**3. High prevalence rates of complications related to diabetes in South Asians**

#### **3.1. Prevalence rate of macrovascular complication**

categories of diabetes: type 1 diabetes (T1DM), type 2 diabetes (T2DM), gestational diabetes (GDM) and other specific types of the disease [2, 3]. In T1DM, also known as insulin-dependent diabetes (IDDM), the body is unable to produce insulin because of the autoimmune destruction of pancreatic islet beta cells (β cells), and as a result, the glucose levels in the blood cannot be maintained at normal concentrations. It ranks as the most common chronic childhood disease. T2DM or noninsulin-dependent diabetes (NIDDM) is characterized by both impaired insulin secretion and impaired insulin action. This type is associated with aging, obesity, a family history of diabetes, physical inactivity and certain ethnicities, although the causes of some of these factors are not well-explored. In GDM, the most widely accepted definition is diabetes that develops by varying insulin sensitivity during pregnancy or diabetes first recognized during pregnancy; in the former case, treatment with insulin can often be finished after pregnancy, as this type of diabetes is acute. Among these categories, T2DM

Diabetes research has mainly focused on people living in developed countries as a disease caused by obesity. However, the prevalence rate of diabetes has been increasing in many developing and newly-industrialized nations as well. In this review, we focused on South Asia as one such region. The prevalence rate of diabetes and its complications in South Asia is higher than in other areas, such as Europe [4], and diabetes has recently become a serious health issue leading to death [5]. Therefore, comprehensive knowledge about the prevalence rate and causes of diabetes in South Asian countries is desired. As part of this review, we investigated the present state, characteristics and causes of diabetes in South Asia and proposed strategies for its prevention. We hope that this appraisal will encourage recognition of the serious state of diabetes among South Asians and become an effective index for eventually solving this issue.

South Asia comprises the Indian subcontinent and is home to a diverse population of ethnic, linguistic and religious groups. The total population of South Asia is about 1.5 billion, representing more than 20% of the global population. The countries that fall under this regional demarcation include India, Pakistan, Sri Lanka, Nepal, Bhutan, Maldives, Afghanistan and Bangladesh. With deviating definitions based on often substantially different reasons (usually political), the British Indian Ocean Territory, Mauritius, Iran and the Tibet Autonomous Region are sometimes included as part of the South Asian subcontinent as well. Nevertheless, for the purpose of this review, we defined South Asia as India, Pakistan, Sri Lanka, Nepal, Bhutan, Maldives, Afghanistan and Bangladesh and focused on the diabetes status of the

A recent study using a Diabetes Population Risk Tool in Canada showed that South Asians have the highest risk of developing diabetes [6], and another study estimated that the prevalence rate of diabetes in South Asians was around four times higher than in other ethnic groups [7]. The total number of people with diabetes in the world is estimated to increase from 171 million in 2000 to 366 million by 2030 [8]; this number among South Asians is predicted to reach 46 million in India, 14 million in Pakistan and 11.1 million in Bangladesh by 2030 [9].

**2. An overview of the prevalence of diabetes in South Asians**

accounts for about 85–95% of diabetes cases worldwide.

2 Diabetes and Its Complications

people living in these countries.

Diabetes is known to be strongly associated with many other disease and complications, and those ultimately lead to organ and tissue damage. The prevalence rates of macrovascular complications and atherosclerosis are especially high in diabetic patients, inducing adverse effects of ischemic heart disease [14], peripheral vascular disease and cerebrovascular disease. Diabetes is suspected to induce macrovascular complications and atherosclerosis. High blood glucose and insulin concentrations in diabetic patients induce structural and functional alterations and chronic inflammation at the arterial cell walls. Macrophages gather and invade the inflammation portion, forming plaque. This advanced plaque buildup is known as atherosclerosis. The main disease leading to death in diabetic patients is cardiovascular disease, with cerebrovascular disease and diabetic stroke being the second and third highest causes of death. The ratio of stroke in diabetic patients is two- to fourfold higher than in nondiabetic patients, and diabetics show a greater possibility of recurrence of stroke [15]. Furthermore, peripheral arterial disease (PAD), which is characterized by the occlusion of the arteries in the limb region and results in functional impairment and disability with intermittent claudication and pain, is also closely related to diabetes [15]. In most unfortunate cases, PAD causes foot ulceration, ultimately requiring amputation [16]. It is known that diabetic patients have a 25-times-greater risk of amputation than nondiabetes population.

