**3. Pathological complications of diabetes mellitus**

The high blood glucose level (hyperglycaemia) that accompanies T1DM and type 2 diabetes mellitus (T2DM) can cause serious health complications including ketoacidosis, kidney failure, heart disease, stroke, and blindness. Patients are often diagnosed with diabetes when they see a physician for clinical signs such as excessive thirst, urination, and hunger [7]. The direct symptoms of type-2 diabetes can be mild and may cause minimal interruption to activities of daily living. However, it is the complications of the disease which lead to damage to vital

Diabetes in the young is often categorized as Type 1 and this comprises the auto-immune Type 1A and non-auto immune Type 1B. T2DM which is mainly diagnosed in adults is increasingly being reported in young people. The increased prevalence of T2DM in young people is associated with the increasing rates of obesity in young people. Type 2 diabetes accounts for

Several statistics from various scientific studies on the incidence, prevalence and global burden of diabetes mellitus are available. While there might be minor discrepancies in these statis‐ tics, the consensus is that they are ominous and call for urgent and definitive action on this

DM is estimated to affect 2.8% of the world's population at present and projected to cross 5.4% mark by 2025 [13]. Over the last decades, the prevalence of diabetes mellitus has reached epidemic proportions in Western societies, and is even higher in some developing countries [14 -16]. According to Shaw *et al.* [17], the world's prevalence of diabetes among adults (aged 20–79 years) will be 6.4%, affecting 285 million adults, in 2010, and will increase to 7.7%, and 439 million adults by 2030 and, between 2010 and 2030, there will be a 69% increase in numbers of adults with diabetes in developing countries and a 20% increase in developed countries. More recently, the International Diabetes Federation (IDF) estimated that in 2011 there were 366 million people with diabetes and this was expected to rise to 552 million by 2030 [18]. The International Diabetes Federation (IDF) reported that 151 million people had diabetes in the 172 IDF member countries with a forecast that 334 million people will have the disease in 2025

**2. Prevalence, global burden and increasing incidence of diabetes**

[19]. The human cost of diabetes has been put at one death every 10 seconds [20].

Zhang *et al.*[21] estimated that global health expenditures to prevent and treat diabetes and its complications would be at US dollar (USD) 376 billion in 2010 and that by 2030, this number will exceed USD490 billion. In addition, diabetes leads to loss in productivity and economic growth. The American Diabetes Association estimated that the US economy lost USD58 billion, equivalent to about an half of the direct health care expenditure on diabetes in 2007, as a result of lost earnings due to lost work days, restricted activity days, lower productivity at work, mortality and permanent disability caused by diabetes [21]. Diabetes and its complications place huge burdens upon individuals, their careers and families and have crippling effects

organs, and consequently, to substantial morbidity and mortality.

90% to 95% of all cases of diabetes [8-10].

140 Antioxidant-Antidiabetic Agents and Human Health

upon national health services [20].

disease [11,12].

Persistent hyperglycaemia and the development of diabetes-specific microvascular (retinop‐ athy, neuropathy and nephropathy) and macrovascular (heart attack, stroke and peripheral arterial disease) complications are the main characteristics of all forms of diabetes mellitus. The importance of protecting the body against persistent elevation of blood glucose cannot be overemphasized because its direct and indirect effects on the human vascular system are the major cause of morbidity and mortality in both T1DM and T2DM [22]. Hospitalisations for complications account for more than half of the healthcare costs of T2DM and three-quarters of people with diabetes die from cardiovascular disease. Research has shown that the risk of development of both microvascular and macrovascular complications associated with elevated blood glucose increases with the length of time blood glucose is uncontrolled [23,24].

As a result of the association of diabetes with accelerated atherosclerotic macrovascular disease affecting arteries that supply the heart, brain and lower extremities, patients with diabetes have a much higher risk of myocardial infarction, stroke and limb amputation [25]. Lower limb amputations are at least 10 times more common in people with diabetes than in non-diabetic individuals in developed countries; more than half of all non-traumatic lower limb amputa‐ tions are due to diabetes [26].

