Type 2 Diabetes

Diabetic Retinopathy

Diabetic retinopathy is one of the most important microvascular complications in type 2 diabetes (T2DM) and is a leading cause of acquired blindness in the industrialized world in persons between the ages of 25 and 74 years (Sheetz and King, 2002). The prevalence of diabetic retinopathy increases with duration of T2DM and occurs in three fourths of all persons with T2DM after more than 10 years of the disease.

After a patient has had T2DM for more than 25 years, about 90% of have background retinopathy, and between 8% and 26% also have proliferative retinopathy. The lesions of diabetic retinopathy can be grouped into those associated with background, preproliferative and proliferative retinopathy. The earliest histopathological hallmark of diabetic retinopathy is loss of pericytes. Background retinopathy includes microaneurysms, dot and the flame hemorrhages, and hard exudates. Microaneurysms arise from the terminal capillaries of the retina and dot and flame hemorrhages appear when erythrocytes escape from the microneurysmis. The retinal vessels are abnormally permeable and leak serous fluid, leading to the formation of hard exudates. With increasingly severe retinopathy, the abnormal vessels can become occluded, leading to retinal ischemia with infarctions of the retina seen as soft, or "cotton wool" exudates (proliferative retinopathy). As a response to ischemia, new vessels develop (neovascularization), and this stage, characterized by new vessels proliferating out of the retinal surface and into the vitreous cavity, is called proliferative retinopathy. Such vessels are fragile and tend to bleed into the vitreous, resulting in subsequent fibroproliferative changes with retinal traction and detachment and loss of vision (Boel et al, 1995).

Diabetic Nephropathy

Diabetic nephropathy has become the leading cause of end stage renal disease worldwide and is associated with an increased cardiovascular risk (Obineche and Adem, 2005). The average duration of type 2 diabetes (T2DM) before the development of diabetic nephropathy is 15-25 years, but only 30%-40% of all patients develop proteinuria. The incidence of nephropathy does not rise continuously with increasing duration of T2DM. It is first characterized by glomerular hemodynamic abnormalities that result in glomerular hyperfiltration, leading to glomerular damage as evidenced by microalbuminuria. As glomerular function continues to decline, overt proteinuria, decreased glomerular filtration rate, and end-stage renal failure will result. Persistently elevated urinary albumin excretion (UAE) above 300 mg/24 h, in a diabetic patient without clinical or laboratory evidence of urinary tract infection or kidney disease other than glomerulosclerosis is a hallmark in the diagnosis of clinical diabetic nephropathy. This clinical syndrome is characterized by hypertension and a progressive, relentless decline of kidney function. The mortality is high, preferentially caused by cardiovascular diseases, and, in the survivors, end-stage renal failure develops within 5-10 years (Boel et al, 1995; Sheetz and King, 2002).

Diabetic Neuropathy

About half of all people with type 2 diabetes (T2DM) have some degree of diabetic neuropathy, which can present as either a polyneuropathy or a mononeuropathy. A peripheral, symmetric sensorimotor neuropathy is the most common form of diabetic neuropathy. The prevalence of neuropathy rose with increasing duration of T2DM and this complication is found in most long-term diabetic patients, independent of the existence of other diabetic complications. Symptoms include; loss of sensation and paraesthesia, and, in a minority, painful peripheral neuropathy with lancinating and burning dysesthesia. Because loss of sensation in feet and altered foot architecture make foot care difficult, the major risk posed by peripheral neuropathy is foot trauma and diabetic ulcers.

Autonomic neuropathy most often affects erectile function, bladder function, cardiac function, and vascular tone, and less often gastric and intestinal motility. Cardiac autonomic neuropathy results in resting tachycardia and postural hypotension (Boel et al, 1995; Sheetz and King, 2002).

