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Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. An explanation
  5. Other risk factors
  6. Next steps and conclusions
  7. Note on sources of information for this commentary
  8. Funding sources
  9. Competing interests
  10. Acknowledgements
  11. References
  12. Appendix

With approximately 1.5 billion people at risk, the staggeringly high risk of Type 2 diabetes in South Asians comprises a global problem. The causes of this high risk are complex, with 23 major risk factors identified in a Lancet seminar. This paper proposes a four-stage explanatory model: (1) the birth of a small, adipose, lowlean mass South Asian baby—the phenotype tracking through life; (2) in childhood and early adulthood, the deposition of any excess energy intake preferentially in upper body and ectopic fat stores rather than in the lower body or superficial subcutaneous fat stores; (3) as a consequence of points 1 and 2, and exacerbated by an environment of low physical activity and excess calories, the accelerated appearance of high levels of plasma insulin, triglycerides and glucose, and the fatty-liver vicious cycle; (4) β-cell failure as a result of fewer β-cells at birth, exposure to apoptotic triggers such as fat in the pancreas, and high demand from insulin resistance, which causes diabetes. Other risk factors—especially energy-dense hyperglycaemic diet and low physical activity—play into this pathway. The recommended behavioural changes fit with this model, which brings clarity to guide future research, policy, practice and health promotion.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. An explanation
  5. Other risk factors
  6. Next steps and conclusions
  7. Note on sources of information for this commentary
  8. Funding sources
  9. Competing interests
  10. Acknowledgements
  11. References
  12. Appendix

The staggeringly high risk of Type 2 diabetes mellitus in urbanized South Asians, especially in wealthy countries—a four to sixfold risk in the UK—was first described in the 1980s in Southall [1] and soon verified as a real, not diagnostic, phenomenon that has been well documented [2]. While South Asians are extremely heterogeneous in a wide range of cardiovascular risk factors (and outcomes), the differences in their risk of diabetes (given similar environments) are small. It is reasonable therefore to reflect on South Asians as a whole, not least because it is clear that a phenomenon observed in the Indian Diaspora is clearly applicable to urban, and increasingly urbanizing, rural India.

The description of this high risk usually evokes the question of why this is so. Specific, coherent and clear explanations for this phenomenon are hard to pinpoint. In general terms, the immediate reasons, usually given for the fourfold or even higher risk of diabetes in South Asians compared with Europeans, lie in weight, diet and physical activity, as stated in an up-to-date UK guideline [3]. This was known nearly 100 years ago [4]. While dietary control and exercise may comprise the main available remedy, this does not mean these are the underlying causes of the problem. There are, furthermore, contradictions to the dietary explanation; for example, the weight (and BMI) of Bangladeshis in the UK is lower than either Europeans, Indians or Pakistanis, yet their Type 2 diabetes risk is the highest [5, 6]. South Asian diets are not intrinsically unhealthy and both recent and earlier accounts indicate they are better on several accounts than those consumed by white British populations [5, 7-9]. For example, the highest UK prevalence in Type 2 diabetes is in Bangladeshis, but their self-reported consumption of five or more portions of fruit/vegetables is the same as the general population in women and higher in men. Fat intake was lower than in the general population [5, 10]. While self-reported leisure-time physical activity is undoubtedly low in South Asians [11], and particularly Bangladeshis [12], this is not, in itself, a full, conclusive explanation for a risk of Type 2 diabetes 4–5 times that of the white population, not least because such populations may be in physically active occupations. For example, many Bangladeshis are in the restaurant trade. Being a waiter is approximately 3 metabolic equivalent (MET) units of activity; i.e. 3 times the resting metabolic rate, equivalent to light-to-moderate activity (Dr Jason Gill, University of Glasgow, pers. comm.; based on published compendium of physical activities) [13]. The 1999 Health Survey for England data (not studied in 2004 survey), however, indicate comparatively low occupational physical activity in all subgroups of South Asian women and Bangladeshi men [9]. Nonetheless, overall activity levels, combining home, leisure and occupational activity, are not well studied, although in UK South Asian children activity levels are low on both reported and objective indicators [14]. Physical activity and fitness are, clearly, important, not just in the Indian Diaspora but also on the Indian subcontinent [15].

