Diabetes Anhang

http://ir.dut.ac.za/bitstream/handle/10321/1534/MALAPERUMAL_2016.pdf?sequence=1&isAllowed=y

[Veshara Malapermal]

Biosynthesis of bimetallic Au-Ag nanoparticles using Ocimum basilicum (L.) with antidiabetic and antimicrobial properties

1.2.1

Characterisation of diabetes mellitus

Diabetes is one of the most common metabolic disorders worldwide (Wild et al.2004), characterised by a loss of glucose homeostasis with disturbances in

carbohydrate, fat and protein metabolism resulting from defects in insulin secretion, insulin action, or both (Katzung et al. 2009).

Without adequate insulin, body tissues, in particular the liver, muscular and adipose tissues fail to take up and use glucose from the blood circulation.

The resultant elevated blood glucose level is known as hyperglycaemia (Jarald et al.2008).

Hyperglycaemia

Adiposetis sue, increased Lipolysis Brain,

Neurotransmitter

Dysfunction

Isletalphacel, In creased glucagonsecretion

Muscle, Decreased peripheral glucose up take Pancreas, Decreased insulinsecretion Stomach, Carbohydrate intake Liver, Increased hepatic glucoseproduction

And decreased hepatic glucose uptake Kidney, Increased glucose reabsorption Digestivesystem, Decreased incretineffect

Diabetes occurs predominantly in two forms, namely:

Type 1 and Type 2.

These two forms differ in terms of pathogenesis but produce essentially similar metabolic derangements (Nowak and Handford 2004).

On the basis of aetiology, the term Type 1 is widely used to describe insulin dependent diabetes mellitus (IDDM) (Nowak and Handford 2004).

This type is the more severe of the two forms, which typically is picked up at a young age, and is less common.

It develops following viral infection, exposure to environmental chemicals, abuse of +/o. exposure to therapeutic drugs or a strong genetic predisposition leading to

antigen alteration and subsequent immune attack, causing Beta-cell (β-cell) destruction and leading to zero functioning of the β-cells, therefore resulting in no secretion

of insulin (Katzung et al. 2009).

Type 2 diabetes mellitus, formerly known as non-insulin dependent diabetes mellitus (NIDDM), is characterised by chronic hyperglycaemia as a consequence of insulin deficiency caused by insufficient synthesis or secretion of insulin from the β-cells, however many contributing factors remain uncertain (Nowak and Handford 2004)

Type 2 diabetes is by far the most common form of diabetes (Hannan et al. 2006), accounting for more than 90% of population cases (Nguyen et al. 2011).

A slow progression or development of symptom; often years will pass without the victim being aware of any change (Nowak and Handford 2004).

Insulin therapy is required less often in this type of diabetes, with the exception being patients that fail to achieve proper glycaemic control, during severe bacterial

infections, ketoacidosis, during pregnancy and in patients with impaired renal or hepatic function (Mizuno et al. 2008).

A minority of cases of Type 3 and Type 4 are due to various specific metabolic or genetic causes. (Bastaki 2005).

1.2.2

Complications of diabetes mellitus

Patients with diabetes experience significant morbidity and mortality from micro- +/o. macrovascular complications (Tayyab et al. 2012).

Microvascular disease is defined as damage to the small blood vessels while macrovascular disease is damage to the larger arteries (Nowak and Handford 2004).

The relationship between glycaemic control and diabetic microvascular disease has been established in both Type 1 and Type 2 diabetes.

Acute complications include diabetic ketoacidosis common to Type 1 diabetic patients, and non-ketotic hyperosmolar coma, common in Type 2 diabetic patients

(Tayyab et al. 2012).

Regardless of common diabetic treatment regimens, chronic hyperglycaemia has been implicated as the main cause of the adverse effects experienced by patients such

as polydipsia, polyphagia and lingering complications over a significant period (McCue et al. 2005).

The resulting long-term complications are caused by damage to organs including the eyes, kidneys, nervous system and blood vessels, causing various pathologies

such as a therosclerotic vascular disease (Gan et al. 1999; Bastaki 2005), ketoacidosis, nephropathy, neuropathy, ulceration, eye complications (retinopathy = most common cause of blindness), diabetic foot’ and limbamputation (Bastaki 2005; Lewis et al. 2010).

Oxidative stress induced by chronic hyperglycaemia (Kil et al. 2004) has been shown to be a major underlying mechanism for the formation of harmful byproducts that accumulate and contribute to development of the long-term complications associated with diabetes (Neri et al. 2005).

Oxidative stress reflects an imbalance between the systemic manifestations of reactive oxygen species (ROS) constantly formed in the human body and the quantities of

antioxidant products required to restore balance, causing vasoconstriction (Kuyvenhoven and Meinders 1999). Excess production of ROS leads to the impairment of equilibrium between pro-oxidants and antioxidant systems (Sharma and Kar 2014).

The activation of a number of metabolic pathways induced by chronic hyperglycaemia produce end products that contribute to the development of long-term complications associated with diabetes (Kuyvenhoven and Meinders 1999).

For example the activation of the polyol pathway causes decreased nitric oxide and prostaglandin synthesis, which results in endothelial dysfunction and hypertension.

Increased polyol pathway activity can induce retinopathy and neuropathy. Similarly, increased protein kinase C (PKC) pathway activity and the formation of non-enzymatic

glycation of proteins can lead to the increased risk of developing nephropathy, neuropathy and retinopathy.

In addition, increased hexosamine pathway activity can potentiate macromolecular damage.

Proper glycaemic control, blood pressure management and lipid modification are important to consider as they may independently slow the progression of diabetic related micro-and macrovascular complications, and thus reduce the rates of diabetic retinopathy, neuropathy, nephropathy, diabetic foot infections, atherosclerosis and other

associated cardiovascular events, including dyslipidaemia, hypertension, hypercoagulability and obesity (Ratner 2001; Mizuno et al. 2008).

1.2.3

Incidence of diabetes mellitus

Diabetes is a major health problem with its frequency increasing every day from most developed and developing countries (Wild et al. 2004). In SA (= South Africa), the prevalence is 4% - 6%. The global prevalence was estimated at 2.8% in 2000 (171 million people affected) (Wild et al. 2004), 382 million people in 2013 and is estimated to reach 592 million people by the year 2035, with a prevalence of 8.3% (Guariguata et al. 2014).

The WHO predicts that diabetes will be the 7^th leading cause of death by 2030 (WHO 2011). associated with urbanisation, modernisation (Hamdan and Afifi 2004), growth

of aged population, increasing trends towards obesity, unhealthy diet, and sedentary lifestyles (Hannan et al. 2006).

Hypertension, coronary heart disease, stroke, genetics and various forms of cancer are amongst the reasons for the global rise in diabetes (Omran 1983; Reddy et al. 1998).

The WHO emphasised the rise over a projected time frame of non-communicable diseases worldwide (WHO 2011). Many countries, including SA, are undergoing health

and epidemiological transition that pose significant threats involving the emergence of debilitating diseases and their associated long-term complications (Omran 1983),

and will increase with or without the impact of HIV/AIDS in SA (Mollentze and Levitt 2005).

The prevalence of diabetes and obesity is an increasing concern affecting the developing countries to a greater extent than the developed world (Wild et al. 2004).

Obesity is a major concern because it indirectly affects or exacerbates the incidence of diabetes, worsening the severity of side effects or accelerating the incidence of

diabetic related complications (Mollentze and Levitt 2005; National Department of Health 2006). These data shows that reliable, cost saving therapy is necessary to lower

the global rise of diabetes (Chiha et al. 2012). Medicinal plants contain enormous potential to provide alternative medicines for treating diabetes, but it is necessary that

their effectiveness is researched and substantiated.

1.2.4

Treatment and management of diabetes mellitus

Over the years, concerted efforts to treat diabetes have evoked breakthrough discoveries, which have facilitated suitable management.

The primary aim is to save a life and alleviate diabetic symptoms and secondary aims are to prevent long-term diabetic complications which encompass a variety of metabolic abnormalities.

Insulin replacement therapy is the mainstay for patients with Type 1 diabetes while diet and lifestyle modifications are considered the foundation for the treatment and management of Type 2 diabetes (Bastaki 2005).

If diet and exercise fail to control blood glucose at the desired level, pharmacological treatments such as insulin or oral hypoglycaemic drugs for management of Type 2 diabetes are then evoked. Yet, due to the rise and progress of the disease, and modernisation of lifestyle, opinion is divided regarding the primary use of conventional hypoglycaemic agents (Wadkar et al. 2007; Mizuno et al. 2008). In addition, patients placed on restricted diets and instructed to exercise in order to lose weight, do not

always comply (Jarald et al. 2008).

Proposed goals of treatment intervention have been to improve β-cell function to increase pancreatic insulin decrease hepatic glucose production, increase glucose uptake peripherally and reduce absorption of carbohydrates (Houghton and Raman 1998).

In addition, novel treatment strategies suggest prescribing according to the individual’s genetic pathogenic profile (Bastaki 2005; van Huyssteen 2007).

The overall treatment of diabetes depends on the severity of hyperglycaemia and the lifestyle of the patient.

