Dr Sarada Bulchand
Duke-NUS Graduate Medical School, Singapore
The human body derives energy from food through metabolism. These life sustaining chemical reactions are designed to regulate and respond to energy requirements and the nutritional status of the body. When the body is in a starved state, lipids from adipose tissue are utilised as the energy source mainly in muscle and the heart, while glucose from the liver functions to regulate the central nervous system. The fed state induces a systemic hormonal response particularly the secretion of insulin in response to glucose in the blood. Insulin, the primary regulator of blood glucose levels and a major anabolic hormone, is secreted by the beta cells of the pancreas, regulating the uptake of glucose into peripheral tissues, mainly muscle and adipose while suppressing glucose output from the liver. This serves to provide glucose as a source of energy to all cells while also maintaining blood glucose levels within acceptable limits. Homeostasis of plasma glucose levels is critical to normal body function wherein both hyper (excess) and hypoglycaemia (low levels of plasma glucose) are severely detrimental to health.
The Metabolic Syndrome (MetS), originally called Syndrome X or insulin resistance syndrome, is a cluster of factors that increase the risk of cardiovascular diseases and Type 2 diabetes mellitus (T2DM). While there have been frequent modifications to the definition, the main components of the syndrome are insulin resistance, abdominal obesity (as well as lipid deposition in other non-adipose sites) with particular emphasis on waist measurement, glucose intolerance/hyperglycemia, dyslipidemia (especially low High Density Lipoprotein (HDL) cholesterol, increased triglycerides, and apolipoprotein B levels) and hypertension. Epidemiological studies have revealed that the prevalence of MetS is influenced greatly by factors like sex, age, race and ethnicity in addition to the defined criteria. Data strongly suggests that metabolic syndrome is often an immediate precursor of Type 2 diabetes and cardiovascular disease with central obesity and insulin resistance amongst the primary risk factors.
Diabetes Mellitus is a group of common metabolic disorders that share the phenotypes of hyperglycemia characterised by decreased glucose utilisation due to insulin resistance, increased glucose production from the liver and decreased insulin secretion from the pancreas. It is classified on the basis of aetiology and clinical presentation into four types of which Type 2 diabetes (T2DM) is the focus of this article. T2DM is characterised by reduced sensitivity of target tissues to insulin action (insulin resistance). Later stages include relative insulin deficiency due to pancreatic beta cell loss as these cells go into overdrive to produce more insulin to cope with high blood glucose levels. T2DM constitutes 90-95% of all cases of diabetes and is often associated with obesity, which itself can cause insulin resistance and lead to elevated blood glucose levels. Highlights of epidemiological trends, risk factors, mechanisms, socioeconomic concerns, prevention and public health policy are discussed in subsequent sections.
The consequences of chronic elevation in blood glucose levels, even when no symptoms are present to alert the individual of diabetes, lead to tissue damage. Uncontrolled diabetes can be fatal due to various complications. When blood glucose is poorly controlled over long periods, blood vessels in multiple tissues throughout the body undergo abnormal structural and functional changes resulting in decreased vascular supply to various organs and tissues. This in turn leads to an increased risk for heart-attack, stroke, end stage renal disease, retinopathy (damage to the retina) and blindness and nerve damage commonly in the feet and legs, leading to major infections and amputations. The inability to use glucose for energy needs leads to increased utilisation of stored proteins and fats eventually resulting in severe wasting of tissues and death. Fasting blood glucose levels > 126mg/dL and impaired glucose tolerance are commonly used diagnostic criteria for diabetes. Levels of glycated haemoglobin (HbA1C) are used to assess the condition over a longer period especially when patients are being treated with anti-diabetics. The risk factors and consequences are diabetes are summarised in Figure 1.
Type 2 Diabetes once prevalent largely in affluent Western countries is now a global health priority with developing nations being hit the hardest. In the last decade, diabetes has emerged as a major public health and socioeconomic burden in Asia and Asia-Pacific. The Asian diabetes paradox reveals a mismatch between affluence and diabetes prevalence. The International Diabetes Federation has predicted that the number of individuals with diabetes will increase from 366 million in 2010 to 551 million in 2025 with 80% of the disease burden in low and middle-income countries. More than 60% of the world population with diabetes will come from Asia and deaths due to diabetes will double between 2005-2025. While China and India top the world list (Figure 2), the other heavily populated nations of Bangladesh, Indonesia, Pakistan, Philippines and Thailand are amongst the top 20 countries in the world for the number of diabetes cases. The prevalence of diabetes in several western pacific islands especially in Kiribati, Marshall Islands and Nauru are very high at ~24%, 21% and 20% respectively. In addition to the number of people with frank diabetes, the prevalence of impaired glucose tolerance is high in many Asian countries suggesting the presence of a large pool of people with the potential to develop diabetes. The rapidly increasing rate of diabetes in Asia is associated with a strong interaction between genes and the environment propelled by accelerated lifestyle changes and modernisation. While overall criteria, definitions and risk factors are similar across the world, a wealth of information indicates that heterogeneity in ethnicity, cultures, stages of socio economic development and local public health policies affect clinical presentation, management and prevention of diabetes.
