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이현석Hyunsuk Lee
서울대학교병원
Genome Med., May 28 2026, | https://doi.org/10.1186/s13073-026-01669-z
PAX4 R192H variant impairs β cell function by disrupting β cell identity and compensatory capacity in response to metabolic stress
Jungsun Park 1,†, Kyun Hoo Kim 1,2,†, Hyunsuk Lee 3,4,5,†, Joon Ho Moon 1,6,†,*, Soo Heon Kwak 4, Jong Il Kim 5,7,*, Hail Kim 1,8,*, Kyong Soo Park 4,9,*
1Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Korea
2Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Daegu, Korea
3Department of Translational Medicine, Seoul National University College of Medicine, Seoul, Korea
4Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
5Genomic Medicine Institute, Medical Research Center, Seoul National University College of Medicine, Seoul, Korea
6Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
7Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea
8Biomedical Research Center, Korea Advanced Institute of Science and Technology, Daejeon, Korea
9Department of Internal Medicine, Konkuk University Medical Center, Seoul, Korea
†These authors contributed equally
*Corresponding authors: correspondence to Joon Ho Moon, Jong Il Kim, Hail Kim or Kyong Soo Park
Abstract
Background
Type 2 diabetes is characterized by progressive β cell dysfunction, yet the mechanisms by which genetic susceptibility contributes to β cell area and function remain poorly understood. PAX4 is a transcription factor critical for β cell development, and a nonsynonymous variant resulting in an arginine-to-histidine substitution at position 192 (R192H) has been associated with increased type 2 diabetes risk and identified only in individuals of East Asian ancestry.
Methods
Here, we generated PAX4 R192H knock-in (Pax4R192H/R192H) mouse and integrated metabolic phenotyping, bulk and single cell transcriptomics, and human cohort analyses to investigate how PAX4 R192H mutation increases the risk of type 2 diabetes.
Results
Homozygote knock-in mice (Pax4 R192H) exhibited normal pancreatic endocrine development but developed glucose intolerance and impaired insulin secretion when fed a high-fat diet. Bulk and single-cell RNA-seq of islets from Pax4 R192H mice fed high-fat diet revealed impaired β cell adaptation to metabolic stress characterized by enhanced endoplasmic reticulum stress and impaired β cell maturity, with upregulation of dedifferentiation and α cell markers and downregulation of β cell identity genes. Pax4 deletion in β cells resulted in similar phenotypic and transcriptomic profiles to Pax4 R192H mice. In humans, the trajectories of β cell function were evaluated over a 14-year period using biennial oral glucose tolerance tests from 4,242 participants, where PAX4 R192H carriers showed 1.4-fold accelerated decline in disposition index, with increasing body mass index further exacerbating their type 2 diabetes risk.
Conclusions
Overall, PAX4 is essential for maintaining β cell identity and compensatory function under metabolic stress, and the R192H variant predisposes to type 2 diabetes by impairing this adaptive capacity.
Type 2 diabetes is characterized by progressive β cell dysfunction, yet the mechanisms by which genetic susceptibility contributes to β cell area and function remain poorly understood. PAX4 is a transcription factor critical for β cell development, and a nonsynonymous variant resulting in an arginine-to-histidine substitution at position 192 (R192H) has been associated with increased type 2 diabetes risk and identified only in individuals of East Asian ancestry.
Methods
Here, we generated PAX4 R192H knock-in (Pax4R192H/R192H) mouse and integrated metabolic phenotyping, bulk and single cell transcriptomics, and human cohort analyses to investigate how PAX4 R192H mutation increases the risk of type 2 diabetes.
Results
Homozygote knock-in mice (Pax4 R192H) exhibited normal pancreatic endocrine development but developed glucose intolerance and impaired insulin secretion when fed a high-fat diet. Bulk and single-cell RNA-seq of islets from Pax4 R192H mice fed high-fat diet revealed impaired β cell adaptation to metabolic stress characterized by enhanced endoplasmic reticulum stress and impaired β cell maturity, with upregulation of dedifferentiation and α cell markers and downregulation of β cell identity genes. Pax4 deletion in β cells resulted in similar phenotypic and transcriptomic profiles to Pax4 R192H mice. In humans, the trajectories of β cell function were evaluated over a 14-year period using biennial oral glucose tolerance tests from 4,242 participants, where PAX4 R192H carriers showed 1.4-fold accelerated decline in disposition index, with increasing body mass index further exacerbating their type 2 diabetes risk.
Conclusions
Overall, PAX4 is essential for maintaining β cell identity and compensatory function under metabolic stress, and the R192H variant predisposes to type 2 diabetes by impairing this adaptive capacity.
논문정보
- Research article
- 2026년 05월 (BRIC 등록일 2026-06-02)
- 국내 연구진
- 의약학 > 유전 및 유전체의학
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