Oral administered hypoglycaemic drugs e.g., sulfonylureas, metformin, thiazolidinediones (TZDs), meglitinides and α-glucosidase inhibitors are prescribed first, either alone

or in combination. Often medical professionals are inclined to suggest combination therapy for patients failing to achieve normal glucose levels (South African Medical Association 2005).

The most common combination is sulfonylurea plus metformin.

If combination therapy fails to attain glycaemic control, patients are placed on insulin monotherapy or combined with oral hypoglycaemic agents (Mizuno et al. 2008).

Common mechanistic classes of hypoglycaemic drugs in use exert their glucose lowering effects by means of:

(1) Enhancement of insulin secretion by pancreatic β-cells (insulin secretagogues) (sulfonylureas and potassium-ATP channel stimulators);

(2) Decreasing hepatic glucose production through inhibition of gluconeogenesis and promoting insulin-stimulated glucose uptake in muscle and changes lipid metabolism

by decreasing plasma triglycerides and free fatty acids (metformin, a biguanide);

(3) Increase muscle and adipose tissue glucose uptake by potentiating insulin action; PPARү activates genes that regulate insulin action, glucose uptake and energy expenditure

[thiazolidinediones (TZDs)];

(4) Increase β-cell insulin secretion (meglitinides);

(5) Inhibition of intestinal glucose digestion and absorption (α-glucosidase inhibitors such as acarbose and migitol competitive inhibitors of intestinal α-glucosidases)

Modern antidiabetic drugs pose many limitations (Mizuno et al. 2008).

The main drawback of insulin is that it has to be administered by injection (Wadkar et al. 2007) and research shows that most of the oral hypoglycaemic agents cannot maintain normal levels of blood glucose for an extended period (Mizuno et al. 2008). For example, glibenclamide is effective for patients that do not lack endogenous insulin but the side effects of this drug are hypoglycaemia with increased cardiovascular risk, [in the elderly and patients with renal problems, and weight gain (Reid et al. 2012)]. In addition, gastrointestinal (GI) disturbances (severe lactic acidosis) are associated with metformin; weight gain, GI disturbances and liver injury with thiazolidine diones; GI disturbances, weight gain and hypersensitivity reactions with meglitinides. Given the association of obesity and insulin resistance, weight gain is problematic, particularly in that are overweight to start with (Mizuno et al. 2008). In pregnancy-induced diabetes, synthetic agents are vigorously used, however, continuous use is prohibited due to the development of hypoglycaemia, weight gain, GI disturbances and liver toxicity

(Swarnalatha et al. 2012).

Therefore, prolonged use of such agents can cause serious long-term complications.

The current mainstay of treatments fail to alter the course of diabetic complications, do not restore glucose homeostasis and pose risks of high secondary failure rates

(Mizuno et al. 2008).

Drug compliance and accurate regulation of blood glucose is difficult to control (Rang et al. 2003). It is therefore essential to look for other means of treatment that will be

as efficacious in the mechanism of action (MOA) as synthetic agents but with minimal side effects and which can delay the chronic complications associated with diabetes.

Apart from the current therapeutic options, many herbal medicines have been proposed for the treatment of diabetes (Jarald et al. 2008).

The use of medicinal plants are part of traditional practice in many countries and cultures (Soumyanath 2006) including South Africa (van de Venter et al. 2008),

because of their availability, effectiveness, minimal side effects and low cost.

Investigation into antidiabetic agents from traditional medicinal plants is a major driver of research (Palatty et al. 2013).

1.3

The use of traditional medicine in the treatment of diabetes

In Africa, many plants are traditionally used for the management and control of various ailments (Baynes 2006) including diabetes (Kavishankar et al. 2011).

Globally, approximately 85,000 medicinal plant species (sp.) are reported as medicinally useful (Liu and Wang 2008); however, few have received scientific scrutiny despite medical and scientific recommendation from the WHO (WHO 2007).

In South Africa, victims of chronic diseases are turning to herbal medicines as alternative sources of treatment as recommended by the National Department of Health (2006)

This renewed interest in plant medicines as alternative therapy to restore health or treat diseases is believed to be motivated by factors such as their effectiveness, that they

are more specific and that they contain diverse secondary metabolites which provide numerous health benefits. The orchestra of chemical compounds within the plants work together synergistically allowing active compounds to be available to produce maximal therapeutic efficiency that are less toxic than high doses of individual components

(van Huyssteen 2007).

Traditional medicine (TM) may provide an effective solution to the threat of diabetes worldwide, thus helping to reduce chronic disease complications and deaths (Fang 2011).

World ethnobotanical information on medicinal plants has reported up to 800 plants used for the treatment of diabetes (Udayakumar et al. 2009).

Numerous medicinal plants offer sustainable management of the sugar levels among diabetic patients and validated for their hypoglycaemic potential using experimental animal models (Yeh et al. 2003).

Plants such as Momordica charantia and Eugenia jambolana have shown to ameliorate diabetic complications such as neuropathy, nephropathy, fructose-induced insulin

resistance, and cataracts in experimental animals (Premila and Conboy 2007). Diabetes is thus a common disease for investigation using natural products.

The mechanism of action +/o. the components that specifically exert blood glucose lowering effects on tissues or organs remain unknown (Prabhakar and Doble 2011;

Palatty et al. 2013). Diabetic research on the therapeutic effectiveness of natural plant products of SA is limited (Afolayan and Sunmonu 2010),

therefore, this study is aimed at improving the management of diabetes by investigating novel compounds and the synergistic action of medicinal plants, marking a promising future and better usage of South Africa’s medicinally important plants.

2.1

The link between nanotechnology and phytotherapy in the treatment of diabetes

Individuals with diabetes and other debilitating diseases have been treated via traditional folkmedicine with a variety of plant extracts from many years (Barnes et al. 2007).

Natural medicinal drugs are reclaiming their position as the primary source of treatment as compared to the current and main forms of synthetic treatment

(Mizuno et al. 2008). The most popular antidiabetic plants studied belong to the following families:

Anacardiaceae, Alliaceae, Asphodelaceae, Asteraceae, Apocynaceae, Bombacaceae, Caesalpiniaceae, Combretaceae, Cucurbitaceae, Fabaceae, Hypoxydaceae, Lamiaceae, Lauraceae, Linaceae, Liliaceae, Menispermaceae, Moraceae, Myrtaceae, Pedaliaceae, Piperaceae, Rutaceae and Zingiberaceae

In the quest for innovative and eco-friendly healthcare, nanobiotechnology now an active field of research, concentrating on the rapid biosynthesis of benign

Nps (= Neuropeptide S, a neuropeptide found in human and mammalian brain) using highly acclaimed antidiabetic medicinal plants possessing active compounds that

serve as natural reducing agents (Rao et al. 2013).

This has led to many researchers developing newer and more efficient green methods of synthesis of biocompatible and inert Nps (Ramteke et al. 2013).

Chemical, physical and microbial methods of synthesising gold (Au), silver (Ag), palladium (Pd), platinum (Pt), indium oxide (In2O3), magnetite (Fe3O4)

and zinc oxide (ZnO) Nps currently exist (Iravani 2011; Naik 2002), however, these methods are toxic, costly, time consuming and difficult, especially in relation to preserving

microbial cultures (Jayapriya and Lalitha 2013).

In light of this, nanomedicine is making use of the vast reserves of phytotherapy to synthesise Nps using various noble metals such as gold, silver and palladium in nanoform.

2.1.1

Green synthesis of metal Nps using medicinal plants

The biosynthesis of silver and gold Nps using medicinal plants has received considerable attention as a suitable alternative to using hazardous chemical and physical

techniques (Iravani 2011). Plants are used for their unique metal tolerance and effective production of metal Nps.

A single medicinal plant contains an orchestra of chemical elements (e.g. proteins, vitamins, enzymes, amino acids, polysaccharides and organic compounds) that are “environmentally benign, yet chemically complex” (Iravani 2011) and therefore serve as ideal tools for enhanced medicinal applications.

It is reported that polyols such as terpenoids, polysaccharides and flavones take part in the bio-reduction, stabilisation and bio-capping mechanisms to form stable silver

(Huang et al. 2007), gold (Shankar et al. 2003) and bimetallic Nps (Shankar et al 2004).

The importance of plant constituents have been shown in the bio-reduction of Ag ions to AgNps using an aqueous (aq.) preparation of Cinnamon zeylanicum bark rich

in terpenoids such as linalool, methyl chavicol and eugenol as well as cinnamaldehyde, ethylcinnamate and β-caryophyllene.

Proteins from C. zeylanicum bark capped and further stabilised the particles of free amine groups +/o. cysteine residues (Sathishkumar et al. 2009).

Phenolic compounds play an important role in the bio-reduction and stabilisation of metal Nps.

Phenols/phenolics are a class of compounds comprising a hydroxyl functional group (-OH) attached to an aromatic hydrocarbon group (Harborne 1998).

Recent interest in phenolic compounds is because of their potential antioxidant action against oxidative damage related diseases such as diabetes, cancer, coronary heart disease and stroke. Phenolic compounds have a high affinity with chelating metals that may inactivate iron ions by chelating and supressing the superoxide driven Fenton reaction, which is the sole source of ROS (Iravani 2011).

