胰腺胰岛细胞中XBP1的表达与血糖控制不佳有关，尤其是在不同种族的年轻非肥胖型糖尿病患者中。

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

作者信息

Siddiqui Moneeza K, Dupuis Theo, Anjana Ranjit Mohan, Dawed Adem Y, Bigossi Margherita, Srinivasan Sundararajan, Hodgson Sam, Adedire Ebenezer Tolu, Taylor Alasdair, Saravanan Jebarani, Sartori Ambra, Davtian David, Venkatesan Radha, McNeilly Alison, Cantley James, Mathur Rohini, Sattar Naveed, Finer Sarah, Pearson Ewan R, Pradeepa Rajendra, Mohan Viswanathan, Palmer Colin N A, Brown Andrew A, Viñuela Ana

机构信息

Wolfson Institute of Population Health, Queen Mary University of London, London, UK.

Madras Diabetes Research Foundation, Chennai, India.

出版信息

Commun Med (Lond). 2025 Sep 24;5(1):396. doi: 10.1038/s43856-025-01076-2.

DOI:10.1038/s43856-025-01076-2

PMID:40993285

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12460670/

Abstract

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, n = 470). In trans-ancestry meta-analyses rs7287124 is associated with 4.32 mmol/mol (95% CI: 2.60-6.04, P = 8 × 10) higher HbA1c. In individuals with young, non-obese onset diabetes, the trans-ancestry effect is 6.41 mmol/mol (P = 2 × 10). 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.

摘要

背景

南亚和东亚血统的个体患2型糖尿病的风险较高，这通常是由β细胞功能受损导致胰岛素缺乏所致。转录因子XBP1通过减轻细胞应激来支持β细胞存活，但其在糖尿病风险和血糖调节中的作用仍不清楚。本研究旨在评估XBP1表达对不同血统人群的糖尿病风险、β细胞功能、血糖特征和治疗反应的影响。

方法

我们进行了共定位分析，以测试胰岛中XBP1表达与2型糖尿病是否共享因果变异。在来自印度的两个南亚队列中鉴定并分析了一个调节XBP1表达的主要变异，以评估其与β细胞功能和血糖水平的关联。我们在英国南亚人和白人欧洲人的队列中使用糖化血红蛋白进一步评估血糖控制情况。我们研究了该变异对旨在改善胰岛素分泌的药物的影响。

结果

XBP1表达在东亚人与糖尿病风险共定位，但在白人欧洲人中不共定位，且较低的表达与较高的糖尿病风险相关。与白人欧洲人（25%）相比，该表达定量性状位点（eQTL）的主要单核苷酸多态性（SNP，rs7287124）在东亚人（65%）和南亚人（50%）中更为常见。使用稳态模型评估的胰岛β细胞功能（HOMA-B）显示，rs7287124与较低的β细胞功能相关（P = 5×10，n = 470）。在跨血统荟萃分析中，rs7287124与糖化血红蛋白升高4.32 mmol/mol（95%CI：2.60 - 6.04，P = 8×10）相关。在年轻、非肥胖起病的糖尿病患者中，跨血统效应为6.41 mmol/mol（P = 2×10）。变异携带者对磺脲类药物的反应受损。