Definition And Characterization Of Diabetes Mellitus Biology Essay

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The World Health Organisation (WHO) have defined diabetes mellitus (DM) as a state of chronic hyperglycaemia due to metabolic disorder {{8 World Health Organisation: 2009}}. It is characterized by an impaired or disabled insulin release from the pancreas, or a basic inability of the body to utilise the insulin that is present {{8 World Health Organisation 2009}}.

DM can be divided into two distinct forms; type 1 DM (Insulin- dependent diabetes mellitus), and also type 2 DM (Non Insulin-dependent diabetes mellitus). There also exists a third category known as 'gestational diabetes', named simply because diabetes is discovered during pregnancy {{15 Fernandez-Morera,J.L. 2010; 16 Hoffert Gilmartin, A. 2008; 8 World Health Organistion: 2009}}, fortunately, this form of diabetes tends to be temporary and usually subsides after the pregnancy.

Type 1 Diabetes Mellitus

Also known as Insulin-dependent diabetes mellitus (IDDM), or 'juvenile-onset diabetes', this form of diabetes accounts for approximately 10% of all diabetes cases {{12 Gero,L. 2010}}. This is an autoimmune dysfunction and so there are no preventative measures for this form of diabetes.

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It is characterized by a complete cessation of endogenous insulin production, caused by the destruction of pancreatic beta cells by the body's own immune system {{13 Skyler,J.S. 2010; 17 Willcox,A. 2009}}. This form of diabetes is insidious and is often only detected after the majority of beta cells have been destroyed. An active lifestyle and good diet will help glycaemic control, and also the severity of symptoms, but the patient will be dependent on exogenous insulin for the rest of their lives {{18 Adi, S. 2010}}.

Type 1 DM causes symptoms such as; polydipsia and polyuria, dehydration, lethargy, and unexplained weight loss {{8 World Health Organistion: 2009}}. Symptoms tend to have a rapid or acute onset, and present in the juvenile years. Patients with type 1 DM are more prone to diabetic ketoacidosis {{8 World Health Organisation: 2009}}

Type 2 Diabetes Mellitus

Type 2 DM is also referred to as Non insulin-dependent diabetes mellitus (NIDDM), or 'mature-onset diabetes'. It is the most common form of DM, accounting for approximately 90% of all known DM cases {{8 World Health Organistion: 2009}}. This form of diabetes is characterized by insulin dysfunction by way of impaired secretion or action, and a resistance to insulin {{23 Weyer,C. 1999}}.

The onset of this disease is a slow progression from normal glucose tolerance, followed by impaired glucose tolerance and finally leading to the onset of type 2 DM{{21 Nyalakonda, K. 2009}}. Firstly, insulin release begins to decrease, and this leads to an inability of glucose in the body to overcome non-glucose states{{24 Porte,Daniel Jr. 2001; 29 Leahy,J.L. 1986}}. Then the basal level of insulin secretion becomes defective, causing the beta cells to die as they try to overcome this but eventually succumb to exhaustion {{24 Porte,Daniel Jr. 2001}}. By the time a diagnosis is made, patients are usually reduced to ~50% beta cell function {{22 Snehalatha,Chamukuttan D.S.C. 2009}}. This loss of beta cell function gives rise to the need for insulin therapy.

The symptoms of type 2 DM are similar to those of type 1 DM; however the onset is much slower and don't tend to be as severe. For this reason, diagnosis can be made up to several years after the disease process begins {{8 World Health Organistion: 2009}}. If a diagnosis is made early enough, the disease can be managed by diet and exercise alone, however, in more advanced cases anti-diabetic drugs will be required. In extreme cases, exogenous insulin therapy may also be needed {{8 World Health Organisation: 2009; 25 Tuomilehto,Jaakko 2001}}.

