**2. The complications of diabetes mellitus (DM)**

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 and retinopathy while macrovascular complications include coronary artery disease, periph‐ eral arterial disease and stroke [5].

Diabetic nephropathy is a major cause of end-stage renal disease worldwide. It is a progressive decline in the glomerular filtration rate, characterized by glomerular hyperfiltration, glomer‐ ular and tubular epithelial hypertrophy, increased urinary albumin excretion, increased basement membrane thickness and mesangial expansion with the accumulation of extracel‐ lular matrix proteins (ECM) [14]. Alteration of the permeability characteristics of the glomer‐ ular capillary wall manifests clinically as abnormal albuminuria [15]. Microalbuminuria progresses to end-stage renal disease through a number of stages including normoalbuminu‐ ria, microalbuminuria and macroalbuminuria [16].

Diabetic retinopathy results from the damage of the small vasculature of the retina, multi cellular and the light sensitive tissue at the back of the eye. It is a major cause of visual impairment worldwide [17, 18]. The retina capillaries are lined with endothelial cells respon‐ sible for maintaining the blood retinal barrier, and are surrounded by smooth muscle cells, pericytes, which provide tone to the vessels [18]. The vascular lesions that are identified at the early stage of diabetic retinopathy include pericytes disappearance from capillaries resulting in pericyte ghosts, obliteration of capillaries and small arterioles, gradual thickening of vascular basement membrane, increased permeability of endothelial cells, and formation of microaneurysms (i.e. weakening of vessel walls that results in the projection of a balloonlike sac), vessel leakage, exudate, and hemorrhage [19, 20].

Neuropathies are characterized by a progressive loss of nerve fiber function. A widely accepted definition of diabetic neuropathy is "the presence of symptoms and/or signs of peripheral nerve dysfunction in people with mellitus after exclusion of other causes" [21]. In the periph‐ eral nervous system, diabetes causes a progressive deterioration of sensory nerves and damage to motor nerves [22]. Diabetic neuropathy is ultimately the leading cause of lower extremity amputation [23]. Peripheral neuropathy is thought to develop because of cellular damage to endothelial cells, affecting nerve blood flow and also damage to the neurons affecting con‐ ductivity of impulses [23]. Signs and symptoms of diabetic neuropathy include decrease or no sweating, numbness, or tingling, and some sort of burning sensation, weakness and loss of reflexes [24].

Both type I and type II diabetes are powerful and independent risk factors for coronary artery disease (CAD), stroke, and peripheral arterial disease [25, 26, 27]. Diabetics have a 2- to 4-fold higher risk for cardiovascular events [28] and nearly 80% of diabetes-associated deaths are caused by cardiovascular disease (CVD) [29]. Atherosclerosis, (excessive accumulation of lipids, cholesterol, inflammatory cells, and connective tissue in the vessel wall) accounts for more than 80% of the CVD-associated death and disability [30, 31]. Formation of atherosclerotic plaques can result in occlusion of vessel lumen and a rapid cessation in blood flow to target tissue [32]. Hyperglycemia, increased free fatty acids, and insulin resistance induce a large number of alterations at the cellular level that contribute to vascular dysfunction and accelerate the atherosclerotic process. These include increased oxidative stress, decreased bioavailability of NO, disturbances of intracellular signal transduction and increased production of several prothrombotic factors [32, 33].
