Introduction
South Asians living in Europe and North America have a two- to fivefold higher risk of developing type 2 diabetes than their counterparts of white European descent living in the same countries and develop the disease at a younger age and lower BMI [
1‐
3]. Furthermore, South Asians exhibit a 30–100% higher mortality risk for coronary heart disease and cardiovascular disease than their white European counterparts [
4‐
6]. In addition, South Asians without diabetes have higher fasting glycaemic indices than white Europeans, and greater levels of insulin resistance [
7,
8]. Conventional cardiometabolic factors do not account for the magnitude of the inter-ethnic differences in the burden of type 2 diabetes and cardiovascular disease. Smoking is less prevalent among South Asians [
8], but overall caloric intake appears not to differ meaningfully between the two ethnic groups, with South Asians consuming larger quantities of polyunsaturated fats [
9]. Diabetes rates are also increasing rapidly in all South Asian countries.
It has been suggested that increased central adiposity and storage of fat in deeper abdominal compartments, such as around the viscera or liver [
1,
10], may be a key pathway leading to greater insulin resistance and subsequent type 2 diabetes and cardiovascular disease in South Asians. Some authors have hypothesised that South Asians have a lower capacity to store fat subcutaneously, leading to earlier ‘spill-over’ into harmful secondary visceral and ectopic depots, the so-called ‘adipose tissue overflow’ hypothesis [
11,
12]. However, the evidence from studies comparing the fat distribution in the two ethnic groups is conflicting; one study suggests that South Asians store more fat subcutaneously [
13], whilst another suggests that they accumulate excess fat both subcutaneously and intra-abdominally [
14], and another showing no substantial difference in fat depots between the two groups [
12]. The fact that many of those studies were relatively small and thus lack of power, together with differences in study characteristics, may have contributed to the discrepancy in the findings. The aim of our study was to systematically collate all existing published data comparing the amounts of subcutaneous (SAT) and visceral (VAT) adipose tissue and liver fat between South Asian and white European adults, and supplement this with unpublished data from our group and the UK Biobank study, to provide the most robust assessment to date of potential ethnic differences in the levels of fat in key metabolic fat compartments.
Methods
The study, which was pre-registered with the OSF Registries (
https://osf.io/w5bf9), was conducted according to the PRISMA guidelines [
15], and followed a structured protocol that was agreed among the authors in advance of the literature search. Data eligible for meta-analysis included both original research and existing publications identified by systematic review.
Discussion
To our knowledge, this evidence synthesis, including data from 1853 participants of South Asian descent and 5162 participants of white European descent, is the largest analysis comparing robust imaging data (CT or MRI) of various abdominal fat compartments between South Asian and white European adults. These data suggest that both South Asian men and women store greater ectopic fat in the liver at a lower BMI compared with their counterparts of white European descent, and that there may be a sex-specific difference in ethnic distribution of SAT. South Asian men had greater amounts of SAT and ectopic fat accumulated in the liver than their white European counterparts despite having a slightly lower BMI, although this was not clearly accompanied by higher levels of VAT. In women, there was no substantial difference in SAT or VAT distribution between South Asians and white European participants; however, like men, South Asian women had more ectopic fat in the liver compared with their white European counterparts, despite having a BMI that was approximately 0.9 kg/m
2 lower. The slightly lower BMI in the South Asian participants compared with white European participants in these studies may have contributed to the absence of a difference in VAT between the two ethnic groups. In the subset of studies where the BMI did not differ between the ethnic groups [
16,
19,
22‐
25], South Asian men and women showed a numerically higher level of VAT, as well as higher levels of SAT and ectopic liver fat, compared with men and women of white European descent, but the statistical power in these subgroup analyses was limited. Thus, taking all data together, we can be most confident about the finding of higher liver fat levels in South Asian participants, as there were similar findings in both South Asian men and women relative to their white European counterparts, and broadly concordant findings in the subgroups of those without diabetes or matched for BMI. In addition, the liver analyses showed a low likelihood of publication bias or small-study effect. However, given the available data, our conclusions about ethnic differences in VAT are more cautious.
The central role of the liver in diabetes pathogenesis has become increasingly apparent in recent years, with the organ being a site of excess fat storage in those with hyperinsulinaemia due to either genetic or familial factors, with consequent excessive hepatic gluconeogenesis [
33]. It has been shown that surrogate markers of liver fat and their change over time predict diabetes [
33,
34], whereas substantial weight loss from use of low-energy diets can lead to rapid fat loss from the liver and improved insulin sensitivity in people with diabetes [
34]. These studies were performed predominantly in participants of white European origin, and align with the importance of liver fat in the pathogenesis of diabetes in this ethnic group, as well with molecular mechanisms whereby fat-derived metabolites impair insulin signalling [
35]. Export of excessive triacylglycerol from the liver may also be a key feature in the beta cell dysfunction in those who develop diabetes [
33], and South Asians are known to have elevated circulating triacylglycerol levels at similar levels of BMI compared with white Europeans [
36]. More recently, genetic studies have further suggested a causal role for liver fat in the pathogenesis of type 2 diabetes [
37].
Greater SAT at a lower BMI in South Asian men implies there must be lower lean muscle mass in this group, which is an additional independent risk factor for type 2 diabetes [
38], and other data has shown that lower lean mass contributes to the higher levels of insulin resistance observed in South Asians compared with other ethnic groups [
39]. Clearly, in view of the present findings, more work on understanding ethnic differences in ectopic fat is urgently needed, including examining why South Asians appear to accumulate liver fat more rapidly at lower BMIs, and whether excess liver fat can be reversed by lifestyle measures, in particular intentional weight loss, in this group.
According to the ‘adipose tissue overflow’ hypothesis [
11,
12], fat deposition starts predominantly in the subcutaneous region until inflammatory mediators halt the recruitment of new adipocytes. At this point, the capacity of subcutaneous tissue for further fat storage is reduced, and positive energy balance leads to an overflow of fatty acids to deeper adipose compartments (i.e. visceral) or ectopic tissues (i.e. hepatic). The ‘tipping’ point at which subcutaneous tissue reaches its maximum storage capacity is thought to vary for each individual, and depends on genetic and environmental factors [
40], and it has been hypothesised that this occurs at a lower BMI in South Asians [
11,
12]. The present findings are partially in agreement with this. South Asian participants of both sexes accumulated more ectopic fat in the liver at similar or lower BMI than white European participants. However, South Asian men also had higher levels of SAT, so the relative importance of a lower capacity for SAT storage vs greater overall adipose tissue accumulation at a given BMI in terms of higher liver fat levels is unclear. Nevertheless, data suggest that South Asian men have larger adipocytes in their subcutaneous compartment compared with their white European counterparts even when they are matched for total and abdominal body fat [
13]. Thus, it is plausible and consistent with our findings that the subcutaneous adipocytes in South Asian men have the capacity to become more hypertrophic and therefore allow accumulation of more fat in superficial depots. In addition, hypertrophic adipocytes are associated with greater insulin resistance, which may be the mediating pathway in the development of type 2 diabetes [
13].
Acknowledgements
The imaging data from the UK Biobank Resource were provided under application 6569. We thank the UK Biobank participants and coordinators for this unique dataset. The authors thank L. Coyle, University of Glasgow, for her assistance with manuscript preparation.
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