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ASIAN PHENOTYPE AND DIABETES MELLITUS

INTRODUCTION:

Asians are more likely than non-Asians to suffer from a variety of illnesses, including nasopharyngeal cancer, Brugada syndrome, and thyrotoxic periodic paralysis. The genesis, biology, genetic predisposition, and uniqueness of diseases in Asians are revealed by epidemiological data from healthcare organizations and disease registries. Public health strategies and research investment are guided by knowledge about diseases that are prevalent in Asia.

The key definition of the Asian phenotype is the recognition of "qualitative differences" in the way diseases manifest between Asians and non-Asians. Since this phenotype most likely exists across a continuum of health and disease, it is imperative to look into its potential causes and implications for science and medicine.

Both native and migrant South Asians are at a significant risk of developing type 2 diabetes mellitus (T2DM). Asians are more likely than Caucasians to have coronary artery disease, cerebrovascular disease, and renal problems, and they also have a lower BMI and a younger onset of type 2 diabetes.

EPIDEMIOLOGY:

It is estimated that 425 million individuals globally, or 8.8% of adults aged 20 to 79, have diabetes. If the age range is extended to 18–99 years, there are 451 million more persons with diabetes. By 2045, 693 million people aged 18 to 99 or 629 million people aged 20 to 79 would have diabetes if these trends continue. In China alone, 121 million people suffer from diabetes, while 74 million people in India have the disease.

Up to 212.4 million people worldwide, or 50.0% of all individuals aged 20 to 79 with diabetes, are unaware that they have the condition.The percentage of South East Asians with undiagnosed diabetes is 57.6%. Diabetes is more common in Asia, where the majority of diabetics are between the ages of 40 and 59, than in Europe, where the majority of diabetics are over 60.

South Asian populations  have a high prevalence of prediabetes and a more rapid progression to diabetes. 59% of those with prediabetes converted to diabetes after a follow-up of 9.1 years.

Prevalence of GDM in different countries, the IDF estimated that 16% of pregnancies globally were affected by hyperglycemia in 2013, with a crude prevalence of 23.1% in the South Asian region.

Asians have higher risk for development of  diabetes for the same level of body mass index or waist circumference than their Caucasian counterparts, since they have increased visceral fat Even in relatively lean subjects, Asians are more insulin resistant than non-Asians with increased concentrations of free fatty acids and inflammatory markers. 

Asians exhibit higher glucose excursion during oral glucose challenge, suggesting lower beta cell function to overcome insulin resistance than non-Asians. These biological differences put Asians at high risk of developing diabetes in the presence of external stressors, such as obesity.

Some risk factors for T2DM have become of great concern among developing countries in Asia.  The increased prevalence of diabetes is related to changes in dietary pattern, sedentary behavior, and obesity superimposed on a background of genetic/epigenetic susceptibility.

Examples of common clinical features in Asian populations with diabetes are given in table 1 the so-called ‘Asian phenotypes’.

Table 1:

Genetic factors:

In South Asians, the Pro12Ala polymorphism of the peroxisome proliferator activator g (PPARg) gene, which has a protective effect on T2DM development in white populations, is present at the same frequency in South Asians with and without diabetes and was not associated with a decreased risk of T2DM. However, in a study on Asian Indian Sikhs they did see a protective

effect of the polymorphism, suggesting that there might be differences between specific South Asian groups.

Insulin resistance:

South Asians have higher fasting insulin concentrations compared with other ethnic groups regardless of age, gender, or BMI, suggesting a higher rate of IR in this population. Hyperinsulinemic euglycemic clamp studies performed in men and women of all age groups and relatively normal BMI show lower insulin sensitivity (up to almost 50%) in South Asians compared with different ethnic populations.

Diet and exercise:

The South Asian diet, characterized by high intake of carbohydrates, trans fats, and saturated fats is associated with increased risk of development of T2DM.  White rice constitutes up to 60% of the glycemic load and was found to be associated with an increased risk of diabetes in Indian and chinese.  Asians appear to have greater glycemic excursion to white rice compared with other populations. Lack of exercise is another risk factor for T2DM.

BMI:

Asians develop diabetes at a considerably lower BMI compared with Europeans. This is mainly because of increased visceral adiposity in Asian populations. As a result, in Asians, lower BMI cutoffs are being used to define obesity as well as lower waist circumference for defining central obesity.

Criteria are a healthy body-mass index of 18.0–22.9 kg/m2, an overweight body-mass index of

23.0–24.9 kg/m2, and obesity greater than or equal to 25 kg/m2. The healthy waist circumference limits are 90 cm for men and 80 cm for women.

BODY COMPOSITION AND FAT DISTRIBUTION:

South Asians have a higher percentage of body fat for comparable levels of BMI compared with White Caucasians and are therefore referred to as ‘metabolically obese’.

South Asian neonates exhibit the ‘thin-fat phenotype’, described as low muscle mass with preserved subscapular (central) fat.  Modi et al.  showed that South Asian neonates have significantly increased abdominal adiposity compared with European babies. The ‘thin fat

phenotype’ is also apparent in prepubertal Indian children who have greater adiposity than White UK children despite significantly lower BMIs.