Specific hypothesis such as the thrifty genotype [16], thrifty phenotype [17], mitochondrial efficiency [18], soldier-to-diplomat [19] and several others (see Appendix, Box A1) help understanding, but in isolation do not provide a coherent explanation, although they have generated valuable research and provided direction for scholarship [20, 21].

Numerous scholars and researchers have attempted an answer to the question, or related questions, posed in this paper [2, 18, 22-29], but they have mainly concluded that the answer is still unknown and that further research is required. For example, in their extremely detailed review of mechanisms, Hall et al. conclude that ‘As the reasons behind the increased prevalence of insulin resistance and diabetes in South Asians remains elusive, further research is required’ [30]. Characteristically, these reviews are comprehensive. Of the 10 pages in the detailed Lancet review by Ramachandran et al., eight are devoted to causes, examined through the risk factors given in Box 1 [28]. No synthesis unites the complex data provided.

Although the phenomenon of diabetes in South Asians has been noted for more than 100 years [4], research has accelerated in the last 30 years. While a coherent explanation has not yet been agreed, some syntheses of diabetes and related metabolic problems provide causal diagrams linking the putative causal factors [31, 32]. The diagrams, with one containing 25 arrows [31], and another 22 arrows [32], echo the complexity seen in text, with multiple pathways. The more focused hypothesis on insulin resistance of Hall et al. has 10 arrows [30]. This complexity, while arguably inevitable as scientific knowledge advances, is a disadvantage in communicating with policymakers, health planners, health promoters and, above all, with the public. I have spoken to a wide range of professional and public audiences on the prevention of diabetes in South Asians, particularly as principal investigator of the Prevention of Diabetes and Obesity in South Asians (PODOSA) trial. The question of the causes of the phenomenon invariably arises, but other than stating that the issue is complex but revolves around diet, exercise and physical activity, as more recently reinforced in the National Institute for Health and Clinical Excellence (NICE) guideline [3], I have not been able to provide a clear explanation, because the scientific reviews of the subject are so complex. I judge that the scientific literature, in essence, contains the answer to the question even although, undoubtedly, more research is needed. I attempt here to narrate a focused explanation of the phenomenon, without including all known risk factors, which have already been considered in the reviews cited. In this account, all comparisons implied are between South Asian and Northern European populations, unless stated otherwise. This paper is not proposing a new original hypothesis. The explanation here draws on the work of others and mostly closely corresponds to that of Misra et al. [31]. My three-arrow linear diagram is concordant with the more complex diagrams of Misra et al. [31], Middelkoop [32] and Hall et al. [30].

An explanation

  1. Top of page
  2. Abstract
  3. Introduction
  4. An explanation
  5. Other risk factors
  6. Next steps and conclusions
  7. Note on sources of information for this commentary
  8. Funding sources
  9. Competing interests
  10. Acknowledgements
  11. References
  12. Appendix

Birth and early life

Figure 1 summarizes this explanation. For reasons unknown but possibly evolutionary, South Asian babies are born comparatively small, yet relative to other tissues, with high amounts of fat (but low muscle mass) [33]. (This is relative to Northern Europeans as already stated—henceforth this will be assumed.] The reasons for the small, adipose South Asian baby is not itself critical to our understanding but may lie in: ambient temperature (small babies will lose heat better) [34]; mothers survival (relatively small-hipped South Asian women can deliver such small babies and still remain healthy); earlier birth—gestation is slightly shorter than in white European mothers—and premature babies are more fatty [35]; the need for the baby to have energy reserves in societies including South Asian ones where there is a tradition of not breastfeeding colostrum [36]; the need for fat to help brain development [19]; the higher insulin and glucose levels of the mother of the fetus and of the fetus itself [37], etc. Small babies have, relative to big ones, fewer β-cell islets in the pancreas, possibly because of genetic factors that predispose to both Type 2 diabetes and low birthweight [37]. Low birthweight is not, in itself, a problem. The problem arises if in later life there is a mismatch between the phenotype at birth and the phenotype in adulthood.