Therefore, plants with high content of phenolic compounds such as Ocimum spp. are suitable candidates for nanoparticle synthesis.

Specific characteristics such as size, morphology, physicochemical properties (charge interaction and surface properties) and dispersity play significant roles in improving

the stability and compatibility of Nps (Song and Kim 2009).

By controlling the metal nanoparticle structure at a precise nanoscale level measured in nano metres (one billionth of a metre), a standard control and modification can be

set to change their surface layer for enhanced aq. solubility, biocompatibility or bio-conjugation (Grace and Pandian 2007).

This enables greater biological activity due to their relatively high surface area to volume ratios compared to their larger counterparts (Mubarak et al. 2011).

For example, remarkable size-dependent properties were presented in the facile green synthesis of AuNps, with a size range of 15 – 25 nm, using the antidiabetic plant

Cassia auriculata (Ganesh et al. 2011); a similar nanorange was reported by Arunachalam et al. (2013) forming biocompatible AgNps and AuNps from Memecylon umbellatum.

Bimetallic Au core-Ag shells Nps was reported by Sheny et al. (2011), with a size range below 10 nm synthesised from Anacardium occidentale, and a size range of

50 – 100 nm was achieved using Neem (Azadirachta indica) with a large percentage of AuNps exhibiting remarkable flat, platelike morphology (Shankar et al. 2004).

The medical applications of AgNps, AuNps and bimetallic Nps synthesised by living plants has advanced dramatically, focusing on improving diagnosis, treatment, drug development and targeted drug delivery systems (Raman et al. 2012; Adekoya et al. 2014).

The applications have huge potential for treating major diseases such as cancer (Anand et al. 2015), diabetes (Daisy and Saipriya 2012) and HIV/AIDS (Raman et al. 2012)

in the near future. Recent trends in diabetic research suggest the potential antidiabetic activity of Nps synthesised using antidiabetic plants as the reducing and stabilising

agents (Ganesh et al. 2011) and raise the question of their potential for improving drug delivery of existing synthetic drugs for enhanced anti-diabetic treatment

(Subramania et al. 2012).

In this study the properties of metal Nps synthesised from Ocimum sanctum (Philip and Unni 2011) and Ocimum basilicum (Sivaranjani and Meenakshisundaram 2013)

will be further extended to investigate their possibly enhanced antidiabetic activity.

2.1.2

In vitro inhibition of carbohydrate metabolising enzymes

A range of in vitro models is available to study the potential antidiabetic activity of plant extracts. Both α-amylase and α-glucosidase enzyme models can be used to

explain many reported herbal interactions (Kim et al. 2005).

The enzyme α-amylase is present in pancreatic juice and saliva and its main role is to start the breakdown of dietary carbohydrates (a major constituent of the human diet)

in the gastrointestinal tract (GIT) via hydrolysis of dietary polysaccharides, to produce oligosaccharides and disaccharides (McCue et al. 2005).

The resulting disaccharides are further hydrolysed to produce glucose and other monosaccharides (fructose and galactose) by the enzymatic action of α-glucosidase

(Sudha et al. 2011). After digestion the liberated glucose and other resulting monosaccharides are absorbed through the small intestine into the hepatic portal vein

and this results in an elevated blood glucose levels known as PPHG.

Glucose is now available for the body cells to use it for energy (Nowak and Handford 2004).

Even though the aetiology of diabetes does not relate to the metabolism of carbohydrates (Lebovit 1998), the inhibition of α-amylase activity (Funke and Melzig 2006)

and inhibition of α-glucosidase activity and other key enzymes. (Akkarachiyasit et al. 2010) have long been targeted as potential avenues for better glycaemic control

in type 2 diabetic patients or as alternative treatment choice for many borderline patients (Subramanian et al. 2008).

The role of selected carbohydrate metabolising enzymes in the digestion and absorption of carbohydrates

Enzyme Catalytic function

Alpha amylase Produced in the pancreas this enzyme hydrolyses dietary starch into disaccharides and trisaccharides.

Alpha glucosidase Present in the brush border of the small intestines, this membrane bound enzyme hydrolyses oligosaccharides, tri-and disaccharides

to glucose and other monosaccharides.

Hexokinase (glucokinase) First enzyme to change glucose during the energy investment phase of glycolysis, allows glucose to remain in the cells.

Glucose-6-phosphatase (G-6-P) Plays a role in homeostatic regulation of blood glucose levels.

Hydrolyses G-6-P to glucose and inorganic phosphate.

Source: (Akkarachiyasit et al. 2010/Ugochukwu and Babady 2003/Udayakumar et al. 2009)

Currently in the market there are several established enzyme inhibitors which are conventionally used to manage diabetes, including

miglitol, voglibose, nojirimycin, 1-deoxynojirimycin and a carbose, commercially known as Glucobay® (South African Medical Association 2005; Nickavar and Yousefian 2009). However, studies have proven that many of these drugs possess limitations, are non-specific, produce serious side effects and fail to alleviate diabetic complications

(McCue et al. 2005; Bhat et al. 2011).

For example, long-term repercussions of acarbose include GIT side effects, such asbloating, abdominal pain/discomfort, diarrhoea, flatulence and abdominal bacterial fermentation of undigested carbohydrates in the colon (Bhat et al. 2011; Sudha et al. 2011).

Research shows that certain plant sources show prominent α-amylase and α-glucosidase inhibition and are able to mimic the MOA of standard commercial agents such

as acarbose and provide better inhibition without the associated side effects (Kim et al. 1999), in particular those possessing important natural producing hypoglycaemic

bioactive compounds (Kim et al. 2005; McCue et al. 2005; Mogale et al. 2011b).

Several chemical compounds exhibit α-amylase and α-glucosidase inhibition (Subramanian et al. 2008), namely alkaloids; stilbenoids (polyphenol); triterpene; phytosterol; myoinositol; flavonoids; flavonolignans; anthraquinones; anthrones; xanthones; feruloylglucosides; flavanone glucosides; acetophenone glucosides; glucopyranoside derivatives; genine derivatives; flavonol and anthocyanin (Benalla et al. 2010).

Thus, diabetic studies are ongoing with the aim of obtaining clinically useful enzyme inhibitors in order to better control diabetes (Jung et al. 1996).

2.1.3

Antidiabetic potential of AgNps and AuNps synthesised via the green route

One of the first attempts at assessing the antidiabetic activity of AgNps was demonstrated using Sphaeranthus amaranthoides extract as a natural reducing agent,

the results of which showed a dose - response inhibitory activity on α-amylase and an IC 50 result lower than the standard drug acarbose (Swarnalatha et al. 2012).

Biogenic AgNps synthesised by Halymenia poryphyroides showed significant in vitro antidiabetic efficacy in a dose – dependent manner with an increase in the

percentage inhibitory activity against α-amylase enzyme, at a concentration of 1.0 mg/ml, 91,30% ± 0,02% inhibition, similarly a significant increase in percentage

inhibitory activity against α-glucosidase enzyme at a concentration of 1,0 mg/ml with 89,10% ± 0.01% inhibition (Vishnu and Murugesan 2013).

More recently, Vishnu and Murugesan (2014) reported the biological green synthesis of AgNps from marine algae, Colpomenia sinuosa that displayed in vitro

α-amylase and α-glucosidase inhibitory activity.

The high biological activity can be explained by the properties of the metal Nps.

For example, AgNps possess a high surface area to volume ratio plus the charge they carry is useful in catalytic studies, as they can easily interact with protein molecules

(Swarnalatha et al. 2012).

As mentioned ROS is a major potentiating factor in diabetic related complications (Iravani 2011).

Barathmanikanth et al. (2010) found that AuNps displayed prominent antioxidant properties, inhibiting the formation of ROS and scavenging free radicals,

therefore increasing the antioxidant enzymes and creating a sustained control over hyperglycaemic conditions revealing the potential of biocompatible AuNps as a safe

therapeutic form of treatment for diabetes and its associated complications.

The main functionalised property associated with AuNps is that they bind readily to a large range of biomolecules such as proteins/enzymes, DNA, amino acids, and

expose a large surface area for the immobilisation of ions of such biomolecules (Ganesh et al. 2011).

The biomedical applications of AuNps include diagnostic assays, thermal ablation, radiotherapy enhancement, gene therapy and improving drug delivery systems.

They are increasingly being researched due to their low toxicity in humans, ease of biodegradability, and chemical stability as evidenced by Anand et al. (2015).

However, there is a lack of catalytic studies testing the antidiabetic potential for AuNps and bimetallic Nps.

In relation to carbohydrate metabolising enzymes, the exact mode of the binding of nanoscale molecules to α-amylase and α-glucosidase (Hamdan et al. 2004) and

the consequent inhibition requires further investigation.

Studies of the biological applications of metal have focused mainly on how matter behaves at a nanoscale level.

The limitation of these studies is that they have not addressed the question of how Nps will react in the human body (Vishnu and Murugesan 2014).