Diabetes nephropathy is also a serious complication. High blood pressure induced by both atherosclerosis and the function of adipose tissue causes the dysfunction of renal tissue. In the early stages, albumin in the urine is excreted at 30–299 mg per 24 h, which is called "microalbuminuria" and leads to renal failure at the final stage. A study found that one-quarter of patients with T1DM suffers from microalbuminuria or its advanced stage, diabetes nephropathy [15]. Some studies have reported on the prevalence rate of diabetic nephropathy in South Asians [27]. A study conducted in 10 countries in Asia, including Pakistan, found that the ratio of patients developing microalbuminuria per diabetic patient was alarmingly high (58.6%) [28]. A similar study conducted in an urban setting in South India revealed that the prevalence rate of microalbuminuria per diabetic patients was 26.3%, although the prevalence rate of overt nephropathy was only 2.2% in the study subjects [29]. These studies suggested that duration of the diabetes and hypertension is highly correlated with the development of nephropathy in South Asians. Microalbuminuria caused by diabetes also induces peripheral nerve dysfunction, and half of diabetic patients consequently develop diabetic neuropathy [15]. The American Diabetic Association has stated that diabetic neuropathy is a sign of peripheral nerve dysfunction [30]. Among the symptoms of diabetic neuropathy, autonomic neuropathy is the most common. This symptom leads to an abnormal heart rate, loss of vascular control and cardiovascular autonomic dysfunction. Cardiac neuropathy caused by diabetes is the second-most common manifestation, depending on age, hypertension, smoking status and obesity. The prevalence rate of diabetic neuropathy in South Asia has been investigated. A study conducted in Sri Lanka reported that the prevalence rate of distal peripheral neuropathy (DPN) among T2DM patients was 24% (females and males: 26% and 20%, respectively). The prevalence rate of neuropathy among T2DM patients in South India was 19.1%, and this number is gradually increasing [31]. A similar study conducted in Indian states reported that the prevalence rate of diabetic neuropathy was 26.1% and was significantly associated with age, glycated hemoglobin and duration of diabetes [30]. Overall, **Figure 1** shows a schematic illustration of the

Diabetes Mellitus in South Asia

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**Figure 1.** Prevalence rates of diabetes and its complications in South Asia (DP: diabetic patients).

It has been reported that Asian patients with diabetes are at a higher risk of developing macrovascular complications, such as cardiovascular disease, than other ethnicities [17]. For instance, a study conducted in Pakistan revealed that 30.5% of the young adult patients diagnosed with ischemic stroke were diabetic—a much higher percentage than in Western settings [18]. Another study performed in ischemic stroke patients of <45 years of age in Sri Lanka revealed that 5% of the study group with ischemic stroke had diabetes [19]. A prospective study was also conducted in 2403 patients with ischemic stroke and 783 patients with intracerebral hemorrhaging in India as a representative South Asian country [20]. That report mentioned that Asian diabetic patients had a high risk of early death due to ischemic stroke [20]. Furthermore, reports on the risks of cardiovascular disease and coronary in the Indian subcontinent have suggested that a leading cause of those diseases was diabetes [21, 22].

#### **3.2. Prevalence rates of diabetic retinopathy, nephropathy and neuropathy**

Another serious complication in diabetic patients is dysfunction of the eyes, kidneys and nerves. Diabetic retinopathy, a typical peripheral microvascular complication, induces acute damage to the retina of the eye [23]. Diabetic retinopathy is divided into two categories: background and proliferative retinopathy [22]. In background retinopathy, slight hemorrhaging develops in the middle layers of the retina, appearing as dots. In proliferative retinopathy, the formation of new blood vessels occurs on the surface of the retina, and white areas on the retina are a sign of this type of disease. Several studies have shown that the occurrence of diabetes retinopathy is influenced by chronic insulin resistance and a high blood glucose concentration, which occur in obese patients [24]. A poorly controlled bloodsugar level is the most significant factor associated with the development of retinopathy. The prevalence rate of retinopathy in diabetic patients in South Asia has been explored in several studies. One study investigated the rate in patients newly diagnosed with diabetes in India and found that the rate was lower (5–7%) than in both Western countries and neighboring countries such as Pakistan (15%), Nepal (19.3%) and Sri Lanka (15%) [25]. However, a similar study conducted in an urban population in Chennai, India, revealed that the prevalence of diabetic retinopathy per diabetic patient was 18%, although the prevalence of diabetic retinopathy in the general population was only 3.5%. Furthermore, men were shown to be at a higher risk than women in that investigation [26].