Diabetes is one of the leading causes of visual impairment and blindness in developed countries [27]. Retinopathy may begin to develop as early as 7 years before the diagnosis of diabetes in patients with T2DM [28]. Osmotic stress from sorbitol accumulation has been postulated as an underlying mechanism in the development of diabetic microvascular complications, including diabetic retinopathy [22]. According to Massin *et al* [29] lens opaci‐ fication leading to cataract is a frequent comorbidity of diabetes, as adults with T2DM are five times more often affected than the general population. They also reported that while juvenile diabetic cataract is rare, adult-onset, mostly cortical cataract in T2DM patients is similar to agerelated cataract in the general population, except for an earlier onset and greater prevalence [29,30]. Major risk factors for cataract in T2DM include hyperglycaemia, diabetes duration and the presence of diabetic retinopathy, although specific risk factors or markers may differ according to cataract subtype. Smoking, for example, is associated with nuclear opacities, whereas ultraviolet radiation increases the risk for cortical opacities, and high blood pressure and corticosteroids raise the odds for subcapsular cataract [31]. Various pathophysiological mechanisms are involved in cataract formation, including osmosis-driven lens overhydration triggered by the polyol pathway (mostly ascribed to juvenile cataract), lens protein glycation and an excess of free radicals, with the latter being particularly associated with the nuclear subset of age-related cataract [32,33].

Studies have shown an increased incidence of erectile dysfunction (ED) in diabetes patients. In addition, ED appears to arise about 10 years earlier in diabetic patients than in the general population [34] and is more severe, decreasing health-related quality of life. ED is most often a forewarning of cardiovascular disease; thus, the treatment of ED among diabetics is a priority. Diabetic ED is multifactorial in aetiology and more resistant to treatment compared with nondiabetic ED [35]

Diabetic neuropathy is the presence of symptoms and/or signs of peripheral nerve dysfunction in people with diabetes after the exclusion of other causes [36]. More than 80% of amputations occur after foot ulceration or injury, which can result from diabetic neuropathy [37].

term pre-diabetes has been used to describe the condition of individuals with a high risk of developing diabetes in the future and already showing a glycaemic abnormality [50,51].

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People with diabetes require at least two to three times the health-care resources compared to people who do not have diabetes, and diabetes care may account for up to 15% of national

Many authors agreed that hyperglycaemia causes tissue damage through the following clearly defined mechanisms [25, 53]: increased flux of glucose and other sugars through the polyol pathway, increased intracellular formation of advanced glycation end products (AGEs), increased expression of the receptor for AGEs and its activating ligands, activation of protein

polyol pathway. It is a cytosolic, monomeric oxidoreductase that catalyses the reduced nicotinamide adenine dinucleotide phosphate (NADPH)-dependent reduction of a wide variety of carbonyl compounds, including glucose [54]. At the normal glucose concentrations found in non-diabetics, metabolism of glucose by this pathway is a very small percentage of total glucose use. But in a hyperglycaemic environment, increased intracellular glucose results in its increased enzymatic conversion to the polyalcohol sorbitol, with concomitant decreases in NADPH [25,55,56]. In the polyol pathway, sorbitol is oxidized to fructose by the enzyme

hyperglycaemia varies from 33% of total glucose use in the rabbit lens to 11% in human erythrocytes [25]. Thus, the contribution of this pathway to diabetic complications may be very much species, site and tissue dependent [25]. It has also been proposed that reduction of glucose to sorbitol by NADPH consumes NADPH [25]. As NADPH is required for regener‐ ating reduced glutathione (GSH), this could induce or exacerbate intracellular oxidative stress. Decreased levels of GSH have in fact been found in the lenses of transgenic mice that overex‐ press aldose reductase, and this is the most likely mechanism by which increased flux through the polyol pathway has deleterious consequences [57]. This conclusion is further supported by recent experiments with homozygous knockout mice deficient in aldose reductase, which showed that, in contrast to wild-type mice, diabetes neither decreased the GSH content of

AGEs are found in increased amounts in diabetic retinal vessels and renal glomeruli and intracellular hyperglycaemia appears to be the primary initiating event in the formation of both intracellular and extracellular AGEs [23]. AGEs contribute to diabetic complications via three principal mechanisms: the modification of intracellular proteins including, most importantly, proteins involved in the regulation of gene transcription [58,59]; diffusion of these AGE precursors out of the cell and their modification of extracellular matrix molecules nearby, which changes signaling between the matrix and the cell and causes cellular dysfunction [60,

1-oxidoreductase, EC 1.1.1.21) is the first enzyme in the

reduced to NADH. Flux through this pathway during

kinase (PK) C isoforms, and overactivity of the hexosamine pathway.

sciatic nerve nor reduced motor nerve conduction velocity [25].

