Other risk factors and explanations

As is usual with medical and scientific puzzles, there have been numerous creative ideas to explain South Asians’ susceptibility to diabetes, CHD, and stroke that have not been developed into either fully articulated hypotheses or have rarely or never been included in hypothesis testing or evaluation studies. These include thyroid dysfunction, lactose intolerance, vitamin B12 and folate deficiency, infection, and chronic inflammation. Vitamin D deficiency has been studied intensively recently in relation to chronic disease including some work on South Asians. Cardiovascular anatomy and physiology has been explored in observational and though these explanations have little theoretical foundation but they need some consideration.

Genetic explanations 2: adaptations in body size, shape, and composition

Central body fat has been shown to be metabolically harmful while peripheral fat is neutral or even beneficial. The adipose tissue (compartment) overflow and the variable disease selection hypotheses aim to explain why South Asians tend to central adiposity. The former proposes it results from a small superficial subcutaneous fat compartment especially in the lower limbs, so excess energy is deposited as fat in central compartments. The evolutionary forces for this are presumed to be climatic. The latter proposes central fat deposits in South Asians are an evolutionary adaptation to combat gastrointestinal infections. South Asians’ also have small muscle mass, and small hips, for which there are no well-defined hypotheses. The small size at birth of South Asians may be relevant to all these observations. These differences in fat distribution, muscle and skeletal structure could explain a tendency to central (apple-shaped) obesity than generalized or peripheral obesity (pear-shaped).

Genetic explanations 1: the thrifty genotype and its variants

The thrifty genotype proposes that populations susceptible to CVD and DM2 have been subjected to intermittent, serious food shortages and have evolved to cope, e.g. through insulin resistance. This means their glucose is not readily entering the muscle to be used there but is preferentially used by the brain and liver. Glucose is converted to fat in the liver and stored for times of food scarcity. This thrifty state is not, however, beneficial in modern times where food is plentiful. This hypothesis remains a common explanation, including for South Asians’ susceptibility to DM2. The hypothesis has lost support, mostly because of lack of confirmatory empirical data, but has sparked-off new ideas, e.g. the mitochondrial efficiency hypothesis as an adaptation to climatic change, and the predation release hypothesis which sees diminishing need for leanness and agility as triggering higher obesity prevalence. These newer ideas need more research.

Implications for health policy, public health, health care, and research

Achieving internationally agreed prevention strategies is extremely difficult and doing so for South Asians, specifically, is tougher still. Most guidance is centred on individual level behaviour change. The challenge is to produce focused, low cost, effective actions, underpinned by clear, simple, and accurate explanations of the causes of the phenomenon. The key messages are that the high risk of CVD and DM2 in urbanizing South Asians is not inevitable. It is not innate or genetic. Similarly, the risks are unlikely to be acquired in utero, birth, or infancy, and programmed in a fixed way. Rather, exposure to risk factors in childhood, adolescence, and most particularly in adulthood is the key. In addition to the established causes we need to research additional factors especially those identified as novel in Chapter 9. National legislation and policy that alters environments to reduce exposure to risk factors and increase exposure to protective factors is essential.

Established CVD and DM2 risk factors: reappraisal in relation to South Asians

The causal basis of the established CVD and type 2 diabetes risk factors rests mainly on cohort studies, sometimes with supplementary data from trials, Mendelian randomization studies, and experiments in animals. In South Asian populations, specifically, the direct evidence is limited but the associations between risk factors and disease outcomes are generally as expected. The lifestyle-related risk factors can be grouped into those where an excess is a problem (e.g. diets leading to adiposity or a high glycaemic load) and those where a deficit is a problem (e.g. insufficient physical activity). These kinds of risk factors, particularly in the context of adverse socio-economic circumstances, provide an excellent basis for causal thinking. So far, even combined with a wide range of biochemical and physiological risk factors, however, such factors are insufficient, though necessary, parts of a convincing explanation for the excess of DM2 and CVD in South Asians.