Type 2 diabetes (T2DM) is associated with a greatly increased risk of cardiovascular disease, which cannot be explained by known risk factors, such as smoking, hypertension, and dyslipidemia. Studies indicate that hyperglycemia is an important contributor to the development of these complications (Lapolla et al, 2007). The connection between T2DM and macrovascular disease is so strong that the current NCEP guidelines have elevated T2DM to the level of a "cardiac risk equivalent." This means that the presence of T2DM carries the same risk for a future cardiac event as established cardiovascular disease. It is said that atherosclerotic disease and T2DM "spring from the same soil." Persons with type T2DM are at two to four times greater risk of myocardial infarction and stroke compared to those without T2DM. A predominant part of this increased risk is due to the common underlying problem of insulin resistance and clustering of cardiovascular risk factors in T2DM. Several observational studies have shown an association between level of glycemia and macrovascular events. Individuals with T2DM are at increased risk not only for CVD, but also for greater cardiovascular mortality. Age adjusted death rates of patients with T2DM are twice those of non diabetic individuals. Furthermore, 75% of the excess mortality in men and 57% of the excess mortality in women were attributable to CVD (Kleinman et al, 1988). An estimated 25% to 46% of patients with T2DM die of ischemic heart disease, 6% to 22% die of other forms of heart disease, and 2% to 16% die of cerebrovascular disease (Kleinman et al, 1988; Bonow and Gheorghiade, 2004). Individuals with T2DM who have had a prior myocardial infarction (MI) also experience increased rates of reinfarction, congestive heart failure, and death (ADA, 1998; Miettinen et al, 1998). In addition, excess risk of CVD may exist in non diabetic individuals who have abnormal fasting blood glucose levels, impaired glucose tolerance, and insulin resistance.

Coronary artery disease (CAD) is the most common cause of death in adults with type 2 diabetes (T2DM) and is responsible for much of the serious morbidity seen in these patients. Compared with non diabetic individuals, patients with T2DM develop heart disease earlier in life and are much more likely to die of it. Individuals with T2DM experience over 4 times the incidence of CAD seen in non diabetic controls. The age-adjusted incidence of MI is also significantly higher in both men and women with T2DM than in their non diabetic counterparts. Thus, patients with T2DM who had no history of MI were at as great a risk of infarction during the next 7 years as were their non diabetic counterparts who had a history of infarction at baseline. In measurements of the carotid artery, the thickness of the intimal wall in patients who had T2DM without CAD was similar to that seen in non diabetic patients with CAD (Haffner et al, 1998).

Type 2 diabetes (T2DM) is also a significant contributor to cerebrovascular disease. Hyperglycemia, hyperlipidemia, and hypertension all lead to carotid artery atherosclerosis, as demonstrated by the greater incidence of calcified atheromas in the carotid arteries of patients with T2DM and by an increased severity of vascular narrowing (Fabris et al, 1994). The frequency of stroke in patients with T2DM is 3.5 times greater than that observed in individuals without this disease (Himmelmann et al, 1988). People with T2DM may also be more likely to suffer recurrent stroke (Hankey et al, 1998). People with T2DM, women in particular, have a dramatically increased risk of stroke mortality (Tuomilehto et al, 1996). T2DM is also strongly associated with stroke-related dementia. This association is even more prominent in African Americans and Hispanic Americans, with 33% to 36% of stroke-related dementia in these 2 groups attributed to T2DM, compared with only 17% among white Americans.

Peripheral arterial disease claims a greater toll on patients with type 2 diabetes (T2DM). The risk of peripheral arterial disease in patients with T2DM is 2.5 to 5 times greater than that of non diabetic individuals, and the probability of developing peripheral arterial disease increases with the duration of T2DM (Uusitupa et al, 1990; Tuomilehto et al, 1996). In addition to a greater likelihood of peripheral arterial disease, individuals with T2DM experience significantly increased morbidity and mortality associated with this condition. The severity of arterial disease in the profunda femoris and all arterial segments below the knee is significantly greater in patients with T2DM. People with T2DM also are more likely to experience painful, disabling symptoms such as intermittent claudication, and are 5 times more likely to undergo lower extremity amputation. Moreover, people with T2DM and peripheral arterial disease are at greater risk of dying than are non diabetic patients with this condition (Jude et al, 2001). Changes in the plasma lipoprotein profile are characteristic of T2DM. Increased plasma levels of VLDL-C, VLDL-triglyceride, and LDL-triglyceride as well as decreased plasma levels of HDL-cholesterol have been found to be associated with intermittent claudication in patients with T2DM. In non diabetic patients, high plasma concentrations of VLDL-C and LDL-cholesterol are associated with claudication (Uusitupa et al, 1990).