Epidemiology and economic burden

The past few decades have seen the incidence of DM soar. It is now estimated that over 220 million people worldwide have a form of diabetes {{8 World Health Organisation: 2009}} and this is set to reach approximately 300 million by 2025{{6 Adeghate,E.R.N.E.S.T. 2006}}.

DM has become a global epidemic, and it is putting strain on today's vulnerable economic state. Due to the disease itself and also the vast array of complications that it presents, healthcare systems worldwide are being overwhelmed and this will only increase, in correlation with the increasing incidence of the disease {{9 Cefalu,W. 2004}} . WHO have calculated that in the years 2006- 2015, China will pay out $558 billion to cover DM expenses {{8 World Health Organisation: 2009}}.

Biosynthesis and release of insulin

Islet cells and their role in homeostasis

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Insulin is synthesised by clusters of cells known as islets of Langerhans within the pancreas. This area contains different types of cells known as; α-cells, δ-cells, pp-cells and β-cells. β-cells are the most predominant form, making up 60% islet cell volume {{28 Rahier,J. 1983}}. It is within these cells that the biosynthesis of insulin occurs {{27 Ashcroft, F.M. 1992}}. In normal physiology, insulin is released in response to raised blood glucose levels and helps restore the body's normal glucose homeostasis.

The other islet cells also play a role in glucose homeostasis. When the plasma is in a state of hypoglycaemia, α-cells release glucagon. This stimulates release of glucose into the blood by breakdown of its storage form; glycogen. Sometimes δ-cells will secrete somastatin, which inhibits both insulin and glucagon {{38 Henderson,J.R. 1981}}, avoiding extremes of glycaemia.

Insulin Biosynthesis

The insulin protein is coded for by a gene coded INS, which is present on the short arm of chromosome 11{{40 Owerbach,D. 1981}}. Insulin gene expression has been studied for many years yet some aspects of its regulation remain as yet unknown {{39 Fred,R.G. 2009}}. What is known is that blood glucose induces the action of three transcription factors known as; PdX-1, NeuroD1 and MafA, which regulates insulin gene transcription at multiple levels {{41 Andrali,S.S. 2008}}. The reading frame of the INS gene actually codes for a product known as preproinsulin, which is formed in the cytoplasm then translocates to the endoplasmic reticulum (ER). This is done as a unique signal molecule is present on preproinsulin which binds its recognition counterpart on the ER membrane {{42 Nishi,M. 1994}}.

Once in the ER, cleavage of the signal molecule from preproinsulin, the remainder of the polypeptide is now known as proinsulin {{43 Weiss,M.A. 2009}}. As proinsulin is processed by the ER, protein folding occurs by way of 3 disulphide bonds, and other bond interactions such as hydrogen bonds and Van der Waals. After it is been processed, proinsulin then moves to the golgi apparatus. Here is where proinsulin is packaged into immature secretary granules which are coated by clatherin {{44 Orci,L. 1984; 45 Lipson,K.L. 2006; 46 Hou,J.C. 2009}}.

The clatherin coat is lost as these granules mature, allowing proinsulin to be cleaved further. Cleavage occurs at two sites along the polypeptide, converting proinsulin to its final product insulin, with a small connecting peptide known as C-peptide {{46 Hou,J.C. 2009}} a by-product of insulin synthesis. The mature insulin is then stored, in its granules, throughout the cytoplasm, allowing a readily available source of insulin as required {{31 Becker, K.L. 2001}}.

Insulin release and mode of action

Regulation of insulin release by glucose is controlled by glucose metabolism {{47 Kahn, C.R. 1994}}. The glucose transporter GLUT-1 in β-cells, allows rapid diffusion of glucose into cytoplasm {{48 Czech,A. 2010}}. Once in the cell glucose metabolism occurs, along the glycolysis pathway, and the citric acid cycle generating adenosine triphosphate (ATP), upping the ATP:ADP ratio, inhibiting the ATP-sensitive potassium channels. As the potassium levels fall, the membrane becomes depolarized. Depolarization of the membrane activates the voltage-gated calcium channels present on the membrane leading to a mass influx of calcium. Elevated calcium levels within the cell causes the insulin granules, mentioned above, to be secreted from the cell via exocytosis {{32 Jensen,M.V. 2008}}.

