GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE330nnn/GSE330587/primaryOK200TranscriptomicsMus musculusExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE330587GEOGSEfalsePax4 R192H variant impairs β cell function by disrupting β cell identity and compensatory capacity in response to metabolic stressType 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. 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. 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. 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.2026/05/11GSE330587GSM9729081GSM9729070GSM9729080GSM9729072GSM9729083GSM9729082GSM9729071GSM9729085GSM9729074GSM9729084GSM9729073GSM9729076GSM9729075GSM9729086GSM9729078GSM9729077GSM972907924247330587Mus musculus