{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE333nnn/GSE333721/"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":null,"additional":{"omics_type":["Transcriptomics"],"species":["Homo sapiens"],"gds_type":["Expression profiling by high throughput sequencing"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE333721"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"A dish-to-biobank framework links β-cell nutrient-stress programs to genetic and dietary risk for Type 2 Diabetes","description":"Type 2 diabetes (T2D) arises from genetic susceptibility and chronic metabolic stress, but whether these converge on shared molecular programs in human populations remains unclear. Here, we develop a dish-to-biobank framework linking controlled β-cell perturbation to population-scale disease genetics through the circulating plasma proteome, and apply it to T2D. scRNA-seq of human stem cell–derived islets under factorial glucose and palmitate exposure identifies their combination (glucolipotoxicity) as the condition eliciting the strongest SC-β cell transcriptional response, with glucolipotoxicity-upregulated genes uniquely enriched for T2D heritability, monogenic diabetes genes, and rare-variant burden signals. CRISPR knockout of β-cell identity regulators PAX6 and PDX1 aligns with this program, establishing convergence of environmental and genetic perturbations on a shared disease-relevant state. We then used the plasma proteome as an accessible population-scale readout of these experimentally defined β-cell stress programs, scoring 45,956 UK Biobank White British participants. We define heritable stress signatures that associate with refined carbohydrate and saturated fat intake, and undergo trans-tissue genetic regulation, with a subset of variants showing diet-dependent effects. Together, these findings establish glucolipotoxicity as a genetically anchored model of β-cell dysfunction and provide a generalizable framework for linking controlled cellular perturbations to human disease genetics at population scale.","dates":{"publication":"2026/05/28"},"accession":"GSE333721","cross_references":{"GSM":["GSM9771819","GSM9771823","GSM9771824","GSM9771820","GSM9771821","GSM9771822"],"GPL":["24676"],"GSE":["333721"],"taxon":["Homo sapiens"]}}