image

Figure 1. A four-stage model explaining the excess of diabetes in South Asians compared with Europeans

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Childhood and early adulthood

In urban societies, particularly in industrialized countries, these small South Asian babies grow up to be children with high levels of subcutaneous truncal fat [38], and young adults with comparatively large, metabolically active adipocytes [39, 40]. There is clear evidence that the superficial subcutaneous fat compartment of South Asians—especially in the legs—is small relative to upper body fat at birth [41] and in later life [40, 42], and this supports the adipose tissue compartment hypothesis of Sniderman et al. for South Asians' tendency to cardiometabolic diseases (see Appendix, Box A1).

South Asian muscle mass is comparatively low [43], especially in the buttocks and their comparatively long, lower limbs, with reduced total body capacity for oxidation and capacity for fatty acid utilization [30], these factors being related to the insulin-resistant phenotype [30]. The muscle of South Asians is relatively insulin resistant [30]. (Unlike in white Europeans, this insulin resistance is not associated with lipid content of muscle and the reason for it is unknown [30, 44]). There is possibly nothing wrong with insulin resistance per se, and it may even have both evolutionary and contemporary benefits, as discussed in detail by Watve and Yajnik in their hypothesis that insulin resistance mediates the transition from muscle-dependent to brain-dependent lifestyles [19]. However, it is an evolutionary mechanism that is out of step with modern lifestyles [16]. With adiposity and insulin-resistant muscle, a high level of muscular fitness is desirable and metabolically beneficial [45]. Unfortunately, many South Asians, at least those living in Europe, do not place a high premium on leisure-time physical activity and sports [5, 46]. This may be related to the fact that most older adults migrated in the 1950s–1980s from a hot climate where air conditioning was rare (exercise generates heat and sweat—problems that warm climate populations have to fight), and where a great deal of physical energy was expended in the workplace, in domestic chores and in transport (private motor car ownership was rare). Apathy to leisure-time exercise is an attitude that is culturally transmitted and somewhat resistant to change [47]. South Asian children in the UK, as in their parents, have low physical activity compared with their white European origin counterparts [14]. Leisure-time physical activity is also low in India [15].

By contrast with physical activity, South Asians' cultural values place a high premium on the enjoyment of good, tasty food, which is at the heart of family life, and hospitality towards family and friends [48]. Being a little overweight is perceived as both healthy and a sign of social and material success, and there is a large gap between perceived and actual overweight [49, 50]. South Asians are, however, right to perceive that being underweight is not healthy, being closely linked to high rates of infection, including tuberculosis, and all-cause mortality, whereas the evidence that a high BMI increases mortality in South Asians is not compelling [51, 52]. (Probably, this is because of socio-economic confounding, whereby the wealthy and knowledgeable are overweight, whereas the poorest are comparatively lean.) BMI cut-off points for overweight and obesity are still under debate, not least because the ideal cut-off depends on outcome [52, 53].

It is unusual for South Asians to meet the South Asian standards for waist cut-offs (90 cm for men and 80 cm for women according to the International Diabetes Federation, and 78 cm for men and 72 cm for women according to the guidelines of Indian cardiologists [54]). Excess energy intake calories would, ideally, be deposited, principally, in the superficial subcutaneous compartments, especially those in the lower limbs—where fat deposit acts like a depot that is either neutral or even protective in relation to cardiovascular and metabolic outcomes [42, 55-57]. Rather, in South Asians the excess energy is too readily stored in the truncal, deep subcutaneous tissues, which are highly active and detrimental to metabolic outcomes [58] and in ectopic fat depots intra-abdominally, and in the liver, pancreas and around the heart [40].