Diabetes nephropathy is also a serious complication. High blood pressure induced by both atherosclerosis and the function of adipose tissue causes the dysfunction of renal tissue. In the early stages, albumin in the urine is excreted at 30–299 mg per 24 h, which is called "microalbuminuria" and leads to renal failure at the final stage. A study found that one-quarter of patients with T1DM suffers from microalbuminuria or its advanced stage, diabetes nephropathy [15]. Some studies have reported on the prevalence rate of diabetic nephropathy in South Asians [27]. A study conducted in 10 countries in Asia, including Pakistan, found that the ratio of patients developing microalbuminuria per diabetic patient was alarmingly high (58.6%) [28]. A similar study conducted in an urban setting in South India revealed that the prevalence rate of microalbuminuria per diabetic patients was 26.3%, although the prevalence rate of overt nephropathy was only 2.2% in the study subjects [29]. These studies suggested that duration of the diabetes and hypertension is highly correlated with the development of nephropathy in South Asians.

glucose and insulin concentrations in diabetic patients induce structural and functional alterations and chronic inflammation at the arterial cell walls. Macrophages gather and invade the inflammation portion, forming plaque. This advanced plaque buildup is known as atherosclerosis. The main disease leading to death in diabetic patients is cardiovascular disease, with cerebrovascular disease and diabetic stroke being the second and third highest causes of death. The ratio of stroke in diabetic patients is two- to fourfold higher than in nondiabetic patients, and diabetics show a greater possibility of recurrence of stroke [15]. Furthermore, peripheral arterial disease (PAD), which is characterized by the occlusion of the arteries in the limb region and results in functional impairment and disability with intermittent claudication and pain, is also closely related to diabetes [15]. In most unfortunate cases, PAD causes foot ulceration, ultimately requiring amputation [16]. It is known that diabetic patients have

It has been reported that Asian patients with diabetes are at a higher risk of developing macrovascular complications, such as cardiovascular disease, than other ethnicities [17]. For instance, a study conducted in Pakistan revealed that 30.5% of the young adult patients diagnosed with ischemic stroke were diabetic—a much higher percentage than in Western settings [18]. Another study performed in ischemic stroke patients of <45 years of age in Sri Lanka revealed that 5% of the study group with ischemic stroke had diabetes [19]. A prospective study was also conducted in 2403 patients with ischemic stroke and 783 patients with intracerebral hemorrhaging in India as a representative South Asian country [20]. That report mentioned that Asian diabetic patients had a high risk of early death due to ischemic stroke [20]. Furthermore, reports on the risks of cardiovascular disease and coronary in the Indian subcontinent have suggested that a leading cause of those diseases was diabetes [21, 22].

Another serious complication in diabetic patients is dysfunction of the eyes, kidneys and nerves. Diabetic retinopathy, a typical peripheral microvascular complication, induces acute damage to the retina of the eye [23]. Diabetic retinopathy is divided into two categories: background and proliferative retinopathy [22]. In background retinopathy, slight hemorrhaging develops in the middle layers of the retina, appearing as dots. In proliferative retinopathy, the formation of new blood vessels occurs on the surface of the retina, and white areas on the retina are a sign of this type of disease. Several studies have shown that the occurrence of diabetes retinopathy is influenced by chronic insulin resistance and a high blood glucose concentration, which occur in obese patients [24]. A poorly controlled bloodsugar level is the most significant factor associated with the development of retinopathy. The prevalence rate of retinopathy in diabetic patients in South Asia has been explored in several studies. One study investigated the rate in patients newly diagnosed with diabetes in India and found that the rate was lower (5–7%) than in both Western countries and neighboring countries such as Pakistan (15%), Nepal (19.3%) and Sri Lanka (15%) [25]. However, a similar study conducted in an urban population in Chennai, India, revealed that the prevalence of diabetic retinopathy per diabetic patient was 18%, although the prevalence of diabetic retinopathy in the general population was only 3.5%. Furthermore, men were shown to be at a

a 25-times-greater risk of amputation than nondiabetes population.

4 Diabetes and Its Complications

**3.2. Prevalence rates of diabetic retinopathy, nephropathy and neuropathy**

higher risk than women in that investigation [26].