Although the most common cause of death in patients with type 2 diabetes (T2DM) is CAD, congestive heart failure, consequent to myocardial ischemic injury, also occurs more frequently in patients with T2DM than in non diabetics. Since infarct size is similar in patients with and without T2DM, the increased incidence of congestive heart failure seems to result from an impaired diastolic function that is characteristic of T2DM-associated myocardial disease. Patients with T2DM also have other cardiac abnormalities that may contribute to left ventricular dysfunction. Compared with matched controls, patients with T2DM have a reduced myocardial flow reserve, even in the absence of overt heart disease. The inability to increase myocardial blood flow has been found to be related to long-term control of blood glucose levels. In addition, the excess turnover of free fatty acids characteristic of T2DM may lead to intracardiac conduction disturbances and arrhythmias, interference with adenosine triphosphate-dependent pumps, and calcium overload and contractile dysfunction. Finally, T2DM and hypertension may interact to cause structural myocardial changes (Yokoyama et al, 1997; Solang et al, 1999; Liu et al, 2001).

Therefore, the enormous burden of cardiovascular disease can be reduced by educating the public and health care providers, and taking practical measures to ameliorate the situation. In the clinical setting, this translates into increased vigilance, screening, treatment of comorbidities, and appropriate use of antiplatelet agents in patients with T2DM.

Studies confirm that hyperglycemia-induced oxidative stress plays a key role in the development of diabetic complications. A single early phenomenon, increased superoxide production at the mitochondrial level, explains the activation of all the recognized pathways involved in the development of diabetic complications. Free radicals are very reactive chemical species, and can cause oxidation injury to the living beings by attacking the macromolecules like lipids, carbohydrates, proteins and nucleic acids. Under normal physiological conditions, there is a critical balance in the generation of oxygen free radicals and antioxidant defense systems used by organisms to deactivate and protect themselves against free radical toxicity (Sies, 1991; Halliwell and Whiteman, 2004).

The human body contains a complex antioxidant system aimed at neutralizing free radicals that are continually generated during normal cellular metabolic processes. This finely regulated balance can be disrupted in situations when increased amounts of reactive species are chronically or acutely generated as a result of pathologies such as type 2 diabetes (T2DM), cardiovascular disease, or acute ischemia. Impairment in the oxidant/antioxidant equilibrium creates a condition known as oxidative stress. Oxidative stress is known to be a component of molecular and cellular tissue damage mechanisms in a wide spectrum of human diseases (Halliwell, 2001; Dalle-Donne et al, 2006). In this framework, among the biochemical alterations characteristic of hyperglycemia, factors involved in determining the chronic complications atherosclerotic disease are:

• • Formation of advanced glycation end products (AGE's)

  • Increased polyol pathway flux

• • Increased hexosamine pathway flux

  • Protein kinase C activation

All of these molecular mechanisms reflect a single hyperglycemia-induced process of overproduction of superoxide by the mitochondrial electron transport chain. Thus, hyperglycemia and increased oxidative stress (Giuliano et al, 1996) lead to tissue damage through common pathways. In particular, AGE's may cause damage through the formation of abnormal cross-links in collagen, thus contributing to vascular stiffening. The modification of lipoprotein, as a result of glycation, may contribute to foam cell formation (Brownlee, 2001; Vlassara and Palace, 2002; Yan et al, 2003; Basta et al, 2004). Studies report that the serum level of AGE's is increased in T2DM patients with coronary heart disease (Ono et al, 1999; Kilhovd et al, 1999; Aso et al, 2000). Immunohistochemical studies have also shown that AGE's accumulate in coronary atherosclerotic plaques and cardiac tissue of patients with T2DM (Nakamura et al, 1993).

