XBP1 expression in pancreatic islet cells is associated with poor glycaemic control especially in young non-obese onset diabetes across ancestries.

Background: Individuals of South and East Asian ancestry have a higher risk of type 2 diabetes, often driven by insulin deficiency due to impaired beta-cell function. The transcription factor XBP1 supports beta-cell survival by reducing cellular stress, but its role in diabetes risk and glucose regulation remains unclear. This study aimed to evaluate the impact of XBP1 expression on diabetes risk, beta-cell function, glycaemic traits, and treatment response across ancestries.

Methods: We performed colocalisation analyses to test whether XBP1 expression in pancreatic islets and type 2 diabetes share causal variants. A lead variant regulating XBP1 expression was identified and analysed in two South Asian cohorts from India to assess associations with beta-cell function and glucose levels. We further assessed glycaemic control using HbA1c in cohorts of British South Asians and white Europeans. We examined the effect of the variant on drugs designed to improve insulin secretion.

Results: XBP1 expression colocalises with diabetes risk in East Asians but not in white Europeans, and lower expression is associated with higher risk of diabetes. The lead SNP of the eQTL (rs7287124) is more common in East (65%) and South Asians (50%) compared to white Europeans (25%). rs7287124 is associated with lower beta-cell function using HOMA-B (P = 5 × 10^-3, n = 470). In trans-ancestry meta-analyses rs7287124 is associated with 4.32 mmol/mol (95% CI: 2.60-6.04, P = 8 × 10^-7) higher HbA1c. In individuals with young, non-obese onset diabetes, the trans-ancestry effect is 6.41 mmol/mol (P = 2 × 10^-4). Variant carriers show impaired response to sulphonylureas.

Conclusions: XBP1 expression is associated with diabetes risk with particular value in under-represented populations at risk of young, non-obese onset diabetes.