ADIPOSE TISSUE DYSFUNCTION AND INFLAMMATION:

South Asians have significantly increased subcutaneous adipocyte size. Hypertrophic adipocytes are considered as dysfunctional and appear to be associated with IR in non diabetic individuals independent of BMI and to be an independent predictor for the development of T2DM.

Nondiabetic South Asians have higher fasting levels of free fatty acids (FFAs) compared with White Caucasians, even when adjusted for body fat content, and fail to completely suppress plasma FFA concentration during hyperinsulinemia induced by an OGTT. This suggests that in

healthy South Asians, insulin is unable to sufficiently inhibit lipolysis, resulting in an excess efflux of FFA, which may play a role in the development of T2DM.

Plasma leptin levels were increased in South Asians as compared with White Caucasian subjects   independent of overall or abdominal obesity. Leptin levels were found to be correlated with SAT and not with VAT.

South Asians exhibit lower levels of adiponectin compared with White Caucasians . Low adiponectin levels were found to be an independent predictor for T2DM development in South

Asians.

South Asians have higher levels of IL6, TNF alpha, CRP compared with Caucasians.

Dysfunctional adipose tissue and inflammation are likely to contribute to the South Asian phenotype of increased IR and T2DM.²³

BROWN ADIPOSE TISSUE(BAT):

Lower resting energy expenditure, non-shivering thermogenesis, and BAT volumes in south Asian populations might underlie their high susceptibility to metabolic disturbances, such as obesity and type 2 diabetes.  Development of strategies to increase BAT volume and activity might help prevent and treat such disorders, particularly in south Asian individuals.²⁴

ROLE OF SKELETAL MUSCLE:

South Asians have less skeletal muscle mass and seem to have lower cardiorespiratory fitness

and reduced capacity for fat oxidation during submaximal exercise, all correlating with their reduced whole-body insulin sensitivity, which is not reflected in reduced expression of oxidative and lipid metabolism genes in the skeletal muscle.

A diminished NO bioavailability in South Asians might thus be caused by both endothelial and HDL-C dysfunction, and might be a factor in the increased incidence of T2DM and cardiovascular diseases in this ethnic group.

INTRAUTERINE ENVIRONMENT:

In utero environment plays an important role in modifying developmental trajectory and physiology, thereby altering the risk of obesity, T2DM, and other chronic diseases in adulthood. Nutritional deprivation in utero may predispose an individual to T2DM in adult life. Early development issues and epigenetics may play an important role in the contemporary burden of diabetes experienced in India.

The thrifty genotype and thrifty phenotype hypotheses seem to apply to Asian populations.

MICRORNA:

Among the altered circulating miRNAs, miR-128  appeared to be a ‘New Lead’ in Indians. It was positively correlated with cholesterol both in prediabetic subjects and in diet-induced diabetic mice, suggesting that its increased level might be associated with the development of dyslipedemia associated with T2DM.

GUTMICROBIOTA:

Complications of diabetes:

WHO Multinational Study of Vascular Disease in Diabetes (WHO MSVDD) had suggested comparatively high rates of albuminuria in Asian centers. In the WHO MSVDD, the prevalence of cardiovascular complications was high in South Asians, but in general was low in centers in China, Hong Kong, and Japan.

South Asians and Chinese, are more likely to suffer from proteinuric diabetic renal disease than from non proteinuric diabetic renal disease. A meta-analysis of studies on the prevalence of diabetic retinopathy noted that South Asians had the lowest prevalence . A lower prevalence of peripheral sensory neuropathy was also reported in Asian patients in the Fremantle Diabetes Study (FDS) in Australia compared with patients of European descent.  Risk of peripheral vascular disease have noted that South Asians are at lower risk of amputations than Europeans.

In the Joint Asia Diabetes Evaluation (JADE) program, among 41,029 patients recruited from across nine countries/regions in Asia, 18% had onset of T2DM below the age of 40 , had longer disease duration, and had higher rates of retinopathy and end-stage renal disease than those with onset of diabetes after the age of 40.

In Asia, while diabetes has been a ‘rich man’s disease’, it is becoming more of a ‘poor man’s disease’ as seen in more affluent societies due to a combination of poverty, poor education, poor food quality, and high level of physical inactivity. The lack of awareness and health literacy often result in high rates of smoking, consumption of energy-dense food, poor sleep hygiene, and sedentary time on the computer and television. These adverse lifestyle choices can be further compounded by psychosocial stresses associated with rapid acculturation. Additionally, chronic exposure to endemic low-grade infections (e.g. hepatitis B infection) and environmental pollutants may result in abnormal neurohormonal responses manifesting as obesity, metabolic syndrome, and diabetes.

From a public health perspective, reduction of poverty, social disparity and health illiteracy through a multisectorial strategy  and using a life course approach such as maternal and child health, vaccination programmes, nutritional policies, universal education and health coverage, tobacco control, and city planning are needed to create a health-enabling environment.

Structured lifestyle modification and early drug therapy can be introduced in a timely manner to prevent silent deterioration of disease with late presentation.

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