Abstract
Type 2 diabetes (T2DM) is a health issue of profound importance for Aotearoa New Zealand (AoNZ). Rates of, and complications from, T2DM affect Māori, Pacific and South Asian New Zealanders disproportionately. Clear relationships between body composition and glucose metabolism exist which may predispose to T2DM. Despite knowledge of significant ethnic differences in body composition in AoNZ, less is known about their impact on glucose metabolism. If we wish to personalise T2DM management to the individual, we must first understand these relationships in greater detail. The overarching theme of this thesis is to understand ethnic differences in glucose metabolism/body composition in AoNZ, laying down groundwork for research into personalised T2DM management options.
In Chapter 3, data from 22 studies in multi-ethnic AoNZ cohorts were collated.Relationships between measures of glucose metabolism/body composition were explored using mixed linear models.Ethnic differences in these relationships were noted. Māori, Pacific and Chinese participants showed greater reduction in HbA1c with increasing fat free mass:fat mass ratio (FFM:FR), compared with Europeans.Steeper relationships between central adiposity and HbA1c/fasting glucose were observed for Māori/Pacific, suggesting greater deleterious effect of central adiposity in these populations.Differences in relationships between generalised adiposity and β-cell function in Pacific, compared with Europeans, were observed. Findings have implications for clinical management and have identified avenues for research in relation to FFM:FR/β-cell function in AoNZ.
Very-low calorie diets (VLCD) improve central adiposity and can lead to T2DM remission. Given Chapter 3 findings, exploration of VLCD interventions in AoNZ is warranted. In Chapter 4, feasibility of a VLCD intervention in a multi-ethnic cohort of 15 men with prediabetes was assessed, with in-depth physiological measures of whole-body/hepatic insulin sensitivity and β-cell function. 9/15 participants achieved 10% weight loss, with mean HbA1c reduction 4.8mmol/mol, improved glucose disposal and reversion to normoglycaemia in n=5/9. The intervention was highly tolerable/culturally acceptable, providing confidence in VLCD use in AoNZ. Surprisingly, no differences in hepatic insulin sensitivity were observed; further exploration of ethnic differences in response to VLCDs in AoNZ is warranted.
A rs373863828-A missense variant in the CREBRF gene is highly prevalent in Māori/Pacific peoples and is associated with greater lean mass and profoundly lower T2DM risk. Given the relationships between FFM:FR and HbA1c above, impact of this allele on body composition/glucose metabolism was explored in Chapter 5. Deep phenotyping of 50 Māori/Pacific women was undertaken; no differences in glucose metabolism were described, however carriers displayed greater FFM:FR. Correlation of this to findings in Chapter 3 is of interest. Areas for further research into impact of the variant on β-cell function have been identified.
This thesis has demonstrated key ethnic differences in relationships between glucose metabolism and body composition. Foundational work, assessing impact of an intervention which exploits these differences, has demonstrated promising results. Exploration of a genetic cause underpinning these relationships has been undertaken with areas for further research identified. This thesis has begun to further our understanding of the pathophysiology of T2DM in AoNZ, so we may seek to find effective management strategies for our peoples.