{"doi":"10.1101/2021.06.25.449947","title":"ROCK1 regulates insulin secretion from β-cells","abstract":"ABSTRACT Objective The endocrine pancreatic β-cells play a pivotal role in the maintenance of whole-body glucose homeostasis and its dysregulation is a consistent feature in all forms of diabetes. However, knowledge of intracellular regulators that modulate β-cell function remains incomplete. We investigated the physiological role of ROCK1 in the regulation of insulin secretion and glucose homoeostasis. Methods Mice lacking ROCK1 in pancreatic β-cells (RIP-Cre; ROCK1 loxP/loxP , β-ROCK1 -/- ) were studied. Glucose and insulin tolerance tests as well as glucose-stimulated insulin secretion (GSIS) were measured. Insulin secretion response to a direct glucose or pyruvate or pyruvate kinase (PK) activator stimulation in isolated islets from β-ROCK1 -/- mice or β-cell lines with knockdown of ROCK1 were also evaluated. Proximity ligation assay was performed to determine the physical interactions between PK and ROCK1. Results Mice with a deficiency of ROCK1 in pancreatic β-cells exhibited significantly increased blood glucose levels and reduced serum insulin without changes in body weight. Interestingly, β-ROCK1 -/- mice displayed progressive impairment of glucose tolerance while maintaining insulin sensitivity mostly due to impaired GSIS. Consistently, GSIS was markedly decreased in ROCK1-deficient islets and ROCK1 knockdown INS-1 cells. Concurrently, ROCK1 blockade led to a significant decrease in intracellular calcium levels, ATP levels, and oxygen consumption rates in isolated islets and INS-1 cells. Treatment of ROCK1-deficient islets or ROCK1 knockdown β-cells either with pyruvate or a PK activator rescued the impaired GSIS. Mechanistically, we observed that ROCK1 binding to PK is greatly enhanced by glucose stimulation in β-cells. Conclusions Our findings demonstrate that β-cell ROCK1 is essential for glucose-stimulated insulin secretion and maintenance of glucose homeostasis and that ROCK1 acts as an upstream regulator of glycolytic pyruvate kinase signaling.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":225446,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9575,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":827882,"name":"Sung-Bin Lim","orcid":"0009-0004-9147-526X","position":1,"is_corresponding":false},{"id":827883,"name":"Jae Hyeon Kim","orcid":"0000-0001-5001-963X","position":2,"is_corresponding":false},{"id":827884,"name":"Won‐Mo Yang","orcid":"0000-0001-6742-720X","position":3,"is_corresponding":false},{"id":269959,"name":"Rohit Kulkarni","orcid":"0000-0001-5029-6119","position":4,"is_corresponding":false},{"id":298024,"name":"Young‐Bum Kim","orcid":"0000-0001-9471-6330","position":5,"is_corresponding":false},{"id":827885,"name":"Moon‐Kyu Lee","orcid":"0000-0002-8728-7184","position":6,"is_corresponding":false},{"id":827881,"name":"Byung-Jun Sung","orcid":"0000-0001-8766-7454","position":0,"is_corresponding":true}],"reference_count":45,"raw_metadata":null,"created_at":"2026-07-18T23:54:26.581453Z","pmid":null,"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":[]}