Insulin then acts on muscle and fat cells to increase glucose uptake by activation of the glucose receptor Glut-4. Glut-4 is activated by several pathways within the cell which can be seen in below {{92 Rang, H.P. 2007}}.

Complications associated with Diabetes Mellitus.

Chronic complications

Over time, DM can Lead to chronic damage of many tissues and organs of the body including; the heart, blood vessels, eyes, kidneys and nerves {{8 World Health Organisation 2009}}. There are microvascular complications such as; neuropathy, nephropathy and retinopathy: and macrovascular complications such as; accelerated atherosclerosis, heart attacks and strokes{{50 Chan,L. 2006}}.

Microvascular complications

Macrovasculature complications

Acute complications

Diabetes sufferers can also suffer from acute complications that develop over a short time; the diabetic acidosis and comas accounting for a large proportion of mortality and morbidity {{49 Becker, K.L. 2001}}. The most dangerous of the diabetic complications are diabetic ketoacidosis (DKA) and also the hyperosmolar hyperglycaemic non-ketotic coma (HONK).

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DKA can be defined as a state of uncontrolled diabetes mellitus in which hyperglycaemia reaches extreme levels >16.7mmol/L, blood pH falls below 7.3 and ketone body concentration in the blood reaches greater than 5.00mmol/L{{49 Becker, K.L. 2001}}. HONK is a similar pathology to this, except that ketone levels do not rise to such an extent. This is due to the levels of insulin, T1DM is more likely to reach a state of DKA whilst T2DM is more likely to develop HONK.

Both pathologies are caused by a lack of insulin. The hyperglycaemic levels associated with DKA, far exceeds the renal threshold for glucose conservation. This causes hyperosmolarity and osmotic diuresis. Thus, symptoms such as; polydipsia, polyuria, dehydration, glucosuria, hypernatraemia and hyperkalaemia are seen{{49 Becker, K.L. 2001}}.

The complete lack of insulin associated with DKA also leads to lypolysis, causing a state of hyperlipedaemia to occur. In conjunction with this, free fatty acids are oxidised forming ketone bodies. At normal pH, these ketone bodies dissociate releasing hydrogen ions and lowering the pH of the blood. This can lead to metabolic acidosis, which is potentially life threatening, sometimes leading to coma and death.

Currently available treatments

Insulin

Owing to the pathophysiology of T1DM (see section 1.1.1), the only treatment option is to supply the body with an exogenous source of insulin {{18 Adi, S. 2010; 17 Willcox,A. 2009}}in order to maintain normoglycaemia. When it was discovered by Frederick Banting in 1922, insulin came from animal sources; the first being from whole beef pancreas {{93 Rosenfeld, L. 2002}}. This was hailed as the most radical discovery in the treatment of diabetes.

Education and alteration of lifestyle

Whilst T1DM cannot be prevented, a healthy diet and lifestyle should be used along with insulin therapy to maintain glycaemic control. Numerous studies have also proven that an active lifestyle can delay the onset of T2DM in up to 59% of people {{94 Walker,K.Z. 2010; 96 Brun,J.-F. 2008}}. In more recent years there has been a worrying increase in the number of children with T2DM {{105 Phillips, J. 2009}} and so it is essential that children are educated on the importance of a healthy lifestyle.

Oral anti-diabetic drugs

Sulphonylureas

Discovered in 1942 by Janbon, after it caused severe hypoglycaemia in typhoid fever patients {{95 Walker, G. 1957}}, Sulphonylureas were one of the mainstays in diabetes therapy until the introduction of biguanides, which will be discussed further in the next section.