**3.2. Increased intracellular formation of advanced glycation end-products**

health care budgets [52].

**3.1. Increased polyol pathway flux**

Aldose reductase (alditol:NAD(P)+

sorbitol dehydrogenase, with NAD+

Diabetic nephropathy has been defined by proteinuria > 500 mg in 24 hours in the setting of diabetes, which is however preceeded by lower degrees of proteinuria, or "microalbuminuria." Microalbuminuria is defined as albumin excretion of 30–299 mg/24 hours. Without interven‐ tion, diabetic patients with microalbuminuria typically progress to proteinuria and overt diabetic nephropathy [22]. This progression occurs in both type1 and type 2 diabetes. As many as 7% of patients with type 2 diabetes may already have microalbuminuria at the time they are diagnosed with diabetes [38]. In the European Diabetes Prospective Complications Study, the cumulative incidence of microalbuminuria in patients with type 1 diabetes was ~ 12% during a period of 7 years. In the U.K. Prospective Diabetes Study (UKPDS), the incidence of microalbuminuria was 2% per year in patients with type 2 diabetes, and the 10-year prevalence after diagnosis was 25% [38-40]. Diabetic nephropathy can progress to end-stage renal disease. Diabetes is the leading cause of renal failure in the United States accounting for nearly 44 percent of new cases [40].

Diabetes increases the risk that an individual will develop cardiovascular disease (CVD) [22]. Although the precise mechanisms through which diabetes increases the likelihood of athero‐ sclerotic plaque formation are not completely defined, the association between the two is profound. CVD is the primary cause of death in people with eithertype 1 ortype 2 diabetes and accounts forthe greatest component of health care expenditures in people withdiabetes [41,42]. Amongmacrovasculardiabetes complications, coronaryheartdiseasehas beenassociatedwith diabetes in numerous studies beginning with the Framingham study [43]. More recent studies have shown that the risk of myocardial infarction (MI) in people with diabetes is equivalent to the risk in non-diabetic patients with a history of previous MI [44]. These discoveries have led to new recommendations by the American Diabetes Association (ADA) and American Heart Association (AHA) that diabetes be considered a coronary artery disease risk equivalent rather thana riskfactor.Patientswithtype 1diabetesbear adisproportionateburdenof coronaryheart disease. Studies have shown that these patients have a higher mortality from ischemic heart disease at all ages compared to the general population [45].

Diabetes is also a strong independent predictor of risk of stroke [46]. Patients with type 2 diabetes have a much higher risk of stroke, with an increased risk of 150–400%. Risk of strokerelated dementia and recurrence, as well as stroke-related mortality, is elevated in patients with diabetes [47]. In addition, the risk of tuberculosis is three times higher among people with diabetes [48].

Insulin resistance and glucose intolerance are components of metabolic syndrome, a group of metabolic risk factors that predisposes people to diseases related to fatty buildups in artery walls such as coronary heart disease, which can lead to heart attack, stroke and peripheral vascular disease [49]. People with this syndrome are also more likely to develop type 2 diabetes. Other components of metabolic syndrome are abdominal obesity, atherogenic dyslipidemia, raised blood pressure, proinflammatory state and prothrombotic state [49]. The term pre-diabetes has been used to describe the condition of individuals with a high risk of developing diabetes in the future and already showing a glycaemic abnormality [50,51].

People with diabetes require at least two to three times the health-care resources compared to people who do not have diabetes, and diabetes care may account for up to 15% of national health care budgets [52].

Many authors agreed that hyperglycaemia causes tissue damage through the following clearly defined mechanisms [25, 53]: increased flux of glucose and other sugars through the polyol pathway, increased intracellular formation of advanced glycation end products (AGEs), increased expression of the receptor for AGEs and its activating ligands, activation of protein kinase (PK) C isoforms, and overactivity of the hexosamine pathway.

