1.1 Diabetes mellitus
The term diabetes mellitus describes a metabolic disorder of multiple cause characterized by chronic hyperglycemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects in insulin secretion, insulin action, or both. Diabetes mellitus affects a large number of population especially in the western world. The defect in insulin activity in diabetes mellitus may be caused by a number of different mechanisms. The hyperglycemia in diabetes mellitus can lead to a large number of problems for the individuals if it is not controlled (Marshall, et al., 2004). Diabetes mellitus is very common in the United Kingdom there about 1.8 million people with diabetes in the UK representing 3% of the population. worldwide there are over 171 million cases. The number of people with diabetes will double worldwide by 2030, according to new estimates from researchers at the World Health Organization (WHO) and several European universities.
There are two main types of diabetes. Type 1, insulin dependent diabetes mellitus (IDDM) is an auto-immune disease where the body's immune system destroys the insulin-producing beta cells in the pancreas. So the body cannot produce any insulin which is a hormone helps the glucose to enter the cells where it is used as fuel by the body. Type 1 diabetes usually appears before the age of 40. It is the least common of the two main types and accounts for around 10 per cent of all people with diabetes (Kumar, et al., 2005).
Type 2, non-insulin dependent diabetes mellitus (NIDDM) develops when the body can still make some insulin, but not enough, or when the insulin that is produced does not work properly (known as insulin resistance). In most cases this is linked with being overweight. This type of diabetes usually appears in people over the age of 40, though in South Asian and African-Caribbean people, it often appears after the age of 25 (Kumar et al., 2005)..
Diabetes mellitus complications:
The effects of diabetes mellitus include long-term damage, dysfunction and failure of various organs. Diabetes mellitus may present with characteristic symptoms such as thirst, polyuria, blurring of vision, and weight loss. In its most severe forms, ketoacidosis or a non-ketotic hyperosmolar state may develop and lead to stupor, coma and, in absence of effective treatment, death. Often symptoms are not severe, or may be absent, and consequently hyperglycemia sufficient to cause pathological and functional changes may be present for a long time before the diagnosis is made. The long-term effects of diabetes mellitus include progressive development of the specific complications of retinopathy with potential blindness, nephropathy that may lead to renal failure, and/or neuropathy with risk of foot ulcers, amputation, Charcot joints, and features of autonomic dysfunction, including sexual dysfunction. People with diabetes are at increased risk of cardiovascular, peripheral vascular and cerebrovascular disease.
Several pathogenetic processes are involved in the development of diabetes. These include processes which destroy the beta cells of the pancreas with consequent insulin deficiency, and others that result in resistance to insulin action. The abnormalities of carbohydrate, fat and protein metabolism are due to deficient action of insulin on target tissues resulting from insensitivity or lack of insulin.
Diabetic hyperglycemia causes a variety of pathological changes in small vessels, arteries and peripheral nerves. Vascular endothelial cells are an important target of hyperglycemic damage. Dysfunction of endothelial cells (EC) is known to promote abnormal vascular growth such as that in atherosclerosis and arteriosclerosis and has been postulated as an initial trigger of the progression of atherosclerosis in patients with diabetes mellitus, and hyperglycaemia is an independent risk factor for the development of cardiovascular disease.
This is a disease of the arterial wall in which the layer thickens, causing narrowing of the channel and thus, impairing blood flow.
It can occur in any area of the body, but is most important when it happens in the heart, brain or blood vessels leading to the brain.
The narrowing is due to the formation of plaques (raised patches) in the inner lining of the arteries. These plaques consist of low-density lipoproteins, decaying muscle cells, fibrous tissue, clumps of blood platelets, cholesterol and sometimes calcium. They tend to form in regions of turbulent blood flow and are found most often in people with high concentrations of cholesterol in the bloodstream.
In people without diabetes, fast blood flow triggers an enzyme called extracellular signal-regulated kinase 5 (ERK-5). ERK5 in turn signals endothelial nitric oxide synthase (eNOS) to produce more nitric oxide and dilate blood vessels. It also activates Kruppel-like factor 2 (KLF2) and peroxisome proliferator-activated receptor-g (PPARg), both of which block the ability of pro-inflammatory immune cells to home in on and adhere to diseased portions of blood vessels.
Atherosclerosis is an inflammatory disease, characterized by a progressive accumulation of lipids (mainly Low density lipoprotein (LDL) cholesterol), calcium and fibrous elements within the intima of large and medium sized arteries (Libby, 2002; Boudi, 2006). The patnogtmesis of atherosclerosis is extremely complex and multifactorial, as many interrelated biological processes and cellular elements are involved (Boudi, 2006). Atherogenesis involves the interaction of: endothelial cells, vascular smooth muscle cells (SMCs), leucocytes, macrophages, platelets, and cytokines (Boudi, 2006; Croce and Libby, 2007). For many years, numerous data have concentrated on hypercholesterolemia and.
Drug therapy in type 2 diabetes is focused upon targeting the acute condition of diabetes mellitus such as hyperglycemia and other associated complications. It has been highlighted that such therapy in diabetes mellitus functions to reduce blood glucose levels in an attempt to slow the progression to macro and micro vascular disease. It is important to demonstrate that anti-diabetic drugs more centered on reducing the sensitivity of target in tissue encouraging insulin facilitated glucose up take.
There are four main types of anti- diabetic drugs: Sulphonylureas (SU), Biguanide commercially known as metformin, Glitazones and Drugs which delay the absorption of carbohydrate such as acarbose. (Bonnie and Silvio,2005)
A new class of anti-diabetic drugs with insulin sensitivity activity have been introduced and are commonly referred to as the Thiazolidinedione (TZds). TDZs are employed in the treatment of type 2 diabetes and their role is to generate an anti-hyperglycemic effect of which is associated with a decrease in circulation insulin and free fatty acids that contribute towards the development of arthrosclerosis and other vascular diseases. The TZDs class of drugs or glitazones as they are called (troglitazone, pioglitazone, ciglitazone, englitazone and rosiglitazone) are specific high-affinity lignds for PPAR?. (Mohan et al.,2000). However, TZDs showed to have some side effects including weight gain and edema which precluded their widespread use for patients with heart failure. Recently most concern has arisen regarding the potential effect of TZDs in heart failure patients; it has been advised that the TZDs not to be used for patients with advanced heart failure symptoms. (Gaal and Scheen, 2002)