Sulphonylureas are not a substitute for insulin, but will amplify insulin release. The drug works by binding the sulphonylurea receptor (SUR-1), a subunit of the K+ channel{{97 Hambrock,A. 2002; 99 Meyer,M. 1999}}, and acting as an antagonist. As the K+ channel closes, the membrane of the beta cell becomes depolarized which then opens Ca2+ channels. The mass influx of Ca2+ stimulates insulin release (see section2.3). Sulphonylureas are costly and also have the undesired of effect of significant weight gain. These drugs can also cause hypoglycaemia{{98 Kwong,P.Y.P. 2002}}. Another class of oral anti-diabetic drugs is meglitinides, also works by stimulating insulin release, and also have the same side effects.

Biguanides

Today biguanides are the most prescribed anti-diabetic drug, with metformin being the most common. Biguanides do not promote insulin release, but instead enhance the body's handling of glucose in peripheral tissues. This is thought to occur via a variety of glucose transporters and activation of AMP protein kinases{{101 DiStefano,J.K. 2010}}, though the exact mechanism of action is not yet fully known{{100 Sakar,Y. 2010}}. Biguanides also inhibit hepatic glucose output, and decreases glucose absorption at the intestine{{101 DiStefano,J.K. 2010}}. These drugs have the benefit of not inducing hypoglycaemia or weight gain, but can have other severe side effects including; dyspepsia and lactic acidosis.

Α- glucosidase inhibitors

Only to be taken in conjunction with other anti-diabetic drugs. Α-glucosidase inhibitors do not affect insulin or the body's sensitivity to glucose, but instead slow down digestion of starch so the body is more able to handle the glucose load{{104 Göke B. Herrmann C. Göke R. Fehmann HC. Berghöfer P. Richter G. Arnold R 1994}}

Thiazolidinediones

Thiazolidinediones (TZDs) are peroxisome proliferator-activated reaceptor gamma (PPARγ) agonists. PPARγ are transcription factors which play a pivitol role in lipid and glucose homeostasis{{102 Cho,N. 2008}}. TZDs are a promising diabetes therapy, but can adverse effects in patients with chronic heart failure{{103 Patel,C. 2005}}.

Justification for new anti-diabetic therapies

Challenges of diabetes treatment and the need for new drugs

Current diabetes treatments have many downfalls; not only do they have adverse side effects such as those mentioned above, but they have a basic inability to restore the body's normal blood glucose levels in a normal physiological manner. The efficacy is low in current drug treatments for diabetes, and they also are unable to retain any level of insulin sensitivity; most drugs will ultimately lead to insulin dependence

In wealthy countries, over 50% of type 2 diabetes patients still have poor glycaemic control despite extensive use multiple drug therapies. Of these 50%, 18% will go on suffer further complications associated with the disease {{62 Bailey,C.J. 2000}}. In poorer countries, diabetic therapy is simply unaffordable to most of their populations. It is because of this that new therapies for the management of diabetes are required. The ideal therapy would have a high efficacy; restoring normal blood glucose levels, increasing insulin sensitivity and β-cell proliferation, and would be without undesirable side effects. A low cost therapy that does all this would be the ideal solution.

Natural anti-diabetic drug discovery

As most drugs today are made from, or are derived from plants, it makes sense to turn to these and other readily available sources such as animal venoms or amphibian skin secretions to search for potential new therapies for type 2 diabetes.

Animal venoms

Recent research has shown that animal venoms are rich in compounds that contain anti-diabetic properties. One of the most recent drug discoveries is exendin, derived from Gila monster, it promotes insulin secretion and stimulates β-cell proliferation {{54 Gallwitz,Baptist 2010}}.

Plants

From the earliest days of the pharmaceutical industry, plants have been used as a source of medicine, and even today current drugs are derived from plants with some 238 plant species with anti-diabetic potential being recognised{{51 Singh,S. 2009;}}. One such plant used for its anti-diabetic properties is Galega officinalis, a French lilac. The drug metformin is a synthetic biguanide derived from this plant {{53 Bailey,C.J. 2004}}. Of all the plant species available to us; not even 1% of these have been screened for their medicinal properties {{52 Grover,J.K. 2002}}, and so this is a huge area for potential ne diabetic therapies. Some of the plants currently being studied are listed below.

