the gap, these drugs should include the realm of natural products, i.e., CAM, but at the same time should be target-specific in action and utilize the different aspects of nanotechnology. The use of CAM drugs in nanoformulations would not only be biodegradable, biocompatible and non-toxic polymers in nature, but also would have a greater ability to enter cells and have a faster action, thereby providing an alternative approach for an optimized cost-effective use of the original drug substances in much reduced (several fold) quantity and entering the body in nanoforms. If the testing in animal models of these drugs is successful, their true potential should then be explored in higher hierarchical animal orders. Finally, a better understanding of the plausible mechanism of the drugs and a proper scientific validation of the drug dose response should be engineered in the highest animal model, a human trial, while developing different therapeutic strategies. Hopefully, research in these directions can achieve the goal of improving the life expectancy and the quality of life of diabetics in the future.

CONCLUSION

In recent years, research on the formulation of advanced organ/tissue/cell-specific drugs that aim to enhance bioavailability of drugs to target organisms or organ systems with better efficacy at a minimum dosage is a top priority area. In this context, nanoencapsulated drugs appear to have greater advantages due to their: (1) small size; (2) more rapid entry into target cells; (3) biodegradable nature; (4) ability to render greater bioavailability of the drug; (5) lesser amount of drug requirement; and (6) ability to cross the BBB. Hopefully, further in-depth research in this direction can pave the way for the discovery of newer drugs that are more precise and organ/tissue-specific in nature from the plant kingdom by utilizing nanotechnology.