The current study investigates the in vitro effect of bimetallic (Au-Ag) Nps and AgNps against α-amylase (derived from porcine) and B. stearothermophilus

α-glucosidase that mimics the catalytic activity of the human pancreatic α-amylases (HPA) and intestinal brush border α-glucosidases.

The rationale for the synthesis of bimetallic (Au-Ag) Nps were twofold:

1) to combine AuNps (chemically inert and less toxicity) with AgNps (higher bioactive properties),

2) increase of the surface phenomenon in the reduction reaction (higher surface area to volume ratio) to achieve greater biological activity in the enzyme assay.

2.2

Antibacterial screening: infectious diseases

2.2.1

Diabetic related infections

Diabetic induced infections are increasing globally at an alarming rate, adding to associated complications and worsening the effects of the disease (Reid et al. 2012).

Previously, diabetes was treated as a single disease; now medical professionals are aware that diabetes covers a wide range of heterogeneous diseases and is itself an

environmental factor that leads to the development of a wider range of disorders (Bastaki 2005; Mizuno et al. 2008). In both developed and developing countries,

the disabling complications from diabetes are rapidly draining health care resources.

Admissions for diabetic foot-related complications is the most common reason for hospital bed occupancies in this patient population (Tudhope 2008).

In sub-Saharan Africa, the increased incidence of infections in diabetic patients (van Huyssteen 2007) is indirectly affected by the increased incidence of HIV/AIDS,

and Tb., where up to 22.9 million people are infected with HIV/AIDS (Reid et al. 2012).

This increase is attributed to several factors, including the growing incidence of antimicrobial resistance to hospital-acquired and community-acquired infections,

poorer socioeconomic conditions, inaccessibility to modern health care needs especially in rural areas, and poorly controlled diabetic cases (Shankar et al. 2005).

Management of infections in diabetic patients is more complex and therefore of greater concern compared to infections in non-diabetic patients (Larkinet al.1985).

Immunological deficiency in diabetic patients is triggered because of poor glycaemic control.

Defects in their defence system may increase the risk and severity of developing diabetic induced infections (Larkin et al. 1985).

Infections of the skin (staphylococci), periodontal disease, postoperative infections, pneumonia caused by Staphylococcus aureus or Klebsiella pneumonia,

urinary tract infections (UTIs) and foot infections can further result in immunological deficiency in the diabetic patient population.

Diabetic peripheral neuropathy (polyneuropathy) among all the other associated co-morbid diabetic conditions is reported to be the primary reason underlying the

severity of bacterial related diabetic foot trauma and ulceration.

Delayed recognition of symptoms due to lack of sensation because of neuropathy together with poor peripheral circulation may delay healing and encourage opportunistic

infections (Shankar et al. 2005).

The worst outcome of infection gangrene which may lead to amputation of the foot or limb and even death if prompt treatment is not instituted (Hall et al. 2011).

In a study by Shankar et al. (2005) diabetic polyneuropathy was found to be common, with the incidence of Gram negative (predominant in chronic diabetes) induced

infections being higher than Gram positive (predominant in acute diabetes) induced infections.

In addition, polymicrobial infections caused by combinations of bacteria such as Staphylococcus, E. coli, Pseudomonas aeruginosa, +/o. Methicillin-resistant Staphylococcus aureus (MRSA) in diabetic foot infections are increasingly becoming a problem in patients previously hospitalised.

Despite the existence of conventional antimicrobial agents on the market, resistant strains are continuously surfacing (Adwan et al. 2010).

Multidrug resistance is developed due to the indiscriminate use of antimicrobial drugs. In addition, there are side effects of antimicrobials including hypersensitivity,

immune-suppression +/o. allergic reactions (Sánchez-Borges et al. 2013).

Ever since humankind suffers from infectious diseases, herbal medicine has been pursued as an effective source of treatment.

New research is ongoing in the fight against the constant mutation and upgrading of bacteria (Adwan et al. 2010).

A major emphasis of industrial antibiotic production is to ward screening programmes for new potent antimicrobial producing agents.

Plants or natural products still appear to be the most promising source of future antimicrobials because of their availability and chemical diversity (Ahmad and Beg 2001).

Historically, plants have created a platform to create new biologically active components, specifically focusing on the isolation and characterisation of unknown compounds expressing interesting properties regarding their antimicrobial activity.

2.2.2

Antimicrobial potential of AgNps and AuNps synthesised via the green route

Plant extracts mediated synthesis of AgNps and their antimicrobial activity against clinically isolated pathogens has been reported on in relation to most prevalent and pathogenic Gram positive, Gram negative bacterial and fungal microorganisms (Ramteke et al. 2013; Rout et al. 2012). Medically, silver is commonly incorporated in to

many topical ointments and creams.

This antimicrobial agent prevents infections caused by burns or open wounds (Singhal et al. 2011). Improving the properties of silver by altering their physicochemical

properties (charge interaction, surface properties and size i.e. nanorange) nanomedicine has generated the facile green synthesis of biocompatible AgNps reported to possess

antifungal, antibacterial, anti-inflammatory, antiangiogenesis, antiplatelet and antiviral properties, thus amplifying the existing medicinal properties of silver ions.

The AgNps formed from Phyllanthus niruri spp. displayed antibacterial properties against Staphylococcus spp., Salmonella spp., Proteus spp and Bacillus spp.

(Krishnamoorthy and Jayalakshmi 2012); AgNps from Artocarpus heterophyllus Lam. seed displayed potent antibacterial activity towards B. cereus, B. subtilis, S. aureus

and P. aeruginosa (Jagtap and Bapat 2013);

AgNps from O. sanctum and Vitex negundo, showed enhanced antibacterial activity against S. aureus, E. coli and P. aeruginosa (Ramteke et al 2013)

and antifungal properties against C. albicans, C. kefyr and A. niger (Rout et al. 2012); AgNps from Andrographis paniculata has shown prominent antifungal properties

(Kotakadi et al.2014).

A study by Singhal et al.(2011)

found that AgNps from O. sanctum displayed greater activity against E. coli and S. aureus than silver nitrate and standard antibiotic ciprofloxacin

and a study by Sivaranjani and Meenakshisundaram (2013) found that AgNps derived from O. basilicum displayed high antibacterial activity against P. aeruginosa.

Antimicrobials are produced naturally by bacteria, fungi, actinomycetes, algae, lichens and green plants (Peláez 2006). Thousands of antimicrobials have been identified,

but few natural sources have been commercially used to treat human diseases (Hackl et al. 2004). Plant communities are among the most complex, diverse and important assemblages of chemical compounds in the biosphere and participate in various biological activities.

They are an important source material in the search for novel antimicrobial agents and molecules with biotechnological im portance (Hackl et al. 2004).

Together with nanomedicine the rich abundance of plants in Africa and South Africa makes it a promising avenue for investigation and discovery of therapeutic drugs.

The reasons for this global rise have been linked to changes in lifestyle

[Mauritius Fortier-Bernoville]

http://ir.dut.ac.za/bitstream/handle/10321/1534/MALAPERUMAL_2016.pdf?sequence=1&isAllowed=y

All the acids have in their pathogenesis a common symptom clearly marked. It is the debility i.e. to say a persistent sense for weakness which is very often seen clinically

in a number of chronic cases. This debility often characterizes the diabetic patient. Not only the patient who has slight or transitory diabetes but also the patient who suffers from important, durable and irremediable glycosuria.

To these patients who are always weak, always fragile, suit the acids. Moreover we must not forget that the acids will act preventively against acidosis which is the greatest danger of diabetes.

Other morbid states + diabetes, when it persists for a long time (for years) these are dyspepsias. We have already shown the value of acid in dyspeptic patients (hypochondria), due to butyric fermentation. These diabetic dyspeptics will have more often important symptoms that will indicate the acids.

These acids are

a) The most important Acet-lac. Bor-ac. Lac-ac. Ph-ac.

b) Less frequently indicates Carb-ac. Fl-ac. Nit-ac. Pic-ac.

Acet-ac.:

Bor-ac.:

Lac-ac.:

Ph-ac.:

Carb-ac.:

Fl-ac.:

Nit-ac.:

Pic-ac.:

2. The Metals

Generally the (heavy) metals used often for the treatment of prolonged chronic disease + deep troubles and definite lesions (often the case in diabetics).

The metals used: Aurum and Argentum the two precious metals; Uranium and Vanadium among rare metals; Plumbum and Cuprum among the common metals.

Aur-met.:

Like Fl-ac. sits to cases of diabetes associated with old acquired and hereditary syphilis.

Exaggerated appetite and thirst.

Tendency to paralysis.

Diplegic, hemianopia sees only the upper half of a n object, mental and physical depression; periodic hopelessness;desire for suicide.

Tendency to general and partial paralysis with hypertension.

Aur-m.: should be preferred to Aur-met. everytime when the tendency to sclerosis is accentuated.

Arg-met.:

Polyuria; turbid and profuse urine with sweetest smell.

Emaciation. Seminal loss without sexual excitation.

Arg-n.:

Trembling, sexual weakness, paralysis of the extremities with numbness for which walking becomes difficulty. All sorts of polyneuritis.

Uran-n.:

Excessive thirst, voracious appetite, abdominal distention, polyuria.

Sexual weakness.