Metabolic changes in later adulthood and middle and old age

A fatty liver does not respond well to insulin, so hepatic glucose and triacylglycerol production is not properly controlled, and blood glucose remains high, maintaining high levels of insulin production [59]. High levels of triacylglycerol inhibit insulin production. Insulin resistance in muscles means that glucose is directed to the liver, where it is converted into fat and stored, thereby creating insulin resistance there and sparking the fatty-liver vicious cycle [59]. This makes it harder to switch off endogenous glucose production, thus increasing glycaemia and inducing the release of more insulin. A new hypothesis has proposed that insulin is influential in directing the storage of fat in deep subcutaneous, intra-abdominal and ectopic depots—away from the primary, superficial, subcutaneous depots [60].

South Asians may also have more efficient mitochondria, less able to use energy to create heat (see Appendix, Box A1) [18, 61]. Their overall requirement for energy is lower, irrespective of basal metabolic rate or mitochondrial efficiency, because a higher proportion of their body is adipose tissue, which is less metabolically active than lean tissue. This, together with the insulin resistance and the propensity to deposit fat truncally, and especially in the liver, means South Asians are sensitized to the adverse effects of excess energy intake, even while their BMI remains comparatively low. Several studies have now demonstrated that, to achieve the metabolic profile of a European origin person with a BMI of approximately 30 kg/m2, a South Asian person needs a BMI as low as 22 kg/m2 [62, 63].

There are three main postulates on why the pancreas malfunctions in diabetes. First, there may be in vitro genetic and developmental reasons for a low number of properly functioning islets. Second, there may be β-cell apoptosis triggered by environmental factors; for example, ectopic fat in the pancreas or dietary factors acting as toxins. Third, there may be β-cell exhaustion arising from a high workload caused by insulin resistance [59]. In South Asians, all three factors seem to apply. With β-cell failure comes diabetes.

Box 1. The major risk/potentially causal factors identified by Ramachandran et al. [28] in discussing the epidemic of diabetes in South Asia

  • Genetic factors (varying prevalence of risk alleles, including thrifty genotype)
  • Higher adenosine-5'-triphosphate (ATP) production, despite more insulin resistance and higher intramuscular triglyceride
  • Thrifty phenotype/maternal undernutrition
  • Low-birthweight/rapid post-natal child growth
  • Maternal imprinting
  • Developmental factors/mismatch between programming and later reality
  • Transgenerational factors—epigenetics
  • Visceral abdominal adiposity
  • Adipose tissue
  • Ectopic fat especially in liver and pancreas—twin cycle hypothesis (of Taylor [59])
  • High non-esterified fatty acids (NEFA) during fasting, not suppressed by oral glucose
  • Low adiponectin/high leptin
  • Large amount of truncal fat and large dysfunctional subcutaneous fat cells
  • Low muscle mass and high intramuscular triglyceride
  • Insulin resistance, and resulting hyperinsulaemia
  • Urbanization/migration/socio-economic progress
  • Physical inactivity increasing with urbanization
  • Change in diet with more, and more refined, food
  • Increase in working hours
  • Decreased sleep and potential role of obstructive sleep apnoea
  • Lipid toxicity
  • Amyloid deposits in pancreas
  • β-cell loss

Other risk factors

  1. Top of page
  2. Abstract
  3. Introduction
  4. An explanation
  5. Other risk factors
  6. Next steps and conclusions
  7. Note on sources of information for this commentary
  8. Funding sources
  9. Competing interests
  10. Acknowledgements
  11. References
  12. Appendix

While other reviews have listed many other risk factors and potential mechanisms, including them makes understanding very difficult and, as I judge them to be factors that increase susceptibility, I have de-emphasized them. Genetic factors beyond those linked to the physiological processes discussed above do not seem to play any role different from those identified in Europeans, at least in diabetes in South Asians [64-66]. Social and economic factors, smoking, migration and the many risk factors listed in Box 1 and discussed in the other major reviews cited above [28, 30, 31] are not central to the explanation in Fig. 1, but will obviously have influence according to local circumstances.

