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

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

doi:10.1038/s43856-025-01076-2

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

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

Research output: Contribution to journal › Article › peer-review

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 -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.

Original language	English
Article number	396
Number of pages	10
Journal	Communications Medicine
Volume	5
DOIs	https://doi.org/10.1038/s43856-025-01076-2
Publication status	Published - 24 Sept 2025

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, Siddiqui, M. K., Dupuis, T., Anjana, R. M., Dawed, A. Y., Bigossi, M., Srinivasan, S., Hodgson, S., Adedire, E. T., Taylor, A., Saravanan, J., Sartori, A., Davtian, D., Venkatesan, R., McNeilly, A., Cantley, J., Mathur, R., Sattar, N., Finer, S., ... Viñuela, A. (2025). XBP1 expression in pancreatic islet cells is associated with poor glycaemic control especially in young non-obese onset diabetes across ancestries. Communications Medicine, 5, Article 396. https://doi.org/10.1038/s43856-025-01076-2

@article{0a01fa9ef354494faa41423802f34770,

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

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 -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.",

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

note = "{\textcopyright} 2025. The Author(s).",

year = "2025",

month = sep,

day = "24",

doi = "10.1038/s43856-025-01076-2",

language = "English",

volume = "5",

}

Siddiqui, MK, Dupuis, T, Anjana, RM, Dawed, AY, Bigossi, M, Srinivasan, S, Hodgson, S, Adedire, ET, Taylor, A, Saravanan, J, Sartori, A, Davtian, D, Venkatesan, R, McNeilly, A , Cantley, J, Mathur, R, Sattar, N, Finer, S, Pearson, ER, Pradeepa, R, Mohan, V, Palmer, CNA & Brown, AA & Viñuela, A 2025, 'XBP1 expression in pancreatic islet cells is associated with poor glycaemic control especially in young non-obese onset diabetes across ancestries', Communications Medicine, vol. 5, 396. https://doi.org/10.1038/s43856-025-01076-2

TY - JOUR

T1 - XBP1 expression in pancreatic islet cells is associated with poor glycaemic control especially in young non-obese onset diabetes across ancestries

AU - Siddiqui, Moneeza K

AU - Dupuis, Theo

AU - Anjana, Ranjit Mohan

AU - Dawed, Adem Y

AU - Bigossi, Margherita

AU - Srinivasan, Sundararajan

AU - Hodgson, Sam

AU - Adedire, Ebenezer Tolu

AU - Taylor, Alasdair

AU - Saravanan, Jebarani

AU - Sartori, Ambra

AU - Davtian, David

AU - Venkatesan, Radha

AU - McNeilly, Alison

AU - Cantley, James

AU - Mathur, Rohini

AU - Sattar, Naveed

AU - Finer, Sarah

AU - Pearson, Ewan R

AU - Pradeepa, Rajendra

AU - Mohan, Viswanathan

AU - Palmer, Colin N A

AU - Brown, Andrew A

AU - Viñuela, Ana

PY - 2025/9/24

Y1 - 2025/9/24

N2 - 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.

AB - 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.

U2 - 10.1038/s43856-025-01076-2

DO - 10.1038/s43856-025-01076-2

M3 - Article

C2 - 40993285

SN - 2730-664X

VL - 5

JO - Communications Medicine

JF - Communications Medicine

M1 - 396

ER -

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

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