The liver is attacked, and goes towards generation and hypertrophic cirrhosis.

Cartier, after a first phase of congestion.

The arterial tension is often high.

Vanad-met.:

Degeneration of the liver and of arteries, arteriosclerosis fatty heart, fatty degeneration of the liver.

Plb-met.:

Diabetes with paralytic tendency. Skin troubles, asthenia, hyposthenia, tendency to coma or convulsion.

Possible ocular lesions, optic neuritis, paralyses of the external muscles of the eyes.

Paralysis of the lower extremities, abolition of rotulian reflexes raid and marked muscular atrophy.

Plb-i.:

This remedy is preferred to Plb-met. in diabetes with urine of high density, of foetid smell like onion, specially when there is acetonuria.

Acidosis and in the tendency to acenominia which causes coma.

Cupr-m.:

Uremia with the tendency to spasm and convulsion of legs and claves.

3. Other Minerals,.

The other metals or metalloids used generally as ground remedies or as remedies of morbid temperament.

The first three the three remedies of burning sensation are united by classical relations.

1. Ars.:

The intoxication by Arsenic is at the same time so intense, so varied and so deep that it may be called one of our great polycrests. In diabetes it is indicated by weakness and prostration if the latter # or + restlessness the periodicity of troubles.

Often thirst, for small quantity of cold water rarely repeated or there may be no thirst.

The diabetes + digestive troubles, periodic diarrhoea of blackish stools having foetid smell; or paralysis, polyneuritis with jerkings, heaviness and trembling. the skin is dry and desquamated.

Diabetes with tendency to gangrene; grave humid gangrene with pain and horrible putrid smell.

Ars-br.:

It is used in diabetes with great tendency to cutaneous eruptions, acne, furuncles or anthrax.

Sulphur.:

Less important than Ars. The individual drinks much, eats less. Sensation of weakness and of goneness (in the stomach towards 11 h.) obliging the patient to eat something for amelioration.

Profuse and less colored urine.

Tendency to cutaneous eruptions.

Sulphur should be used always prudently in diabetic patients, because its repeated use (in high dilutions), may produce some abscesses, furuncles, or anthrax which are always dangerous.

In this case, better use Psorinum in he place of Sulphur, specially if the patient is chilly, weak and forced to put on multiple under garments.

Very often Hepar, Sulphur are to be used every time when it is indicated by suppurations.

Phos.:

It is very important remedy of diabetes.

Deep action not only on the liver, but also on the pancreas. A remedy of all lofts of degeneration.

Diabetes complicated with digestive troubles; Exaggerated hunger which reappears just after meals, unquenchable thirst for cold drinks.

1. debilitating Diarrhoea without pain 2. great weakness after stools. Sexual troubles, impotence after an exaggerated desire, with lascivious dreams and involuntary seminal loss; Nervous troubles;

Motor paralysis with weakness, trembling by the least exercise. Sensation of numbness; eye troubles; Cataract amblyopia. diplopia,. paresis of the motor muscles of the eyes of grave lesions of the retina and of the optic nerve.

Whatever may be its indications, it is the remedy that should be well understood and should be prescribed uniquely, from a synthetic point of view of similar pathological troubles observed in the

individual than by its key symptoms. the characteristics of Phosphorus are almost always of the field of anatomy-pathology as well as of pure pathogenesis.

Sil.:

By its supportive tendency Silicea will very often be indicated with Hep. in diabetes who have pancreas, and furuncles.

In all these cases all the remedies of suppuration of septicemia may be indicated; Ars., Echi., Pyrog. in very grave cases. Lach., Apis, Bell., Ferr-p., Arn. Sil. may sometimes favour the suppuration dangerously. Hep. is better in acute cases, will stop menacing suppuration the latter on the contrary. Sil. suits to chronic suppuration which are weakening and with fistula.

[http://bestonhealth.com/diabetes-2/]

[http://bestonhealth.com/homeopathy-home/]

Homeopathy treats the total, taking the total symptom picture of the patient into consideration, not just the metabolic disorder. It also modifies your temperament so that you react appropriately

to stressful situations. The homeopathic medicines influence and balance a person’s neurological, hormonal and immune systems. Homeopathic treatment aims to cure the disease of the patient

by stimulating the vital force (power of resistance) of the sick person. But if this power of resistance weakened by damaging influences of toxic and infective agents (chronic miasm- fundamental

cause of chronic diseases), then H. advised to remove these obstruction to eliminate chronic miasm so that no interference may come in the way of cure.

Deficiency of insulin is the chief obstruction to cure diabetes mellitus. Therefore, where insulin deficiency (Type 1 diabetes) is present and cannot be stimulated by homeopathic medicines then it

should be given simultaneously to remove the obstruction to cure.

In the light of Hahnemannian principles the homeopathic remedies may be divided into three categories:

I. Homeo-miasmatic remedies: These remedies are similar to the damaging influences, toxins and infecting agents that derange the power of resistance (vital force) of the patient. These damaging miasms (miasm are infectious, excessively minute agents causing diseases, these were first discovered by H. which cause diabetes of three types:

Acute uncured miasm like influenza, whooping cough, diphtheria etc. (Remedies which may help are: Infl. Pertussin, Diph.

Suppressed influences like effects of suppressed emotions like anger, grief (Remedies which may help are: Ign. Nat-m. Nux-v. Staph. Aur-met. Lach. Lyc. Psor.

Chronic miasms (chronic infective agents): Remedies which may help are: Psor. Tub. Thuj. Syph. Med. Sulph. Merc.

II. Homeo-constitutional remedies: These remedies are similar to the personality of the patient. To select these remedies homeopathic physician must carefully assess your entire symptom picture, figure out your personality, hopes and fears, family history, and put it all together to come up with the single individual remedy that best fits your picture.

Important homeo-constitutional remedies incl. Arg-met. Acet-ac. Ars. Bor-ac. Bov. Caus. Grap. Hep. Helon. Lac-ac. Lyc. Nat-m. Nit-ac. Op. Ph-ac. Phos. Plb-met. Sec. Sil. Sulph. Tarent-h. Van-met.

III. Specific Homeopathic remedies: These medicines have symptoms similar to the symptoms of diabetes and are therefore specific for this condition.

These remedies include: Adren. Ars. Anthrac. Cupr-ars. Glyc. Insulin. Lac-ac. Lecithin, Pancreatin. Nat-s. Phloridizin, Ph-ac. Uran-n. Syzyg.

Even though Homeopathy may not be able to cure diabetes completely, the above remedies help in:

Stimulating the resistance power of the patient thereby controlling the disease.

Fighting against the weakness.

Maintain the patient in a state of equilibrium (both mentally and physically).

Checking and managing the complications of diabetes.

[W. Karo]

Diabetes mellitus

Usually starts much earlier than the patients become aware of it. The first symptoms are vague and general to such a degree that they may be applied to other diseases (of the digestive organs).

Consequently we have to examine the urine in all cases whatsoever, before giving any advice or any treatment. Not to do, I must say, would be an inexcusable mistake.

Diabetes mellitus begins with disorders of the digestive organs. The patient at first complains of uneasiness, painful sensations and tightness in the region of the liver/stomach, + irregular opening of the bowels, sometimes by acid eructation and vomiting of a brownish, very bitter tasting liquid. The patient complains of headache, sleeplessness, intense fatigue, giddiness, buzzing in the ears, eyes weak, palpitation of the heart, burning sensations in the heads and feet; simultaneously the mental condition of the patient gets entirely altered.

Certainly all these symptoms are of an entirely general nature and may be found also in many other diseases. But if the disease progresses, we get confronted with a very characteristic symptoms, i.e. the strikingly increased thirst, especially after eating and during the night.

Naturally the patient is constantly seeking to allay it, and the quantity of liquid consumed is proportional to the amount of urine passed.

According to the increased secretion of urine the patient has to urinate very often (at night), again and again interrupting the patients sleep. As a rule the average quantity of the urine during 24 hours amounts to 3-5 pints. But there are cases in which the quantity may be much greater. I remember patients secreting nearly 12 pints urine daily.

The urine is usually clear, pale in colour, has a sweet taste and is of high specific gravity (1030 to 1050).

When diabetic urine is boiled with cupric salt, which has a bluish of green color, the latter is reduced to a cuprous salt having a brown or yellow colour, and a process depending upon this chemical reaction from the usual method of recognizing and estimating the amount of sugar present in the urine. The sugar can also be tested by measuring the amount of carbonic acid gas set free on fermentation by yeast and by the extent to which a specimen of the urine rotates the pane of polarized light. The quantity of sugar passed in twenty-four hours may vary from a few ounces to several pounds, and it is, of course, markedly increased after sugary or starchy food has been taken. In light cases of diabetes the urine contains only 2 – 1% sugar, in the most serious cases 10% or even more; in these serious cases there is also albumen in the urine. In such serious cases the urine contains two other components, i.e. acetone and acetone-acetic acid; their presence in the urine we may conclude already from the winy smell of the urine or from the patients breath.

If the patients breath has the characteristic unpleasant pomaceous smell, we may be sure that acetone and acetone-acetic acid are not only in the breath, but also in the urine of the patient. Whoever has repeatedly perceived that smell will always recognize it, hence it is called the acetone-smell.