Among AGE's in patients with T2DM, high serum pentosidine (a marker of glycoxidation induced cross linking) is associated with both increased carotid intima media wall thickness and arterial stiffening (Yoshida et al, 2005). Malondialdehyde (MDA) is frequently measured as an indicator of lipid peroxidation and oxidative stress in vivo and is elevated in patients with T2DM with macroangiopathy (Gallou et al, 1993). Peripheral artery disease (PAD) is a strong predictor of coronary and carotid atherosclerosis (Walters et al. 1992; Zheng et al, 1997) and affects about 29% of patients with T2DM (Hirsch et al, 2001). Hyperglycemia induces the overproduction of oxygen free radicals and consequently increases the protein oxidation and lipid peroxidation. A significant difference in the mean plasma concentration of total antioxidant status has been observed in IDDM patients. Recent findings suggest that T2DM in an altered metabolic state of oxidation-reduction and that it is convenient to give therapeutic interventions with antioxidants (Ramakrishna and Jailkhani, 2007). In T2DM, oxidative stress plays a key role in the pathogenesis of vascular complications, and an early step in such damage is considered the development of endothelial dysfunction (Giugliano et al, 1996; Cai and Harrison, 2000). Some studies have demonstrated that hyperglycemia directly induces, in both persons with T2DM and normal subjects, an endothelial dysfunction and attenuates endothelium-dependent relaxation (Bohlen and Lash, 1993; Giugliano et al, 1997; Kawano et al, 1999).

Other studies (Tesfamarian and Coehen, 1992; Ceriello et al, 2000) showed that this effect, mediated by production of free radicals, is contrasted by antioxidants. Recently Brownlee (Brownlee, 2001) has noted the key role of superoxide production in endothelial cells during hyperglycemia in the pathogenesis of diabetic complications. This is consistent with the four pathways involved in the development of diabetic complications:

• • Increased polyol pathway flux

  • Increased formation of advanced glycosylation end products (AGE's)

• • Activation of protein kinase C (PKC)

  • Increased hexosamine pathway flux

Superoxide generation in hyperglycemia represents only a first step in the production of the endothelial dysfunction in T2DM. Nitric oxide production plays a central role in modulating endothelial function (Moncada et al, 2001). Nitric oxide is generated from the metabolism of L-arginine by the enzyme nitric oxide synthase (NOS), of which there are three isoforms: the constitutive types bNOS (brain NOS) and eNOS (endothelial NOS) and the inducible type iNOS (Nathan and Xie, 1994); the latter is induced de novo by various stimuli, including hyperglycemia, and leads to the production of large amounts of nitric oxide (Baox et al, 1993). The superoxide anion may quench nitric oxide, thereby reducing the efficacy of a potent endothelium-derived vasodilator system that participates in the general homeostasis of the vasculature (Benz et al, 2002), and evidence suggests that during hyperglycemia, reduced nitric oxide availability exists.

Consistently, in hyperglycemic conditions an overproduction of both superoxide and nitric oxide has been reported, with a threefold increase in superoxide generation (Cosentino et al, 1997). The simultaneous over generation of nitric oxide and superoxide favors the production of a toxic reaction product, the peroxynitrite anion. The peroxynitrite anion is cytotoxic because it oxidizes sulfhydryl groups in proteins, initiates lipid peroxidation, and nitrates amino acids such as tyrosine, which affects many signal transduction pathways (Beckman and Koppenol, 1996). A currently favored hypothesis is that oxidative stress, through a single unifying mechanism of superoxide production, is the common pathogenic factor leading to insulin resistance, b-cell dysfunction, impaired glucose tolerance (IGT) and ultimately to T2DM. Furthermore, this mechanism has been implicated as the underlying cause of both the macrovascular and microvascular complications associated with T2DM. It follows that therapies aimed at reducing oxidative stress would benefit patients with T2DM and those at risk for developing T2DM (Wright et al, 2006).

