{"doi":"10.1016/j.jbc.2022.101729","title":"Glucose-6-phosphatase catalytic subunit 2 negatively regulates glucose oxidation and insulin secretion in pancreatic β-cells","abstract":"Elevated fasting blood glucose (FBG) is associated with increased risks of developing type 2 diabetes (T2D) and cardiovascular-associated mortality. G6PC2 is predominantly expressed in islets, encodes a glucose-6-phosphatase catalytic subunit that converts glucose-6-phosphate (G6P) to glucose, and has been linked with variations in FBG in genome-wide association studies. Deletion of G6pc2 in mice has been shown to lower FBG without affecting fasting plasma insulin levels in vivo. At 5 mM glucose, pancreatic islets from G6pc2 knockout (KO) mice exhibit no glucose cycling, increased glycolytic flux, and enhanced glucose-stimulated insulin secretion (GSIS). However, the broader effects of G6pc2 KO on β-cell metabolism and redox regulation are unknown. Here we used CRISPR/Cas9 gene editing and metabolic flux analysis in βTC3 cells, a murine pancreatic β-cell line, to examine the role of G6pc2 in regulating glycolytic and mitochondrial fluxes. We found that deletion of G6pc2 led to ∼60% increases in glycolytic and citric acid cycle (CAC) fluxes at both 5 and 11 mM glucose concentrations. Furthermore, intracellular insulin content and GSIS were enhanced by approximately two-fold, along with increased cytosolic redox potential and reductive carboxylation flux. Normalization of fluxes relative to net glucose uptake revealed upregulation in two NADPH-producing pathways in the CAC. These results demonstrate that G6pc2 regulates GSIS by modulating not only glycolysis but also, independently, citric acid cycle activity in β-cells. Overall, our findings implicate G6PC2 as a potential therapeutic target for enhancing insulin secretion and lowering FBG, which could benefit individuals with prediabetes, T2D, and obesity.","journal":"Journal of Biological Chemistry","year":2022,"id":248766,"datarank":0.5101796072493234,"base_score":3.4011973816621555,"endowment":3.4011973816621555,"self_citation_contribution":0.5101796072493234,"citation_network_contribution":0.0,"self_endowment_contribution":0.5101796072493234,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":29,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.953,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":370584,"name":"Arya Y. Nakhe","orcid":null,"position":1,"is_corresponding":false},{"id":888290,"name":"Deveena R. Banerjee","orcid":"0000-0002-0750-5138","position":2,"is_corresponding":false},{"id":705758,"name":"Emily M. Overway","orcid":null,"position":3,"is_corresponding":false},{"id":304324,"name":"Karin J. Bosma","orcid":"0000-0002-1221-1169","position":4,"is_corresponding":false},{"id":343209,"name":"Jonah C. Rosch","orcid":null,"position":5,"is_corresponding":false},{"id":729140,"name":"James K. Oeser","orcid":null,"position":6,"is_corresponding":false},{"id":665981,"name":"Bo Wang","orcid":"0000-0002-6047-1221","position":7,"is_corresponding":false},{"id":331785,"name":"Ethan S. Lippmann","orcid":"0000-0001-5703-5747","position":8,"is_corresponding":false},{"id":345680,"name":"David A. Jacobson","orcid":"0000-0003-1816-5375","position":9,"is_corresponding":false},{"id":54268,"name":"Richard M. O’Brien","orcid":"0000-0003-2153-9761","position":10,"is_corresponding":false},{"id":329120,"name":"Jamey D. Young","orcid":"0000-0002-0871-1494","position":11,"is_corresponding":false},{"id":356888,"name":"Mohsin Rahim","orcid":"0000-0001-8407-5621","position":0,"is_corresponding":true}],"reference_count":62,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T00:24:14.794521Z","pmid":"35176280","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}