Allium cepa

Allium cepa, also known as onion, is well noted for its health benefits. It is an Indian plant, known to contain flavonoids and sulphur compounds believed to be beneficial to health, possessing anti-diabetic, hypolipidaemic and antibiotic properties{{63 Taj Eldin,I.M. 2010}}. Tested on induced diabetic rats, an amino acid extracted from the onion bulb, was found to show significant hypoglycaemic and hypolipidaemic activity {{64 Mathew,P.T. 1975}}.

Ether extracts?

Aloe barbedensis millar

Aloe vera gel is widely used as a multi-purpose health remedy, particularly for its benefits to the skin in wound and burn healing{{67 Chithra,P. 1998}}. It grows wild in India, and has been used in the Arabian Peninsula as a folk remedy for diabetes {{52 Grover,J.K. 2002}}. It is native to North Africa but is also cultivated in other eastern areas.

Aloe vera gel, given as oral doses for eight weeks to diet-induced NIDDM rats, showed significant hypoglycaemic effects. Circulating blood glucose levels were reduced, as too was the plasma insulin levels suggesting that aloe vera works by increasing insulin sensitivity {{65 Kim,H. 2009}}. Further tests were also carried out in which the aloe vera plant was divided into its two constituent parts. Gel extract and the leafy pulp left over were tested on type I and II diabetic rats. Both the leafy pulp and the gel extract, had hyperglycaemic effects on type I diabetes rats, and the leafy pulp showed a marked decrease in blood sugar in type II diabetes rats. However, the aloe vera gel extract showed hyperglycaemic effects on the type II rats {{66 Okyar,A. 2001}}. Chronic administration of aloe is shown to have the most significant effect on blood sugar levels{{68 Ajabnoor,M.A. 1990}}, suggesting that the aloe vera plant may also play a role in insulin synthesis.

Several phytosterols within aloe vera have been identified, and found to have hyperglycaemic properties. The phytosterols when tested on rats, gave no adverse side effects {{69 Tanaka,M. 2006}}, thus aloe vera could be useful in the management and treatment of diabetes.

Asparagus adscendens

Asparagus adscendens is a common Indian plant that has long been used as a traditional herbal remedy in treating cases of dysentery and diarrhoea amongst others. When tested on clonal rat pancreatic β-cell lines BRIN-BD11 {{70 McClenaghan,Neville H. 1996}}, increased glucose-dependant insulinotropic actions were observed. By testing the plant extract along with various insulin modulators, it was seen that the plant acts by way of the ATP sensitive K+ channel and by inhibiting the voltage-gated Ca2+ channel. The same study also confirmed A.adscendens glucose uptake in 3T3-L1 adipocytes, and reduced starch digestion by 21% {{73 Mathews,Jacqueline N. 2006}} when tested on an in vitro model.

Asparagus racemosus

Grown in many countries of the world such as India, Asia, Africa and Australia, A.racemosus has long been used for its medical properties in medical systems including; Ayurveda, Unani and Siddha{{71 Bopana,N. 2007}}. It is used in treating gastric ulcers, dyspepsia, liver and nervous disorders, and inflammation {{72 Goyal, R.K. 2003}}.

When tested on a perfused rat pancreas; aqueous, ethyl acetate and butanol extractsof the plant increased insulin secretion when compared with the control. Ethanol, butanol, ethyl acetate and hexane extracts increased insulin secretion when tested on BRIN-BD11 cell lines, and these same extracts also insulin secretion when tested on isolated rat islets {{74 Hannan,J.M. 2007}}.