The Obesity Epidemic: Numerous studies in animal models and population studies in human patients have repeatedly shown that there is a strong correlation between obesity, insulin resistance, diabetes and its complications. Asia has undergone a tremendous change in demography and lifestyles with greater movement in populations from rural to urban areas, improved socioeconomic conditions, change in diets with higher intake of cheap calorie dense foods high in saturated fat, like palm oil and high fructose corn syrup (HFCS) in sweetened beverages. The greater availability of processed foods both eastern (instant noodles) and western (burgers and fries) together with sedentary lifestyles has resulted in over-consumption and an expansion of waistlines. The rate of increase in obesity in Asia has been far more rapid compared to other parts of the world. Asian populations especially those of South Asian descent are more prone to abdominal obesity with increased insulin resistance compared to their Western counterparts. Thus, waist circumference reflecting central obesity is a useful measure of obesity-related risk of T2DM especially in individuals with normal BMI values. Using imaging technologies like computed tomography (CT scans) to measure total body fat and specific fat depots it was observed that healthy Chinese and South Asian individuals had a greater amount of visceral obesity than Europeans with the same BMI or waist circumference. This and other studies suggest that Asians seem predisposed towards developing abdominal obesity. In Singapore alone, the obesity prevalence which stood at 5% in 1984 was 10.2% in 2010 and prevalence of T2DM was 11% in 2011. The increasing trend of childhood obesity in Asia, due to overnutrition and underexertion places many young individuals at risk for T2DM in early adulthood. Once considered a disease of the elderly, T2DM is disproportionately high in young to middle aged adults in countries like India and China not just due to obesity but also due to increased stress, depression, shorter sleeping hours and higher rates of smoking all of which are associated with changing lifestyles. In a meta-analysis study, depression was associated with a 60% increased risk of T2DM while smoking was associated with a 44% increased risk of developing T2DM indicative of psychosocial risk factors. It has been shown that structured diet and exercise have clear benefits by reducing visceral fat and increasing insulin sensitivity.
Developmental and Epigenetic Factors: Increased insulin resistance that is not accounted for entirely by fat distribution or obesity has led researchers to investigate evolutionary and genetic differences viz., the ‘thrifty gene’ hypothesis. Intrauterine and postnatal environments can affect the future risk of diabetes via epigenetic fetal programming. Conditions like low birth weight and exposure to undernutrition in utero are common in countries like India where 30% of infants are underweight. These infants are subsequently exposed to calorie rich diets which their genomes have not been programmed for. The mismatch between metabolic phenotype that was programmed during fetal growth and the nutritionally rich postnatal environment puts the infant at increased risk for obesity, insulin resistance and diabetesits. A study in India showed that underweight in infancy and overweight at 12 years of age was associated with increased risk of developing impaired glucose tolerance or diabetes in young adulthood. Additionally, offspring of women who are obese, have T2DM or have had gestational diabetes during pregnancy are at increased risk of developing diabetes themselves due to several reasons like genetic predisposition, familial lifestyles and in utero exposure to increased levels of insulin which promotes excessive growth in the fetus. In the view of increasing childhood obesity and increasing number of young women with diabetes in Asia, this is likely to create of viscous cycle of diabetes begetting diabetes.
Genetic Factors: Diabetes does run in families, suggestive of a strong genetic component. But teasing apart the causative genes is challenging due to the polygenic nature of T2DM. Although, prior to the age of genome wide surveys, using the candidate variant or gene approach, data from multiple studies identified two genes that act as targets for widely used anti-diabetic drugs, PPARg (Peroxisome proliferator-activated receptor gamma) and KCNJ11 (potassium inwardly-rectifying channel, subfamily J, member 11). In a recent milestone in 2011, a genome wide association study amongst people originating from South Asia (India, Pakistan, Sri Lanka and Bangladesh) identified six new genetic variants linked to type 2 diabetes in these populations. These findings give important new insight into genetic predisposition to diabetes in this population, which in the long term might lead to new treatments. Further identification of DNA variants across populations will, it is hoped, provide clues to the processes involved in the pathogenesis of obesity and diabetes. Given the multi-faceted nature of T2DM, it would not be surprising if each patient has an individual ‘barcode’ of susceptibility alleles and protective alleles across many loci. For example, Pro 12 Ala polymorphism of the PPARg gene which affords protection against diabetes and insulin resistance to Caucasians, does not appear to protect Indians. Therefore, it is important to study the same problem in different ethnic groups and such genetic data would be most useful if integrated with clinical and biochemical data.
