Endocrine Abstracts

Type 2 diabetes (T2D) is a debilitating, multifactorial disease with a complex mix of genetic and environmental pathomechanisms. For this reason, effective treatment of T2D requires a varied arsenal of therapeutic strategies and indeed, it is an excellent candidate for precision medicine. Essential for this, we need a more detailed understanding of the genetic drivers and how these differ between individuals. There is an ever-intensifying global effort to identify genetic associations with diabetes and their mechanisms; however, these efforts mostly exclude indigenous populations which have been shown to have unique genetic variants and often higher rates of T2D. In New Zealand/Aotearoa we have indigenous Māori population as well as a large population of Pacific peoples and we are exploring unique variants associated with diabetes and metabolic disease with a focus on enabling precision medicine. A coding SNP (p.Arg457Gln) in the Creb3 regulatory factor (CREBRF) gene, found in ~25% of Māori and peoples of the Pacific islands, is associated with a large increase in BMI, yet paradoxically, it is also associated with an approximately 50% reduction in the incidence of type-2 diabetes and gestational diabetes [Minster et al 2016, Krishnan et al 2020]. The mechanisms by which the variant drives diabetes protection remains unknown and CREBRF itself was only identified in 2008 [Audas et al 2008]. To date, CREBRF has been shown to regulate cAMP response element binding proteins (CREB3 and CREBL2) that are ubiquitously expressed and have roles in several key cellular processes including ER/Golgi stress and cell metabolism. CREBRF has also been shown to regulate glucocorticoid receptor (GR) signalling [Penney et al 2018, Martyn et al 2012]. We have characterised 20-month-old mice carrying the variant and show there are differences in body composition that manifest at this age and in males this is accompanied by lower myostatin levels [Lee et al 2022]. We have also shown the variant to alter GR transcriptional activity in vitro and in vivo. This includes differential responses of GR-mediated genes such as Dusp1 and Hsd11b1. Despite this, the mice show no overall changes in cortisol nor ATCH, no difference in response to dexamethasone suppression test and no difference in acute restraint test. This differential regulation of GR activity has the potential to explain diabetes protection in carriers of the variant and inform effective therapeutic approaches in non-carriers and therefore we are further exploring impacts on islet, adipose and muscle function.