Gestational Diabetes Mellitus (GDM) is a rising global concern that has been linked to maternal diet, with a prevalence of approximately 6% in Aotearoa New Zealand. The CREBRF missense variant rs373863828, common among Māori and Polynesian populations , is associated with a reduced risk of GDM and type 2 diabetes. However, the mechanism for these protective effects is poorly understood. We explored this effect of the variant and diet on maternal metabolic health, using a novel CRISPR/CAS9 knock-in (KI) mouse model with a human equivalent CREBRF variant (ARG458Gln).
KI and wild-type (WT) female mice were placed on normal protein (21%) or high protein (42%) isocaloric diets and grouped by reproductive status(Pregnant /Virgin). On gestation day 17.5, an intraperitoneal glucose tolerance test (GTT) was performed, followed by body composition analysis and organ collection. We observed that high-protein diet influenced impaired glucose tolerance and increased weight of the liver and pancreas during pregnancy, suggesting that a high-protein diet during pregnancy could be a risk factor for GDM. However, this effect was unaffected by genotype. This indicates that maternal physiological adaptations are influenced by diet, but not the CREBRF genetic variant, in specific conditions. Our results suggest that, while the CREBRF rs 373863828 variant may not affect maternal glucose intolerance directly, diet is highly influential. Further studies are warranted to investigate tissue and pregnancy-specific mechanisms through which the CREBRF missense variant may exert protective metabolic effects.