Mechanisms: Given the complexity of type 2 diabetes at the cellular and molecular levels it is critical to understand the pathways that contribute to this dysfunction of multiple organ systems through basic and clinical research. This would serve dual purposes of deciphering diabetes at a mechanistic level and opening the doors to potential preventive and therapeutic measures. Obesity and insulin resistance at the cellular level involve a host of molecular and biochemical factors all of which are under intense investigation and most of which are not completely understood. Toxic lipid metabolites deposited in tissues not suited to store lipids, like liver and muscle have been strongly implicated in the development of insulin resistance. Saturated fats from the diet are metabolised into these toxic species that inhibit insulin signalling. Another dietary factor that has more recently been shown to disrupt insulin sensitivity, also possibly through lipid deposition, is fructose in the form of high fructose corn syrup present in processed foods and juices. These calorie dense, low fibre diets have influenced the progression of diabetes in Asia. Research has also focused on events leading to loss of function and mass of pancreatic beta cells. While lipotoxicity and glucolipotoxicity are popular theories, the exact cause of this loss is not known. Several studies have also focused on the role of lipids in oxidative stress and mitochondrial dysfunction.
Metabolomics: Mechanisms of disease are unravelled also through technological advances that help uncover mechanisms of disease while simultaneously serving as platforms for the discovery of biomarkers and novel therapeutic strategies. Genome wide association studies and mRNA profiling have revealed significant amounts of information but are relatively mature technologies. The analysis of metabolites through metabolomics is a relatively newer and powerful approach to study diabetes both at the systems and molecular levels. Metabolomics measures biological chemicals that result from genomic, trascriptomic and proteomic variability thus providing an integrated profile of biological status for comparisons in health and disease. Duke-National University of Singapore Graduate Medical School is on its way to housing a metabolomics facility with the vision of understanding fundamental mechanisms of metabolic disorders like MetS and diabetes.
One of the major metabolomic platforms is mass spectrometry. Given the role of lipids in diabetes and MetS and the increasing number of patients with these disorders, a detailed analysis of cellular lipids is highly valuable. While it is easier to study proteins and carbohydrates, lipidomics is fairly challenging due to the immense structural and molecular diversity of lipids-in the hundreds of thousands according to some estimates- and also the highly specialised technology required to extract, purify, separate and analyse lipids. But plasma, tissue, cell and even organelle lipidomic studies have the potential to identify new avenues of research and improve quantification of disease risk amongst other advantages.
Public Health Policy: Tackling the growing twin epidemics of obesity and diabetes is no small challenge. At the recently held UK-Singapore diabetes and obesity symposium, 2011, engaging discussions highlighted pertinent socioeconomic and public health concerns. These disorders result in the loss of economic productivity due to premature mortality and increasing disabilities which may be more than the direct medical cost incurred especially in low income households in countries like China and India. The lack of subsidised healthcare makes the problem more severe. In countries like India, Sri Lanka and Malaysia there is a lack of good quality public hospitals and lack of drug supplies. There is a flourishing private hospital sector which is curative but not preventive, coupled with a severe lack of primary healthcare especially in low income areas. Additionally, screening and identification of risk groups is weak. Countries like China, South Korea, Taiwan, Philippines and Vietnam have marginally better healthcare but it is also curative. The importance and relevance of ‘prevention is better than cure’ cannot be overstated in the current scenario. There is a need for a greater concerted effort towards prevention of obesity and diabetes through better and more effective public health policies that do not simply remain on paper but are implemented and sustained on the ground. While some countries are beginning to consider changes in their healthcare policies, others like Singapore are already implementing practical measures to reduce incidences of diabetes for example by collaborating with hawker centres to provide people with healthier food options. Clearly these twin epidemics are not just a scientific and medical problem but that which also needs to be addressed by the sectors of law, agriculture and the food industry, business, advertising and education. Making exercise an interesting routine, education of the masses and implementation of measures that make the food industry more accountable are some preventive strategies that could be considered. As fundamental and clinical research advances towards understanding mechanisms of diabetes and obesity, more effective primary healthcare and public policy measures could help reduce this growing threat in Asia.
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