The human body contains a complex antioxidant system aimed at neutralizing free radicals continually generated during normal cellular metabolic processes. This finely regulated balance can be disrupted in situations when increased amounts of reactive species are chronically or acutely generated as a result of pathologies such as type 2 diabetes (T2DM), cardiovascular disease, or acute ischemia (Cozma, 2007). In T2DM, reduced antioxidant defenses have also been described, thus providing an additional contribution to the development of chronic complications (Ceriello et al, 1997). Alterations in the antioxidant defense system in T2DM have recently been reviewed. Reactive species can be eliminated by a number of enzymatic and nonenzymatic antioxidant mechanisms.

SOD immediately converts superoxide anion (•O2-) to hydrogen peroxide (H2O2), which is then detoxified to water either by catalase in the lysosomes or by glutathione peroxidase in the mitochondria. Another enzyme that is important is glutathione reductase, which regenerates glutathione that is used as a hydrogen donor by glutathione peroxidase during the elimination of H2O2. Maritim and colleagues recently reviewed in detail that type 2 diabetes (T2DM) has multiple effects on the protein levels and activity of these enzymes, which further augment oxidative stress by causing a suppressed defense response (Maritim et al, 2003).

Nonenzymatic antioxidants include vitamins A, C and E; glutathione; a-lipoic acid; carotenoids; trace elements like zinc and selenium; coenzyme Q10 (CoQ10); and cofactors like folic acid, uric acid, albumin, and vitamins B1, B2, B6 and B12. Glutathione (GSH) acts as a direct scavenger as well as a cosubstrate for GSH peroxidase. It is a major intracellular redox tampon system. Vitamin E is a fat-soluble vitamin that prevents lipid peroxidation. It exists in 8 different forms, of which a-tocopherol is the most active form in humans. Hydroxyl radical reacts with tocopherol, forming a stabilized phenolic radical which is reduced back to the phenol by ascorbate and NAD(P)H dependent reductase enzymes (Hensley et al, 2000; Hensley et al, 2004). CoQ10 is an endogenously synthesized compound that acts as an electron carrier in the Complex II of the mitochondrial electron transport chain. Brownlee et al reported that this is the site of superoxide generation under hyperglycemic conditions (Nishikawa et al, 2000; Brownlee, 2004). Vitamin C (ascorbic acid) increases nitric oxide production in endothelial cells by stabilizing NOS cofactor tetrahydrobiopterin (BH4) (Heller et al, 2001).

There are several lines of evidence to suggest that antioxidant defenses may be lower in type 2 diabetes (T2DM) (Laight et al 2000). These include reports of:

• • Reduced plasma/serum total antioxidant status or free radical scavenging activity

  • Increased plasma oxidisability in type 2 diabetics

• • Reduced levels of specific antioxidants such as ascorbic acid and vitamin E

  • Diminution in the endothelial synthesis of nitric oxide resulting of oxidative stress has been suggested in T2DM

Antioxidant nutrients may reduce oxidative stress. In general, exogenous antioxidants can compensate for the lower plasma antioxidant levels often observed in NIDDM and in individuals at risk of developing type 2 diabetes (T2DM), whether their T2DM is primarily genetic in origin or due to obesity and a sedentary lifestyle. It has long been suspected, but only recently demonstrated, that the consumption of fruits and vegetables rich in vitamins and other antioxidants can increase overall antioxidant status. In studies of humans and rodents, dietary supplementation with antioxidants is associated with decreased risk of NIDDM and induced changes that could be beneficial in reducing insulin resistance and protecting vascular endothelium (Ruhe and McDonald, 2001).

Antioxidant therapy, achieved by supplementation with pharmaceutical preparations of antioxidant nutrients and/or non-nutrients, may conceivably confer both cardiovascular and metabolic benefits in T2DM. Furthermore, it is apparent that antioxidant intervention in both experimental and clinical diabetes can reverse endothelial dysfunction which may itself be related to an insufficient antioxidant defense (Laight et al 2000). Since numerous studies demonstrated that oxidative stress, mediated mainly by hyperglycemia-induced generation of free radicals, contributes to the development and progression of T2DM and related contributions, it became clear that ameliorating oxidative stress through treatment with antioxidants might be an effective strategy for reducing diabetic complications.