Next steps and conclusions

  1. Top of page
  2. Abstract
  3. Introduction
  4. An explanation
  5. Other risk factors
  6. Next steps and conclusions
  7. Note on sources of information for this commentary
  8. Funding sources
  9. Competing interests
  10. Acknowledgements
  11. References
  12. Appendix

This explanation above builds on recent primary research and the hypotheses in the Appendix (Box A1). The hypotheses in Box A1 mostly already have some empirical evidence to support them. More work is needed on the biological explanations for the comparatively low birthweight of UK South Asian babies, which is surprisingly stable across generations [67] and on their high adiposity coupled with low lean mass. The Born in Bradford Cohort Study, with nearly 50% of the babies being South Asian, has the potential to unlock this question [68]. The empirical basis of the mitochondrial efficiency hypothesis requires strengthening [18]. The adipose tissue compartment hypothesis—that South Asians have a comparatively small superficial subcutaneous adipose tissue compartment—has been supported with evidence from birth onwards [41, 42, 69]. The importance of ectopic fat, especially in a fatty liver, is already clear [59] and empirical evidence for this in South Asians is available [40]. The reasons for enhanced muscle insulin resistance [70] in South Asians needs new work, incorporating evolutionary perspectives of the kind being pursued in the soldier-to-diplomat hypothesis [19]. While these are biological issues, and hence require a genetic perspective, the answers lie in gene–environment interactions and hence epigenetic effects [23].

Given that biological explanations for ethnic variations in disease have contributed to harmful racist science [71], we need to be circumspect. The four-stage explanation here places emphasis on a life history of gene and environment interactions (the basis of all complex disorders)—which have consequences for all humans, although to varying degrees. There is no inherent disadvantage in the biological issues raised (low birthweight, low muscle mass and adipose tissue distribution), except in the modern environment, and that is changeable. Whether new generations of South Asians, conceived and born in times of plenty, will also have high risk of diabetes remains to be seen, but at this point the signs are that they will be at even higher risk [72], given the importance of life years of exposure to adiposity and the high prevalence of gestational diabetes in South Asian mothers [73, 74]. Future work also needs to assess whether the causal phenomena are the same in Indians on the Indian subcontinent and in the Indian diaspora, which seems likely.

While there is no doubt that the research effort must continue, and the full complexities will need to be considered, it is also important to confront the epidemic in South Asians. To do that, a cogent and relatively clear-cut explanation is required that researchers, scholars, policymakers, health planners and health promoters can largely agree on. Otherwise, the complexity of the matter can become bewildering to the public and clinical professionals alike, fostering inertia and hesitancy. This explanation, summarized in the simple four-stage linear model in Fig. 1, lays the foundation for public health action at all stages of the life cycle. The nature of the public health actions needed has been vigorously extolled by many, including Misra and colleagues (see Box 2) [29]. While this explanation has focused on South Asians, it is likely to be relevant to many populations that have particularly high diabetes risk.

Box 2. The condensed essentials of public health actions as proposed by Misra et al. [29]

  1. Raised awareness of high risk among South Asians
  2. Adequate nutrition during the intrauterine period
  3. Particularly target actions at those with a family history, or those who are overweight or abdominally obese, or have other components of the metabolic syndrome
  4. From childhood, increase physical activity and restrict sedentary activity
  5. BMI to be 19–23 kg/m2
  6. Waist measurement below 90 cm for men and 80 cm for women
  7. National control programmes

Note on sources of information for this commentary

  1. Top of page
  2. Abstract
  3. Introduction
  4. An explanation
  5. Other risk factors
  6. Next steps and conclusions
  7. Note on sources of information for this commentary
  8. Funding sources
  9. Competing interests
  10. Acknowledgements
  11. References
  12. Appendix