Microalbuminuria caused by diabetes also induces peripheral nerve dysfunction, and half of diabetic patients consequently develop diabetic neuropathy [15]. The American Diabetic Association has stated that diabetic neuropathy is a sign of peripheral nerve dysfunction [30]. Among the symptoms of diabetic neuropathy, autonomic neuropathy is the most common. This symptom leads to an abnormal heart rate, loss of vascular control and cardiovascular autonomic dysfunction. Cardiac neuropathy caused by diabetes is the second-most common manifestation, depending on age, hypertension, smoking status and obesity. The prevalence rate of diabetic neuropathy in South Asia has been investigated. A study conducted in Sri Lanka reported that the prevalence rate of distal peripheral neuropathy (DPN) among T2DM patients was 24% (females and males: 26% and 20%, respectively). The prevalence rate of neuropathy among T2DM patients in South India was 19.1%, and this number is gradually increasing [31]. A similar study conducted in Indian states reported that the prevalence rate of diabetic neuropathy was 26.1% and was significantly associated with age, glycated hemoglobin and duration of diabetes [30]. Overall, **Figure 1** shows a schematic illustration of the

**Figure 1.** Prevalence rates of diabetes and its complications in South Asia (DP: diabetic patients).

typical course of diabetes and its complications in South Asia, as explained in this section. It is evident that the prevalence rates of diabetes and its complications in South Asians are much higher than in other countries. Therefore, recognition of this critical situation is duly warranted in order to mitigate the propagation of the disease condition.

South Asia revealed a considerable degree of genetic contribution to the onset of T2DM [45]. The researchers identified novel six loci (GRB14, ST6GAL1, VPS26A, HMG20A, AP3S2 and HNF4A) showing correlations with T2DM [45]. Therefore, the diabetic constitution in South Asia is suspected to be related to other genes in addition to the Asian Indian phenotype.

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Individuals' profiles are important to consider when examining the prevalence rate of diabetes [46]. The incidence of the disease in a patient's family is often involved in a given individual's risk, as the variant genotype of thrifty genes is passed down from parents to offspring. Studies comparing the effect of family with others estimated that the risk factors for diabetes in offspring with a single diabetic parent and two diabetic parents are, respectively, 3.5- and 6-fold higher than those without parental diabetes [47]. Among patterns of inheritance, diabetes and its related traits are both polygenic and heterogeneous, with multiple genes involved in different combinations [48]. However, the number of risk genes and their relative contributions are complicated and remain somewhat uncertain. A relationship is known to exist between diabetes and age, probably because the β-cells of older individuals have a reduced proliferative capacity and secreting activity, reduced expression of cell cycle activators, increased expression of cell cycle inhibitors, reduced pdx1 expression and increased amylin aggregation [49]. This decreased functional status is exacerbated in diabetic patients by increased rates of beta cell apoptosis [38]. In addition, in South Asia, elderly people tend to have a decreased

In South Asians, diabetes does not always develop in the elderly, and the characteristics are remarkable. An investigation on the prevalence rate of diabetes in various age groups of South Asians showed that the diabetes population was highest among those ≥60 years of age for both males and females. However, the rate of diabetes among relatively young individuals was found to be higher in South Asians than Caucasians [37]. Furthermore, in India, the prevalence rate of diabetes peaks at 60–69 years of age [42], and Indian people develop the disease even in their youth [41]. Similar results to those in India were found in Pakistan and Sri Lanka [47]. The development of diabetes in younger generations is likely caused by changes in lifestyle brought about by urbanization [42]. The prevalence rate of diabetes (5.02%) was found to be associated with age-adjusted impaired glucose intolerance (5.27%) in a rural community in Sri Lanka [47]. Diabetes develops at any age, and the change in the prevalence over time is

The prevalence rate is also related to gender in South Asia. Diabetes is the second leading cause of death among South Asian women with diabetes, although it is only the ninth leading cause globally [9]. A relationship was reported between age and gender in Bangladesh diabetes patients [50]. The proportion of female diabetic patients (31.2%) was higher than that of male diabetic patients (28.5%) among subjects 31–50 years of age. Among subjects >50 years of age, the diabetic male population was 18.1% and that of the female population was 12.9%. However, below 31 years of age, only 3.3% of the male population had diabetes, whereas 6% of the female population was diabetic [51]. A study conducted in four provinces of Sri Lanka showed that the prevalence of severe obesity among males was 2.4%, whereas that among

hypothesized to be associated with the rural to urban population shift [49].

*4.1.2. Effects of family history, age and gender*

muscle mass due to sedentary lifestyles [17].