As a rule the skin of the diabetic patient is dry and harsh with a peculiar papery consistency. Owing to the poor vitality of the tissues, various skin eruptions appear, boils and carbuncles being especially common and, in the fact, sometimes giving the first signs of the presence of the disease. The sugar deposited from the urine is very liable to cause itching about the groins and eczema of various parts of the body is set up by the presence of sugar in the sweat. There is a special tendency to gangrene of the skin of the feet, commencing with the toes, and this from is a very serious complication of diabetes and a not uncommon from of fatal issue.

Regarding the nervous symptoms I have already mentioned the general symptoms as there are a certain feebleness, exhaustion, dislike of physical or intellectual work, great weakness after the slightest exertion, sensation of formication and numbness in the limbs, headache, depression. But one symptom of the nervous system is a very characteristic one, i.e. the typical neuralgia, especially frequently affecting the sciatic nerve, usually called ischias or sciatica.

Whenever it affects both sides, it may be an early symptom of the diabetes; besides the sciatica there are also cases with neuralgia in the occiput or in the face as well as cases of a specific migraine (sick headache). In other cases of diabetes we find paralysis of the limbs.

The most serious symptom of the disease is the so-called diabetic coma; it usually begins with some slighter general nervous symptoms as there are headache, nausea, a certain unrest, oppression and anguish, very soon increasing and aggravating. the patient gets delirious, jumps out of the bed and gets excited to such a degree that he behaves as raving mad. As soon as the excitation has passed away, a characteristic enervation and somnolence sets in, aggravating in the most serious cases up to complete unconsciousness and to that deathlike sleep, called coma. The patients breathe extremely deeply and noisily, their faces get bluish red, cyanotic, the pulse is very much accelerated and low, the temperature decreasing.

Such a coma may continue for several days, but in the majority of cases it starts like an apoplexy. In any case the coma always is the most alarming and the most fateful symptom, it is due to a self-poisoning as a result of the absorption of the waste products of metabolism or of the products of decomposition within the intestine. In nearly

all cases the coma is the consequence of inappropriate nourishment (meat and eggs). Overloaded digestive organs with nourishment which cannot be digested, slags remain, poisoning the central nervous system.

Diabetes, as a rule, advance comparatively slowly, except in the case of young people, in whom its progress is apt to be rapid. Indeed, in a general way, it is more serious,

the younger the subject of the disease. Various complications arise in its course; some of them I have already mentioned; as one of the most alarming complication I will call attention to the cataract, followed by dimness and loss of sight, furthermore to inflammatory chest affections, of which pulmonary consumption is the most common and is

a frequent termination of diabetes. Occasionally death occurs from exhaustion or from the coma diabeticum spoken of above. But the majority of cases continue suitable diet and treatment for many years without materially getting worse, and in a great number of cases complete cure apparently takes place. The most unfavorable cases are those in children, also cases in which the disease has already become of severe character, and has established before it has been recognized.

There is no other disease in which diet is of such a decisive importance as it is in diabetes. It would be a serious mistake to prescribe schematically the same diabetic diet for

all cases; each case has to be treated individually according to the age, weight and activity of the patient as well as to the stage reached by the diabetes. The amount of energy that must be supplied by the food in order to carry on the vital processes of life, such as body warmth, the action of the heart, he such as body warmth, the action of the heart, the movements of the chest, in breathing, and the chemical activities of the secreting glands, is, for an adult of about 140 lbs. in weight, approximately 1,600 calories daily.

For a patient, lying quietly in bed, little more is needed; for sedentary occupations such a patient requires about 2,000 calories, while if he is doing muscular work, the equivalent of 3,000 calories is needed. I desist from discussing that problem thoroughly, though it is of the greatest importance.

Generally speaking the diabetic diet ought to be composed of albumen. green vegetable and fats. Uncooked food ought to be the main constituent; especially I call the attention to uncooked fermented cabbage, plentifully containing vitamins, mineral salts and an insulin-like body; I usually prescribe 1 to 2 lbs. daily. Furthermore, once or twice weekly, the patient ought to take only fruit, especially berry fruits; owing to their abundance of bases, they alkalize the acids and diminish the demand for albumen. Green vegetables, especially green beans, salads, onions, horseradish, celery, carrots, radish, potatoes baked in their jackets, fresh cucumbers, nuts, especially walnuts, oatmeal porridge, old and very well toasted rye-bread, cream cheese, fresh butter, daily one to two large spoons of walnut oil and the yolk of an egg, mixed with lemon juice, are of

the greatest value for the patients. For, generally speaking, vegetable albumen is more wholesome to the diabetic patient than animal albumen; at least sausage ought to be prohibited.

Regarding the beverages I must call the attention to the wholesome effect of the various herbal teas, as there are hips, leaves of bilberries, bean-skins, dandelion; furthermore we ought to give berry fruit juices, lemon, mineral waters, sea-water preparations, buttermilk. I am giving to all my patients, as I have already mentioned in my paper on goitre (No. 4 of the journal), the Adinolan tea; due to its constituents it has the best effect on the metabolism. it purifies the whole body and stimulates the vital reactions of the patient.

Before discussing the Homoeopathic treatment of diabetes, I call attention to yeast as to a remedy of the greatest importance. It is indeed a tonic roborant as well as a remedy for the whole constitution of the patient; also, in serious cases its effect is such a striking one that no homoeopath ought to slight it. By giving 20-30 gr. daily we may, even

in serious cases, save insulin, Insulin is the principal remedy not only in allopathy, but it is also used by a great number of homoeopaths. I refer only to Stiegele, the most prominent German homoeopath, who is of the opinion that Homeopathy is not able to replace the insulin; but, as the effect of the insulin is only a short one, Homoeopathy has supplement it. Certainly, a great many homoeopaths refuse insulin at all. I will not discuss thoroughly all the pros and cons of the insulin question. In my opinion, we so not need it in light cases, but I would not like to miss it in serious cases (coma); the homoeopath, who in coma cases would not given insulin, would be responsible for the patients death. Furthermore, we dare not to stop insulin entirely at once in patients who up to the beginning of the homoeopathic treatment have been using insulin for a long time. I remember such a tragedy.

The homoeopathic treatment of diabetes has to be based on the fact that the glycosuria is only symptom of the disease; to find the most suitable drug for the patient we have to keep in mind the whole constitution of the patient; i.e. we have to consider not only the physiological cases we have to treat the constitution of the patient rather than the glycosuria. That point is very important, especially here are far reaching points of view.

Sulph.: a constituent of the insulin-molecule, having far reaching connections with the metabolism (oxidizing process); it provokes symptoms on the skin and in the links, so frequently in diabetic patients; furthermore, there is the same psychical irritability, voracious or loss of appetite, sleeplessness.

Nat-s.: hydrogenoid constitution/tongue is brownish coated, dry; bitter taste; mouth and pharynx very dry, disorders of the liver, gall bladder and bowels; Dropsy., oedema.

Phos.: connected with the metabolism of the fats and with the storing of glycogen; especially in cases, complicated by gout, tuberculous and other diseases of the bronchial ways or the lungs. Instead of Phosphorus itself we may give Kali-p. Ferr-p. Calc-p.

Ph-ac.: nervous symptoms are to be considered first, especially in cases, due to grief, care and trouble, indifferent, unconcerned about their family; there is a great mental and physical weakness, loss of appetite, but extremely increased thirst. Many furuncles. Urine very much increased, much sugar, many phosphates; the urine has a pale, milky colour. Before the micturition anguish, after it burning. Especially indicated in diabetic children, suffering from stomach troubles, or having grown up too quickly.

Acet-ac.: suffering from great anaemia and weakness, polyuria, face emaciated, salivation, burning thirst, vomiting after each meal, pyrosis, increased acidity in the stomach; burning pains in the stomach. Suitable to serious cases, especially to patients suffering from the stomach, burning pain, burning thirst, pyrosis, vomiting after each meal, salivation; anaemia of a high degree, greatest weakness, skin very dry, sweat, face emaciated, wax-coloured; polyuria, urine very light and pale.

Iod.: increased appetite, skin very dry, many nervous symptoms, disorders of the glandular system and of the liver metabolism.

Sec.: Emaciation, gangrene of the toes, extremities cold; worse by heat.

Bry.: Very thirsty, lips very dry, bitter taste the patients are weakened, peevish, sad, appetite normal, disorders of the liver.

Uran-n.: Suitable to cases due to disorders of the assimilation, characterized by disposition to ascites or to general dropsy, great weakness, indigestion, urine increased, acid, very much sugar in the urine, burning sensation in the urethra, very thirsty, mouth dry, emaciation in spite of good appetite.

Syzyg.: improves the general condition of the patient, decreases the quantity of the sugar of the blood as well as of the urine; suitable to patients suffering from thirst, great weakness and emaciation; furunculosis; specific gravity of the urine very high.

Plb-met.: Hering: one off the most important remedies, especially suitable to patients suffering from nervous troubles and constipation.

Ars.: very thirsty; emaciation; especially for cases of gangrene.