In addition to reading definitive recent accounts, for example Ramachandran et al. [28], examining my personal 27-year collection of papers and books on the topic of South Asian health, and consulting colleagues, I did repeated searches early 2012 on Google and Google scholar to check for recent reviews on the topic, using keyword such as diabetes, metabolic syndrome, causes, hypotheses, explanations, South Asians, Indians, Pakistanis, Bangladeshis. Most of the relevant material accessed has been cited in this paper.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. An explanation
  5. Other risk factors
  6. Next steps and conclusions
  7. Note on sources of information for this commentary
  8. Funding sources
  9. Competing interests
  10. Acknowledgements
  11. References
  12. Appendix

I thank the scholars and researchers whose work this paper draws upon; Professor Nigel Unwin for extensive comments on two earlier drafts; Professor Aziz Sheikh whose incisive feedback made me think harder; three anonymous referees for careful and thoughtful feedback; and Mrs Anne Houghton for secretarial assistance.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. An explanation
  5. Other risk factors
  6. Next steps and conclusions
  7. Note on sources of information for this commentary
  8. Funding sources
  9. Competing interests
  10. Acknowledgements
  11. References
  12. Appendix
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Appendix

  1. Top of page
  2. Abstract
  3. Introduction
  4. An explanation
  5. Other risk factors
  6. Next steps and conclusions
  7. Note on sources of information for this commentary
  8. Funding sources
  9. Competing interests
  10. Acknowledgements
  11. References
  12. Appendix

Box A1. Some major published hypotheses to explain why South Asians have high susceptibility to diabetes and related metabolic disorders

  • A
     Genetic/evolutionary hypotheses
    • 1.
      Thrifty genotype hypothesis and related ideas [75, 76]
      • South Asians have developed insulin resistance in response to intermittent food shortages over long periods as this helps to store fat for times of food scarcity. Evolutionary benefits of intramuscular triglyceride, used as a fuel during prolonged exercise, are no longer beneficial, but merely lead to insulin resistance.
    • 2.
      Adipose tissue compartment hypothesis [42]
      • For reasons that may relate to heat dissipation, South Asians who have relatively long limbs, have a smaller superficial adipose tissue compartment, particularly in the lower limbs where fat stores are metabolically not harmful (perhaps beneficial), so excess energy is too readily stored in metabolically active, deep subcutaneous, intra-abdominal and organ sites.
    • 3.
      Mitochondrial efficiency hypothesis [18]
      • Given evolution in hot climates, South Asians' mitochondria are less prone to using energy to generate heat, so excess energy is more likely to be stored.
    • 4.
      Soldier to diplomat hypothesis [19]
      • In moving from a hunter–gatherer to a settled, agricultural lifestyle, South Asians' physiology evolved to preserve glucose for use by the brain. Insulin resistance in muscle achieves this, as muscle then uses relatively more lipids. Also insulin aids brain function so insulin resistance leads to higher delivery of glucose and insulin there.
    • 5.
      Variable disease selection hypothesis [77]
      • The anatomical location and metabolic profile of adipose tissue arose from its role in the immune system and the varying exposure of populations to infections. For South Asian populations, gastrointestinal disease may have been especially important and intra-abdominal adipose tissue is an asset to combat them and protect intestinal function.
  • B
     Developmental, intergenerational hypotheses [17]: thrifty phenotype and adaptation–dysadaptation hypotheses
    • 6.
      Adaptation responses to undernutrition, whether attributable to maternal, placental or fetal factors (as reflected in the proxy indicator of low birthweight) lead to permanent change in metabolism, body composition and organ structure that predispose to cardiometabolic diseases.
  • C
     Lifestyle and socio-economic circumstances hypotheses [6]
    • 7.
      Excess: social, cultural and economic factors lead to behaviours that lead to an excess of risk factors; for example, high calorie, high glycaemic-load diet that leads to adiposity/obesity.
    • 8.
      Deficit: the above factors lead to a deficit of behaviours that protect against cardiometabolic disorders; for example, physical activity and a high fruit–vegetable diet.
    • 9.
      Other specific hypotheses, including micronutrients and toxins [78-80]
      • Although specific causes have not been articulated as coherent hypotheses, micronutrient deficiency (vitamin D, vitamin B12, etc.) and unnamed toxins, for example in cooking, have been the topic of previous commentaries.