Genetic explanations 3: neurobehavioural explanations

These hypotheses propose brain and behavioural evolution as the driver of the adaptations that are now leading to CVD and DM2. Of these, the behavioural switch, also known as the soldier-to-diplomat, hypothesis is best developed. The concept is that as humans moved from hunter-gatherer to settled agricultural lives, complex changes occurred to support this lifestyle, e.g. reduced aggression, more resources to nurture fewer children, and preferential use of glucose by the brain rather than by muscle. Insulin resistance is seen as a secondary—once beneficial—adaptation underlying this change. This hypothesis implies insulin resistance is valuable and it also provides an explanation for South Asians’ reduced muscle mass. Similar ideas have been proposed on longer evolutionary timescales, e.g. the aggression control hypothesis. At present the evidence from these hypotheses does not explain South Asians’ particular susceptibility to CVD and DM2. The hypotheses do, valuably, point to the brain’s central role in glucose metabolism.

Introduction to the causes of cardiovascular disease and type 2 diabetes mellitus, South Asians, and the structure and approach of this book

Coronary heart disease (CHD) and stroke, collectively cardiovascular disease (CVD), are caused by narrowing and blockage of the arteries supplying the heart and brain, respectively. In type 2 diabetes (DM2) insulin is insufficient to maintain normal blood glucose. Until the 1980s, CHD, stroke, and DM2 were seen as problems of the modern lifestyles of rich countries. South Asians should have been protected, e.g. by less smoking, more vegetarianism, and lower levels of obesity. However, the contrary was true and South Asians have high susceptibility to these diseases. The established causes cannot account for the susceptibility. For example, obesity tends to be lower in South Asians than in European origin people but DM2, though caused by obesity, is about three times commoner. About ten major groups of explanations have been published. The aim of this book is to produce a synthesis of the causal explanations to guide prevention, clinical care, and research.

A causal synthesis and models

This chapter synthesizes explanations that are relevant to each of diabetes, CHD, and stroke, and all three collectively. This synthesis emphasizes glycation of tissues, possibly leading to arterial stiffness and microcirculatory damage. In addition to endothelial pathways to atherosclerosis an external (adventitial) one is proposed, i.e. microcirculatory damage to the vasa vasorum, the network of arterioles that supplies nutrients to the larger arteries themselves. DM2 plays into this pathway through glycosylation and dyslipidaemia. The cause of the high prevalence of DM2 in South Asians may lie in protective factors in Europeans not just detrimental ones in South Asians. The high glucose level is considered as an allostatic mechanism controlled by the brain. In addition to the ectopic fat in their liver and pancreas as the cause of beta cell dysfunction, two additional ideas are proposed, i.e. firstly, microcirculatory damage and secondly, glycation, possibly compounded by dietary factors including neoformed contaminants, e.g. AGEs.

Socio-economic development and the demographic and epidemiological transitions: effects on psychosocial circumstances and lifestyles

Diabetes mellitus, CHD, and ischaemic, but not haemorrhagic stroke, are closely linked to rising affluence and the accompanying changes in life expectancy and in lifestyles. These changes take place in the context of the demographic and epidemiological transitions. These phenomena could explain the rise in diabetes, CHD, and stroke in populations including South Asians but not why the rates of these diseases exceed those in populations who are already at an even more advanced stage in these transitions. Changes in psychosocial status, including the stresses of migration, social change, and work patterns and lifestyle accompanying these transitions have been especially rapid in the South Asian diaspora. The recent high-heat cooking hypothesis, which proposes South Asians’ cooking styles produce atherogenic substances including advanced glycation products and trans-fatty acids, illustrates how affluence and behaviours might influence disease. Together, these general explanations set the stage to examine specific risk factors.

The thrifty phenotype and related developmental hypotheses

The developmental origins of health and disease (DOHAD) hypothesis proposes that impairment of fetal and infant development leads to lasting, perhaps permanent, changes in organ structure, body composition, and metabolism. The critical factor, however, is thought to be dysadaptation, whereby the environmental circumstances in later life do not match those the person is programmed for. This kind of mismatch is particularly likely in migrant populations leaving rural parts of South Asia (where nutrition is sometimes limited) and settling in affluent, nutrition-rich countries. South Asian babies are born small but with relatively well-preserved fat depots, especially on the torso and intra-abdominally. This relative central preservation of fat is a characteristic that remains through life. The thrifty phenotype and related hypotheses attribute it to fetal and early life growth and development. The empirical evidence suggests, however, a modest role for these ideas in explaining disease outcomes in South Asians in adulthood.