Factors That Influence the Development of Diabetes Mellitus

Patients with diabetes are at the risk of development of acute metabolic complications such as diabetic ketoacidosis, hyperglycaemic hyperosmolar nonketotic coma and hypoglycaemia (English and Williams, 2004; Umpierrez et al., 2002). In addition to this, diabetics are also at risk of experiencing chronic complications such as coronary heart diseases, retinopathy, nephropathy and neuropathy, and foot ulceration (ADA, 1998). Complications may be macrovascular (related to atherosclerosis of larger arteries) (which include ischeamic and coronary heart disease: angina and myocardial infarction, peripheral vascular disease and stroke) (Adler et al., 2000), Diabetes also causes 'microvascular' complications—damage to the small blood vessels (Boussageon et al., 2011). Microvascular complications include (neuropathy, retinopathy and nephropathy) and both micro- and macrovascular (diabetic foot). The mortality and morbidity of diabetes are associated more with macrovascular degeneration as compared to the risks of microvascular complications in older patients (Wallace, 2004). In general, complications of diabetes mellitus can be categorized into two groups (Wallace, 2004; Mohan, 2002):

• acute complications (Metabolic): These are short term and include hyperglycemia, diabetic ketoacidosis (DKA) and hyperglycaemic hyperosmolar non-ketonic coma, Polydipsia, polyuria, fatigue, blurred vision.
• chronic complications (Systemic): These are long term complications, they include diabetic nephropathy, microangiopathy, blindness, diabetic neuro- and retinopathy, atherosclerosis, peripheral vascular disease, cerebrovascular disease, infections and amputation. They are classified into Macrovascular and Microvascular complications.

Years of poorly controlled hyperglycemia lead to multiple, primarily vascular complications that affect small vessels (microvascular), large vessels (macrovascular), or both (Leung and Lam, 2000). The injurious effects of hyperglycemia are separated into microvascular (involving small vessels, such as capillaries) and macrovascular complications (involving large vessels, such as arteries and veins). Microvascular complications include diabetic nephropathy, neuropathy, retinopathy, cataracts and hepatopathy while macrovascular complications include coronary artery disease, hypertension, peripheral vascular disease, and stroke (Fowler, 2008). Together with perivascular disease in the legs, neuropathy contributes to the risk of diabetes-related foot problems (such as diabetic foot ulcers) that can be difficult to treat and occasionally require amputation.

The mechanisms by which vascular disease develops include glycosylation of serum and tissue proteins with formation of advanced glycation end products; superoxide production; activation of protein kinase C, a signaling molecule that increases vascular permeability and causes endothelial dysfunction; accelerated hexosamine biosynthetic and polyol pathways leading to sorbitol accumulation within tissues; hypertension and dyslipidemias that commonly accompany DM; arterial microthromboses; and proinflammatory and prothrombotic effects of hyperglycemia and hyperinsulinemia that impair vascular autoregulation. Immune dysfunction is another major complication and develops from the direct effects of hyperglycemia on cellular immunity. Microvascular disease underlies the most common and devastating manifestations of DM:

• Retinopathy
• Nephropathy
• Neuropathy
• Hepatopathy

Cardiomyopathy Microvascular disease may also impair skin healing, so that even minor breaks in skin integrity can develop into deeper ulcers and easily become infected, particularly in the lower extremities. Intensive control of plasma glucose can prevent or delay many of these complications but may not reverse them once established. Macrovascular disease involves atherosclerosis of large vessels, which can lead to:

• Angina pectoris and MI
• Transient ischemic attacks and strokes
• Peripheral arterial disease

A variety of factors influence the development of diabetic pathologies. Insulin resistance which develops from obesity and physical inactivity acts as substrate for genetic susceptibility (DeFronzo and Ferrannini, 1991). Since food intake influences the amount of insulin required to meet blood glucose target goals, the food especially carbohydrate intake could contribute to the pathology of diabetes. Dietary carbohydrate influences postprandial blood glucose levels the most and is the major determinant of meal-related insulin requirements. The intermediate- or longer-acting insulin usually covers the effects of protein and fat. It has been shown that low carbohydrate ketogenic diet is effective in the amelioration of many of the deleterious consequences of diabetes (Al-Khalifa et al., 2011). It has been observed that insulin secretion declines with advancing age, and this decline may be accelerated by genetic factors.