Lac-ac.: suffering from disorders of the liver and of the whole digestive system, very thirsty, appetite very much increased, nausea vomiting; urine in profusion, clear yellow, sweetishly smelling.

Podo.: Bitter taste, tongue white coated, disorders of the liver, better by pressing the region of the liver.

Arg-met.: Polyuria, urine cloudy, sweetishly smelling, micturition frequent and abundant.

Arg-n.: great longing for sweets, though they are making worse all troubles; disorders of the stomach, eructation; feet very cold. Better by eructation, fresh air, cold and pressure.

Chion.: Sensation of great dryness, not improved by water, pinching pains in the umbilical region, enlargement of the liver, jaundice, constipation, stools

whitish grey, mellow; diseases of the pancreatic and other glands. Urine bilious with very much sugar high specific gravity, dark brown colour.

Lyc.: Suitable to the well-known Lycopodium constitution; I have learned by my own practice, that at least 40% of the diabetic patients have very characteristic Lycopodium symptoms; in all these cases Lycopodium, especially given alternating with Natrum sulfuricum , improved the diabetic condition of the patients very quickly.

In cases of coma diabeticum we my give drugs like Echinacea, Belladonna, Helleborus niger, Hyoscyamus, Cuprum met, Opium or Acidum muriaticum.

But I must repeat: I would not dare to rely upon the homeopathic drugs alone in such serious cases, but would rather give high doses of insulin.

[Yumi None Imai, University of Pennsylvania, Philadelphia, PA, U.S.]

Role of neuropeptide Y in diabetes and obesity

Obesity has reached epidemic levels worldwide and is feared to cause significant toll with its co-morbidity, especially type 2 diabetes. Pathogenesis of type 2 diabetes incl.

both insulin resistance and islet failure. Although several hypotheses link obesity and insulin resistance, the mechanism responsible for the development of islet failure in obesity is not well understood. Interestingly, neuropeptide Y (NPY), the peptide in the brain that is known to play a role in the development of obesity, is also found in the pancreatic islets and decreases insulin secretion. Therefore both NPY in the brain and the pancreas may contribute to islet dysfunction and potentially serves as a link between diabetes and obesity. The goal of this study is to clarify the role of NPY in the development of islet failure in type 2 diabetes. The regulation of insulin secretion by NPY in the brain and the pancreas will be studied by placing NPY deficient mice on high fat diet to induce obesity and diabetes. We will analyze whether the lack of NPY prevents the development of diet-induced diabetes and improves insulin secretion in NPY deficient mice. The role of NPY in the brain will be tested by administration of NPY to the brain and measurement of glucose stimulated insulin secretion. The inhibitory effect of pancreatic NPY will be analyzed by adding NPY to isolated islets. The study will provide a unique opportunity to test the role of NPY in islet failure and its link with obesity. In addition to deepening our knowledge of islet dysfunction in type 2 diabetes, the project will provide superb training for the principal investigator, Dr. Imai, to develop an academic career in Diabetes/ Endocrinology. The study will be carried out in the Penn Diabetes Center and the Division of Endocrinology, Diabetes, and Metabolism at the University of Pennsylvania under the supervision of Dr. Rexford Ahima and Dr. Franz Matschinsky. The division has expertise in diabetes and obesity research, and will provide an outstanding environment to conduct the proposed project.

[Farokh J. Master]

What is the Homoeopathic approach to control Diabetes Mellitus

Homoeopathic approach for Diabetes mellitus is strictly individualizing every single case, analyzing the physical as well as mental constitutional symptoms and selecting single homoeopathic remedy. During constitutional homoeopathic treatment diabetes mellitus we usually advice investigations periodically on an average 3 months and I some cases early also.

Following are the common tests:

a) Plasma glucose concentration (Fasting and Post Prandial).

b) Glycosylated hemoglobin, to measure long term glyceamic control.

c) Plasma lipid levels to rule out increase level of triglycerides and low density lipoproteins.

d) Routine urine for albumin to rule out early evidence of diabetic nephropathy.

e) Serum creatine levels.

f) Regular eyes check up to detect early diabetic retinopathy.

g) Weekly measurement of blood pressure to rule out hypertension which is so frequently associated with diabetes mellitus.

The following homoeopathic medicine has been extremely useful in my practice.

a) Cod.: when there is excessive skin irritation (Itching due to diabetes mellitus).

b) Ph-ac.: when diabetes mellitus starts after some nervous exhaustion, working too hard or disappointment in relationship.

c) Remedies like Gun. Staphcoc. Melal. extremely useful for diabetic carbuncle and gangrene.

d) Remedies like Urea pura. Ampe. extremely useful for diabetic nephropathy.

The treatment for diabetes mellitus in homoeopathy is extremely effective but people do not come to us in early state and hence once the pathology is advanced we cannot cure but only palliate the condition. On an average in my Homoeopathic Health Centre I receive approximately 20-30 new patients every month with high creatine level and uncontrolled diabetes mellitus. There patients have been advised dialysis but with my experience of last 20 years I am able to prevent dialysis in majority of these people with the help of constitutional treatment and proper diet control. I have been successful to arrest the further progress of diabetic nephropathy. In our clinic we give advice for diabetic diet:

a) Fruit and leaves of drumsticks (saijan ki phalli) and patola (= Luffa.) very useful for the diabetic patient.

b) Fenugreek (methi/= Foenm-g.) seeds, when given in varying doses of 25 grams to 100 grams daily, diminishes reactive hyperglycemia in diabetic patient. Soak 10-12 fenugreek (methi) seeds in one-fourth cup of water overnight and have both the seeds and the water, next day in the morning with a glass of water. This is beneficial for people with diabetes. You can also powder the methi seeds and take one teaspoonful of this powder with low fat milk daily for at least two months. This will keep the blood sugar level under control.

c) The diabetics should take two raw string beans (runner beans or French beans) daily.

d) Have bhindi (okra/= Hibiscus esculentus) soup daily, this will keep the diabetic patient healthy.

Recipee:

Take 6-7 raw bhindis and wash them thoroughly. Slit them lengthwise (do not cut the bhindi into two halves, just slit them). Boil them in one litre of water till the water is reduced to half. Strain this liquid and drink it plain or with salt and pepper if you so desire. You mat throw away the boiled bhindi, do not squeeze the bhindis while straining.

Having bhindi water is also useful, the method is wash and cut 3-5 bhindis lengthwise in two pieces or in two halves and soak them overnight in some water. The next morning, remove the bhindis from the water and drink that water. Doing this regularly will make the sugar level normal within a couple of months.

Diabetes mellitus associated with

- Cardiac failure

- Constipation

- Dropsy

- Dyspepsia

- Hepatic dysfunction

- Impotency

- Prostration

[Henriette Kress]

[Anthroposofisch.]

Der menschliche Organismus entfaltet durch alle seine Glieder hindurch Tätigkeiten, die ihre Impulse allein in ihm selber haben können. Was er von außen aufnimmt, muss entweder bloß die Veranlassung dazu sein, dass er eine eigene Tätigkeit entwickeln kann; oder es muss so im Körper wirken, dass die Fremdtätigkeit sich nicht von einer inneren Tätigkeit des Körpers unterscheidet, sobald sie in diesen eingedrungen ist.

Die notwendige Nahrung des Menschen enthält z. B. Kohlehydrate. Diese sind zum Teil stärkeähnlich. Als solche sind sie Substanzen, die ihre Tätigkeit in der Pflanze entfalten. In den menschlichen Körper gelangen sie in dem Zustande, den sie in der Pflanze erreichen können. In diesem Zustande ist die Stärke ein Fremdkörper. Der menschliche Organismus entwickelt keine Tätigkeit, die in der Richtung dessen liegt, was Stärke, in dem Zustande, in dem sie in den Körper kommt, als Tätigkeit entfalten kann. Was z. B. in der menschlichen Leber als stärkeähnlicher Stoff entwickelt wird (Glykogen), ist etwas anderes als pflanzliche Stärke. Dagegen ist der Traubenzucker eine Substanz, die Tätigkeiten erregt, welche von gleicher Art sind wie Tätigkeiten des menschlichen Organismus selbst. Stärke kann daher in diesem nicht Stärke bleiben. Soll sie eine Wirkung entfalten, die in dem Körper eine Rolle spielt, so muss sie verwandelt werden. Und sie geht, indem sie vom Ptyalin der Mundhöhle durchsetzt wird, in Zucker über. Eiweiß und Fett werden vom Ptyalin nicht verändert. Sie treten zunächst als Fremdsubstanzen in den Magen ein. In diesem werden die Eiweißstoffe durch das von ihm abgesonderte Pepsin so verwandelt, dass die Abbauprodukte bis zu den Peptonen entstehen. Sie sind Substanzen, deren Tätigkeitsimpulse mit solchen des Körpers zusammenfallen. Dagegen bleibt Fett auch im Magen unverändert. Es wird erst von dem Absonderungsprodukt der Bauchspeicheldrüse so verwandelt, dass Substanzen entstehen, die sich aus dem toten Organismus als Glycerin und Fettsäuren ergeben.