#### **3.1. Increased polyol pathway flux**

Diabetic neuropathy is the presence of symptoms and/or signs of peripheral nerve dysfunction in people with diabetes after the exclusion of other causes [36]. More than 80% of amputations

Diabetic nephropathy has been defined by proteinuria > 500 mg in 24 hours in the setting of diabetes, which is however preceeded by lower degrees of proteinuria, or "microalbuminuria." Microalbuminuria is defined as albumin excretion of 30–299 mg/24 hours. Without interven‐ tion, diabetic patients with microalbuminuria typically progress to proteinuria and overt diabetic nephropathy [22]. This progression occurs in both type1 and type 2 diabetes. As many as 7% of patients with type 2 diabetes may already have microalbuminuria at the time they are diagnosed with diabetes [38]. In the European Diabetes Prospective Complications Study, the cumulative incidence of microalbuminuria in patients with type 1 diabetes was ~ 12% during a period of 7 years. In the U.K. Prospective Diabetes Study (UKPDS), the incidence of microalbuminuria was 2% per year in patients with type 2 diabetes, and the 10-year prevalence after diagnosis was 25% [38-40]. Diabetic nephropathy can progress to end-stage renal disease. Diabetes is the leading cause of renal failure in the United States accounting for nearly 44

Diabetes increases the risk that an individual will develop cardiovascular disease (CVD) [22]. Although the precise mechanisms through which diabetes increases the likelihood of athero‐ sclerotic plaque formation are not completely defined, the association between the two is profound. CVD is the primary cause of death in people with eithertype 1 ortype 2 diabetes and accounts forthe greatest component of health care expenditures in people withdiabetes [41,42]. Amongmacrovasculardiabetes complications, coronaryheartdiseasehas beenassociatedwith diabetes in numerous studies beginning with the Framingham study [43]. More recent studies have shown that the risk of myocardial infarction (MI) in people with diabetes is equivalent to the risk in non-diabetic patients with a history of previous MI [44]. These discoveries have led to new recommendations by the American Diabetes Association (ADA) and American Heart Association (AHA) that diabetes be considered a coronary artery disease risk equivalent rather thana riskfactor.Patientswithtype 1diabetesbear adisproportionateburdenof coronaryheart disease. Studies have shown that these patients have a higher mortality from ischemic heart

Diabetes is also a strong independent predictor of risk of stroke [46]. Patients with type 2 diabetes have a much higher risk of stroke, with an increased risk of 150–400%. Risk of strokerelated dementia and recurrence, as well as stroke-related mortality, is elevated in patients with diabetes [47]. In addition, the risk of tuberculosis is three times higher among people with

Insulin resistance and glucose intolerance are components of metabolic syndrome, a group of metabolic risk factors that predisposes people to diseases related to fatty buildups in artery walls such as coronary heart disease, which can lead to heart attack, stroke and peripheral vascular disease [49]. People with this syndrome are also more likely to develop type 2 diabetes. Other components of metabolic syndrome are abdominal obesity, atherogenic dyslipidemia, raised blood pressure, proinflammatory state and prothrombotic state [49]. The

disease at all ages compared to the general population [45].

occur after foot ulceration or injury, which can result from diabetic neuropathy [37].

percent of new cases [40].

142 Antioxidant-Antidiabetic Agents and Human Health

diabetes [48].

Aldose reductase (alditol:NAD(P)+ 1-oxidoreductase, EC 1.1.1.21) is the first enzyme in the polyol pathway. It is a cytosolic, monomeric oxidoreductase that catalyses the reduced nicotinamide adenine dinucleotide phosphate (NADPH)-dependent reduction of a wide variety of carbonyl compounds, including glucose [54]. At the normal glucose concentrations found in non-diabetics, metabolism of glucose by this pathway is a very small percentage of total glucose use. But in a hyperglycaemic environment, increased intracellular glucose results in its increased enzymatic conversion to the polyalcohol sorbitol, with concomitant decreases in NADPH [25,55,56]. In the polyol pathway, sorbitol is oxidized to fructose by the enzyme sorbitol dehydrogenase, with NAD+ reduced to NADH. Flux through this pathway during hyperglycaemia varies from 33% of total glucose use in the rabbit lens to 11% in human erythrocytes [25]. Thus, the contribution of this pathway to diabetic complications may be very much species, site and tissue dependent [25]. It has also been proposed that reduction of glucose to sorbitol by NADPH consumes NADPH [25]. As NADPH is required for regener‐ ating reduced glutathione (GSH), this could induce or exacerbate intracellular oxidative stress. Decreased levels of GSH have in fact been found in the lenses of transgenic mice that overex‐ press aldose reductase, and this is the most likely mechanism by which increased flux through the polyol pathway has deleterious consequences [57]. This conclusion is further supported by recent experiments with homozygous knockout mice deficient in aldose reductase, which showed that, in contrast to wild-type mice, diabetes neither decreased the GSH content of sciatic nerve nor reduced motor nerve conduction velocity [25].

