Adiposity and diabetes risk mechanisms in South Asians

The prevalence of type 2 diabetes mellitus (T2DM) worldwide has increased dramatically in the last three decades. In 2014 there were 64.5 million individuals with diabetes in India alone. South Asians (SA) have a two to fourfold increased risk of T2DM at a significantly lower body mass index (BMI), occurring at a younger age and with a greater risk of diabetic related complications, when compared with white Europeans (EU). The rise in T2DM rates have coincided with increased levels of adiposity, ‘westernised’ diets and lower levels of physical activity, with more people living in urbanised environments. Even adjusting for these variables SA still have an increased risk of T2DM and the reason for this is unknown. Observational studies have demonstrated that SA phenotypically have higher levels of total fat (adipose tissue), less lean tissue (muscle), and lower cardiorespiratory fitness, as well as typically undertaking less physical activity compared with their EU counterparts. Whilst studies have indicated that these factors contribute to insulin resistance with varying degrees, the relationship between adipose tissue (AT) and insulin resistance has never been properly understood. Triacylglycerol is the main storage form of fat. Due to poor diet and lower levels of physical activity, excess calories are stored in adipocytes in several adipose tissue depots in the body. Location of depots appears important, and evidence indicates that visceral (VAT) and ectopic fat depots significantly correlate with insulin resistance. Subcutaneous adipose tissue (SAT), and specifically superficial subcutaneous adipose tissue (SSAT) depots, have been associated with lower levels of insulin resistance and metabolic inflammation. As well as fat depot location cellular response of adipocytes is relevant, adipocytes can either expand in size (hypertrophy), or increase in cell number (hyperplasia) to accommodate excess energy. Hyperplasia has been associated with lower levels of inflammation and insulin resistance whilst hypertrophy has been associated with increased risk of T2DM and pro-inflammatory metabolic state. Adipogenesis is the process by which new adipocytes are recruited and fully differentiate to mature adipocytes with the ability to safely store triacylglycerol. Impairment of this process and dysfunctional adipogenesis has been associated with insulin resistance, T2DM, increased number of hypertrophic adipocytes, small adipocytes and ratio of small to large adipocytes. South Asians have higher levels of total fat compared to EU, and it has been commonly presumed that more visceral and ectopic fat is present in SA causing insulin resistance. However, the limited number of studies analysing fat depots in SA have not all consistently demonstrated this. Cross-sectional studies of SA adipocyte morphology and function have found hypertrophic adipocytes associated with insulin resistance, but the causality and pathogenesis underlying these observations is not known. In 2007 the adipose tissue expandability hypothesis was proposed, implying that SA have limited ability to safely store fat in SSAT and therefore store excess fat in visceral and ectopic depots, causing insulin resistance and diabetes. To explore the relationship between adiposity and insulin resistance in South Asians the Glasgow Visceral and ectopic fat with weight gain in South Asians (Glasvegas) study was proposed in 2014. This thesis is based on initial findings as part of the Glasvegas study and includes meta-analysis conducted to investigate adiposity distribution in South Asians. Given limitations of cross-sectional research the best way to observe underlying mechanisms is via a prospective weight gain/overfeeding study. In this thesis a group of male SA and EU participants gained ~6.4% body weight via supplemental overfeeding diet. Measurements were taken at baseline and following weight gain. These included whole-body MRIs to analyse fat depots, metabolic rate assessments, fitness tests, mixed-meal tolerance tests, subcutaneous adipose tissue biopsies, physical activity and dietary measurements. The findings of this thesis demonstrated that whole-body insulin sensitivity decreased by 38% in young, lean South Asian men with ~6.4% weight gain, but not in white Europeans. Adiposity analysis indicated that South Asians at baseline had more total fat, subcutaneous, deep subcutaneous (DSAT) and liver fat, but not visceral fat. South Asians had twice as much DSAT compared to EU (0.17 litres vs. 0.08 litres, p=0.003) and more liver fat (4.11% vs. 2.05%, p=0.01). Meta-analysis of studies of SA adipose distribution supported the finding that male SA have more SAT but not necessarily VAT. The novel aspect of this study was prospective overfeeding. Unexpectedly the EU group gained more VAT than SA (0.56 litres vs. 0.23 litres, p=0.005) but there were no differences in liver or muscle fat gained between groups. White Europeans also gained significantly more lean tissue with overfeeding than SA (2.43 litres vs. 0.67 litres, p=0.02). There was no indication of a limited SSAT capacity in SA, which is contrary to expectations and the adipose tissue expandability hypothesis. Correlations were observed in SA with insulin resistance and the deep subcutaneous adipose tissue depot, which is larger in South Asians and metabolically akin to VAT. There were no contributions of fitness, physical activity or metabolic rate accounting for differences in insulin sensitivity. Adipocyte findings indicated that EU increased size of adipocytes by hypertrophy in response to weight gain, without any change in insulin sensitivity. South Asians conversely already had larger adipocytes but did not change mean size with weight gain. South Asians increased numbers of very small and large adipocytes, and this is associated with dysfunctional adipogenesis and T2DM. There was also a trend to adipocyte hyperplasia noted in SA. The combined findings of this thesis supported our hypothesis that SA would develop insulin resistance with weight gain, but adiposity findings were contrary to expectations. South Asians appear to have more subcutaneous and deep subcutaneous fat, but not visceral fat. This likely contributes to excess insulin resistance at lower BMI and there is evidence of dysfunctional adipogenesis with weight gain. Ongoing analysis of samples taken during this thesis, to investigate adipocyte gene expression and signalling pathways, is underway. Future studies are also required to help prevent adiposity in SA, reduce risk of dysfunctional adipogenesis and type 2 diabetes