Nun aber geht die Verwandlung der Stärke in Zucker durch den ganzen Verdauungsvorgang hindurch. Es findet auch eine Umwandlung der Stärke durch den Magensaft statt, wenn diese Umwandlung nicht schon durch das Ptyalin stattgefunden hat.

Wenn die Umwandlung der Stärke durch das Ptyalin stattfindet, so steht der Vorgang an der Grenze dessen, was sich im Menschen im Bereich dessen abspielt, das in dem Kapitel II die Ich- Organisation genannt worden ist. In deren Bereich geht die erste Umwandlung des von außen Aufgenommenen vor sich. Traubenzucker ist eine Substanz, die im Bereich der Ich-Organisation wirken kann. Er ist dem Geschmack des Süßen entsprechend, der in der Ich-Organisation sein Dasein hat.

Entsteht aus dem Stärkemehl durch den Magensaft Zucker, so bedeutet dies, dass die Ich- Organisation in den Bereich des Verdauungssystems eindringt. Für das Bewusstsein ist dann der Geschmack des Süßen nicht da; aber, was im Bewusstsein - im Bereich der Ich-Organisation - vorgeht, während «süß» empfunden wird, das dringt in die unbewussten Regionen des menschlichen Körpers, und die Ich-Organisation wird dort tätig. In den uns unbewussten Regionen hat man es nun im Sinne von Kapitel II zunächst mit dem astralischen Leib zu tun. Es ist der astralische Leib da in Wirksamkeit, wo im Magen die Stärke in Zucker verwandelt wird.

Bewusst kann der Mensch nur sein durch dasjenige, was in seiner Ich-Organisation so wirkt, dass diese durch nichts übertönt oder gestört wird, so dass sie sich voll entfalten kann. Das ist innerhalb des Bereiches der Fall, in dem die Ptyalinwirkungen liegen. Im Bereich der Pepsinwirkungen übertönt der Astralleib die Ich-Organisation. Die Ich-Tätigkeit taucht unter in die astralische. Man kann also im Bereich des Materiellen die Ich-Organisation an der Anwesenheit des Zuckers verfolgen. Wo Zucker ist, da ist Ich- Organisation; wo Zucker entsteht, da tritt die Ich-Organisation auf, um die untermenschliche (vegetative, animalische) Körperlichkeit zum Menschlichen hin zu orientieren.

Nun tritt der Zucker als Ausscheidungsprodukt auf bei Diabetes mellitus. Man hat es dabei mit dem Auftreten der Ich-Organisation an dem menschlichen Organismus in einer solchen Form zu tun, dass diese Organisation zerstörend wirkt. Sieht man auf jede andre Region des Wirkens der Ich-Organisation, so stellt sich heraus, dass diese untertaucht in die astralische Organisation. Zucker unmittelbar genossen ist in der Ich-Organisation. Er wird da zum Veranlasser des Süß-Geschmackes. Stärke genossen und durch das Ptyalin oder den Magensaft in Zucker verwandelt, zeigt an, dass in der Mundhöhle oder im Magen der astralische Leib mit der Ich-Organisation zusammenwirkt und die letztere übertönt.

Zucker ist aber auch im Blute vorhanden. Indem das Blut Zucker enthaltend durch den ganzen Körper zirkuliert, trägt es die Ich-Organisation durch diesen. Überall da aber wird diese Ich-Organisation durch das Wirken des menschlichen Organismus in ihrem Gleichgewicht gehalten. In dem Kapitel II hat sich gezeigt, wie außer der Ich-Organisation und dem astralischen Leib in der menschlichen Wesenheit noch der ätherische und der physische Leib vorhanden sind. Auch diese nehmen die Ich- Organisation auf und halten sie in sich. So lange dies der Fall ist, sondert der Harn keinen Zucker ab. Wie die Ich-Organisation, den Zucker tragend, leben kann, das zeigt sich an den an den Zucker gebundenen Vorgängen im Organismus.

Beim Gesunden kann der Zucker im Harn nur auftreten, wenn er zu reichlich, als Zucker, genossen wird, oder wenn Alkohol, der unmittelbar, mit Übergehung von Verwandlungsprodukten, in die Körpervorgänge sich hineinzieht, zu reichlich aufgenommen wird. In beiden Fällen tritt der Zuckerprozess als selbständig, neben den sonstigen Vorgängen im Menschen auf.

Bei Diabetes mellitus liegt die Tatsache vor, dass die Ich-Organisation beim Untertauchen in den astralischen und ätherischen Bereich so abgeschwächt wird, dass sie für ihre Tätigkeit an der Zuckersubstanz nicht mehr wirksam sein kann. Es geschieht dann durch die astralischen und ätherischen Regionen mit dem Zucker dasjenige, was mit ihm durch die Ich-Organisation geschehen sollte.

Es befördert alles die Zuckerkrankheit, was die Ich-Organisation aus der in die Körpertätigkeit eingreifenden Wirksamkeit herausreißt: Aufregungen, die nicht vereinzelt, sondern in Wiederholungen auftreten; intellektuelle Überanstrengungen; erbliche Belastung, die eine normale Eingliederung der Ich-Organisation in den Gesamtorganismus verhindert. Das alles ist zugleich damit verbunden, dass in der Kopforganisation solche Vorgänge stattfinden, die eigentlich Parallelvorgänge der geistig-seelischen Tätigkeit sein sollten; die aber, weil diese Tätigkeit zu schnell oder zu langsam verläuft, aus dem Parallelismus herausfallen. Es denkt gewissermaßen das Nervensystem selbständig neben dem denkenden Menschen. Das aber ist eine Tätigkeit, die das Nervensystem nur im Schlafe ausführen sollte.

Beim Diabetiker geht eine Art von Schlaf in den Tiefen des Organismus dem Wachzustande parallel. Es findet daher im Verlaufe der Zuckerkrankheit eine Entartung der Nervensubstanz statt. Diese ist die Folge des mangelhaften Eingreifens der Ich-Organisation.

Eine andere Begleiterscheinung sind die Furunkelbildungen bei Diabetikern. Furunkelbildungen entstehen durch ein Übermaß in der Region der ätherischen Tätigkeit. Die Ich-Organisation versagt da, wo sie wirken sollte. Die astralische Tätigkeit kann sich nicht entfalten, weil sie gerade an einem solchen Orte nur im Einklange mit der Ich-Organisation Kraft hat. Die Folge ist das Übermaß der ätherischen Wirksamkeit, die sich in der Furunkelbildung zeigt.

In alle diesem sieht man, wie ein Heilungsvorgang für Diabetes mellitus nur eingeleitet werden kann, wenn man die Ich-Organisation bei dem Diabetiker zu kräftigen imstande ist.

[Anderson]

NewScientist.com news service

Just ½ a teaspoon of cinnamon a day significantly reduces blood sugar levels in diabetics, a new study has found. The effect, which can be produced even by soaking a cinnamon stick your tea, could also benefit millions of non-diabetics who have blood sugar problem but are unaware of it.

The discovery was initially made by accident, by Richard Anderson at the US Department of Agriculture's Human Nutrition Research Center in Beltsville, Maryland.

"We were looking at the effects of common foods on blood sugar," he told New Scientist. One was the American favourite, apple pie, which is usually spiced with cinnamon. "We expected it to be bad. But it helped," he says.

Sugars and starches in food are broken down into glucose, which then circulates in the blood. The hormone insulin makes cells take in the glucose, to be used for energy or made into fat.

But people with Type 1 diabetes do not produce enough insulin.

Those with Type 2 diabetes produce it, but have lost sensitivity to it. Even apparently healthy people, especially if they are overweight, sedentary or over 25, lose sensitivity to insulin.

Having too much glucose in the blood can cause serious long-term damage to eyes, kidneys, nerves and other organs.

Molecular mimic

The active ingredient in cinnamon turned out to be a water-soluble polyphenol compound called MHCP. In test tube experiments, MHCP mimics insulin, activates its receptor, and works synergistically with insulin in cells.

To see if it would work in people, Alam Khan, who was a postdoctoral fellow in Anderson's lab, organised a study in Pakistan. Volunteers with Type 2 diabetes were given one, three or six grams of cinnamon powder a day, in capsules after meals.

All responded within weeks, with blood sugar levels that were on average 20% lower than a control group. Some even achieved normal blood sugar levels. Tellingly, blood sugar started creeping up again after the diabetics stopped taking cinnamon.

The cinnamon has additional benefits. In the volunteers, it lowered blood levels of fats and "bad" cholesterol, which are also partly controlled by insulin. And in test tube experiments it neutralised free radicals, damaging chemicals which are elevated in diabetics.

Buns and pies

"I don't recommend eating more cinnamon buns, or even more apple pie - there's too much fat and sugar," says Anderson. "The key is to add cinnamon to what you would eat normally."

The active ingredient is not in cinnamon oils. But powdered spice can be added to toast, cereal, juice or coffee.

Anderson's team were awarded patents related to MHCP in 2002. But the chemical is easily obtained. He notes that one of his colleagues tried soaking a cinnamon stick in tea. "He isn't diabetic - but it lowered his blood sugar," Anderson says.

The group now plans to test even lower doses of cinnamon in the US, and also look at long-term blood sugar management with the spice.

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