Mucuna pruriens

This plant is an herb found throughout tropical India, and has been noted for its anti-diabetic properties. When the seeds of this herb were given orally, decreased blood sugar levels were noted in normal rats and also in alloxan-induced diabetic rats, although higher doses were required for the diabetic rats {{75 Akhtar,M.S. 1990}}. Good indication is given that, M.pruriens acts by stimulating insulin release or by direct insulin-like action.

The aqueous extract of the seeds was fed to normal and streptozotocin-induced diabetic rats. In both cases, blood glucose levels were significantly reduced after an oral glucose load. Blood sugar levels were also reduced following a 21 day oral administration of the extract to diabetic rats {{76 Bhaskar, A. 2008}}.

Ocimum sanctum

Also known as holy basil, it is found throughout India both wild and cultivated in gardens and temples {{52 Grover,J.K. 2002}}. O.sanctum Linn seed was fed to alloxan-induced diabetic rabbits at a dose of 0.8gm/kg/day for a period of two weeks without any significant anti-diabetic effect {{78 Gupta,S. 2006}}. However, the ethanol extract has previously shown hypoglycaemic activity on streptozotocin-induced rats {{77 Narendhirakannan,R.T. 2006}}.

A further study of the ethanol extract and five of its partition fractions showed that the ethanol extract and its aqueous, butanol and ethyl acetate fractions stimulated insulin secretion from perfused rat pancreas, isolated rat islets and also on the BRIN-BD11 cell line. By addition of various modulators of insulin action, it was found that O.sanctum stimulated insulin secretion by stimulation of Ca2+ channels{{84 Hannan,J.M. 2006}}.

Plantaga ovate

Commonly referred to as psyllium, the husks of this plant are widely used as a source of fibre in the treatment of constipation. The aqueous extract of these husks, administered orally to normal, T1DM and T2DM rats in a sugar solution, showed increased glucose tolerance by way of decreased sucrose absorption{{85 Hannan,J.M.A. 2006}}.

P.ovata also showed significant improvement in glycaemic control when used in double-blind placebo-controlled studies of T2DM outpatients {{80 Anderson,J.W. 1999; 81 Rodríguez-Morán M. Guerrero-Romero F. Lazcano-Burciaga G 1998; 79 Ziai,S.A. 2005}} These studies indicate this plant could be used in conjunction with current diabetes therapies to improve tolerance.

Sambucus nigra

It is also known as elder. Aqueous extracts of this plant, when tested on in vitro models insulin-sensitive muscle preparations, showed increased glucose uptake, increased glucose oxidation and glycogen synthesis. This occurs as the extract utilizes the normal insulin pathway {{86 Gray,A.M. 2000}}.

When tested in a diabetic group, indications of hypoglycaemic, hypolipidaemic and antioxidant effects could be seen {{82 Ciocoiu M. Mirón A. Mares L. Tutunaru D. Pohaci C. Groza M. Badescu M 2009}}. Thus, S.nigra could be used as a dietary adjunct in diabetes treatment.

Tinospora cordifolia

Seen in India, China, Burma and Sri Lanka and also known as Guduchi (plant which protects from diseases), it has long been used for its medicinal properties. Extracts of this plant are believed to be; hapatoprotecting, antioxidant, immunomodulatory and anti-diabetic {{83 Panchabhai,T.S. 2008}}.

An alcohol extract was fed to alloxan-induced diabetic rats for six weeks which resulted in significantly decreased blood and urine levels. Also, any decrease in body weight was prevented {{87 Stanely Mainzen Prince,P. 2003}}. When administered to normal and alloxan-induced diabetic rats, the aqueous, alcohol and chloroform extracts showed significant hypoglycaemic effects. Doses were given up to 200mg/kg body weight without any observed toxic effects. Thus, T.cordifolia is a promising potential new therapy in the treatment of diabetes {{89 Wadood,N. 1992}}.

Trigonella foenum-graecum

More commonly known as fenugreek

Current literature says....