Abstract:
Obesity and Type 2 Diabetes are a concern for all New Zealanders, though Māori and Pacific
peoples are disproportionately affected. A single nucleotide polymorphism (SNP) in the cyclic
adenosine monophosphate-response element-binding protein 3 regulatory factor (CREBRF)
gene (rs373863828: G > A; p. Arg457Gln), prevalent in up to 30% of Māori and Pacific peoples
yet virtually absent in all other populations, is one of the first genetic variants shown to be
associated with increased BMI (1.38-1.45 kg/m2 per copy of the minor A allele), yet
paradoxically 40-50% reduced risk of T2D in Māori and Pacific peoples. This thesis aimed to
investigate associations between the CREBRF rs373863828 minor A allele and the phenotype
of young, overweight/obese but otherwise healthy men of Te Moana Nui a Kiwa [Pacific ocean;
Aotearoa New Zealand Māori and/or Pacific peoples (Polynesian)] descent, in order to develop
hypothesis as to how the variant may be acting to increase BMI and yet reduce risk of T2D.
Two hundred and sixty four young (18-45y), overweight/obese (BMI ≥ 25kg/m2) men of Te
Moana Nui a Kiwa [Pacific ocean; Aotearoa New Zealand Māori and/or Pacific peoples
(Polynesian)] descent attended phenotyping sessions for the assessment of body composition
through anthropometric measurements and DXA scan, resting metabolic rate and the
assessment of glucose and lipid metabolism using a mixed meal tolerance test. A subset of 44
participants were invited back to undertake an abdominal MRI for further assessment of fat
distribution and a Botnia clamp for further assessment of insulin sensitivity and secretion.
Thirty three participants also undertook a hyperglycaemic clamp with arginine stimulation test
for further assessment of beta-cell function. The CREBRF rs3738638282 minor A allele was initially hypothesised to increase BMI by
promoting increased adiposity and protect against Type 2 Diabetes via the preferential storage
of fat in less metabolically ‘risky’ subcutaneous fat depots. We found that for an equivalent
BMI, the CREBRF rs373863828 minor A allele does not associate with any measure of relative
or total fat mass or lean mass in young, overweight/obese but otherwise healthy men of Te
Moana Nui a Kiwa [Pacific ocean; Aotearoa New Zealand Māori and/or Pacific peoples
(Polynesian)] descent. Further we found no associations between the variant and any measure
of fat distribution including subcutaneous, visceral, android, gynoid and limb fat. We did find
an association between the CREBRF minor A allele and reduced myostatin, a negative
regulator of muscle mass which may have implications for body composition in a wider cohort.
As CREBRF is a known negative regulator of glucocorticoid receptors, we also investigated
associations between the minor A allele and cortisol response to waking. Though we found a
large amount of variability in response, we provide evidence of a trend towards blunting of the
waking cortisol profile in carriers of the CREBRF minor A allele, which may have implications
for both body composition and glucose tolerance.
The highlight of this thesis is the finding that in our cohort, for an equivalent blood glucose
and level of insulin sensitivity, the CREBRF rs373863828 minor A allele is associated with
greater plasma insulin during the early phase response to a mixed meal tolerance test
(MMTT) and intravenous glucose tolerance test (IVGTT). This suggests an effect of the
minor A allele on beta-cell mass and/or function. Whilst the mechanisms involved remain to
be elucidated, enhanced functional beta-cell mass is a promising hypothesis to account for the
40-50% reduced risk of T2D associated with the CREBRF rs373863828 minor A allele.