#### **3.2. Increased intracellular formation of advanced glycation end-products**

AGEs are found in increased amounts in diabetic retinal vessels and renal glomeruli and intracellular hyperglycaemia appears to be the primary initiating event in the formation of both intracellular and extracellular AGEs [23]. AGEs contribute to diabetic complications via three principal mechanisms: the modification of intracellular proteins including, most importantly, proteins involved in the regulation of gene transcription [58,59]; diffusion of these AGE precursors out of the cell and their modification of extracellular matrix molecules nearby, which changes signaling between the matrix and the cell and causes cellular dysfunction [60, 61]; and diffusion of AGE precursors out of the cell and their modification of circulating proteins in the blood, such as albumin, which can then bind to AGE receptors and activate them thereby causing the production of inflammatory cytokines and growth factors, which in turn cause vascular pathology [62-65].

**4. Management of diabetes mellitus**

and insulin therapy.

of diabetes [82-85].

**4.2. Oral antidiabetic drugs**

**4.1. Diet and lifestyle modification**

unrefined) carbohydrate content.

Diabetes mellitus is a syndrome implying that efforts targeted at its management should be multifaceted. Adequate consideration should be given to all the accompanying comorbidities and all symptomatic and asymptomatic features. Efforts should be geared towards the attainment of normal or near normal glucose levels. The general objective of diabetes man‐ agement include to (i) relieve symptoms (ii) correct associated health problems and reduce morbidity, mortality and economic costs of diabetes (iii) prevent as much as possible acute and long-term complications (iv) monitor the development of such complications and provide timely intervention and, (v) improve the quality of life and productivity of the individual with diabetes [77]. The orthodox approach to the management of diabetes mellitus has always included lifestyle modification and dietary therapy, administration of oral antidiabetic drugs,

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Weight reduction and an increase in daily energy expenditure decrease insulin resistance and increase glucose tolerance [78]. Advice on diet and exercise are an important part of the treatment of T2DM and overweight patients are normally advised to restrict calorie intake, consume food with low total (especially saturated) fat content and high (predominately

Dietary and lifestyle modifications are regarded as the mainstay of treatment and management for T2DM. The majority of people with T2DM are overweight and usually have other metabolic disorders of the insulin resistance syndrome. Therefore, the major aims of dietary and lifestyle changes are to reduce weight, improve glycaemic control and reduce the risk of coronary heart disease (CHD), which accounts for 70- 80% of deaths among those with diabetes [79]. Even modest weight reduction is associated with a reduction in insulin resistance, a reduction in hepatic glucose production, and perhaps, an improved islet β-cell function [80,81]. Several studies have demonstrated the effectiveness of diet and exercise in reducing the progression

Fat is the most energy-rich of all nutrients and reduction of fat intake helps to reduce total energy intake, which is important for many people with type 2 diabetes and some with type 1 diabetes. Results from several research studies suggest that populations consuming a low saturated fat diet have lower incidence and mortality from CHD compared with those living in countries with a high intake of saturated fat and that reduced saturated fat intake is

Oral antidiabetic drugs (OADs) are normally introduced when lifestyle modifications fail to adequately control glycaemia. They are very useful for managing hyperglycaemia, especially in the early stages of disease. However, there are several limitations that prevent OADs from reaching their potentials [88]. Sulfonylureas cause hypoglycaemia by stimulating insulin

associated with reduced levels of low-density lipoprotein (LDL) – cholesterol [86,87].
