{"doi":"10.2337/db25-0215","title":"Regulatory Roles of IGF2R in Insulin Secretion and Adaptive β-Cell Proliferation","abstract":"Insulin-like growth factor-2 receptor (IGF2R), also known as cation-independent mannose-6-phosphate receptor, is localized in cytosolic vesicles and is unique in its ability to transport enzymes to the lysosome and to clear IGF2 from the cell surface by acting as a scavenger receptor. To evaluate the direct role of IGF2R in β-cell biology, we undertook complementary in vitro knockdown and in vivo knockout approaches. A β-cell line with a stable knockdown of IGF2R (IGF2RKD) exhibited decreased glucose-induced insulin secretion and enhanced cell proliferation. Tamoxifen-inducible β-cell-specific IGF2R knockout mice exhibited impaired glucose tolerance and blunted insulin secretion after high-fat-diet loading that was likely secondary to reduced β-cell mass due to attenuated proliferation. β-cells with IGF2RKD had fewer autophagosomes after starvation and reduced expression of p62, LC3B, and ULK1. Aged mice also had impaired autophagy in βIGF2R-deficient β-cells. Reduced IGF2R function and N6-methyladenosine (m6A) mRNA methylation were observed in islets from both mouse and human type 2 diabetes. Taken together, these data point to IGF2R as an important regulator of insulin secretion, cell proliferation, and autophagy in mammalian β-cells. ARTICLE HIGHLIGHTS: The significance of insulin-like growth factor-2 receptor (IGF2R) in β-cells remains unclear. To assess the physiological role of IGF2R in β-cells, the effects of IGF2R deficiency in vivo and in vitro were investigated. IGF2R modulates insulin secretion, cell proliferation, and autophagy in β-cells. IGF2R plays a role in the regulation of β-cell biology.","journal":"Diabetes","year":2025,"id":522161,"datarank":0.26876392038420827,"base_score":1.791759469228055,"endowment":1.791759469228055,"self_citation_contribution":0.26876392038420827,"citation_network_contribution":0.0,"self_endowment_contribution":0.26876392038420827,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":5,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9562,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":294804,"name":"Dario F. De Jesus","orcid":"0000-0001-8826-9095","position":1,"is_corresponding":false},{"id":891662,"name":"Takahiro Tsuno","orcid":"0000-0002-5463-4493","position":2,"is_corresponding":false},{"id":294808,"name":"Giorgio Basile","orcid":"0000-0001-9900-4922","position":3,"is_corresponding":false},{"id":891661,"name":"Ryota Inoue","orcid":"0009-0002-5573-5920","position":4,"is_corresponding":false},{"id":531219,"name":"Tomozumi Takatani","orcid":null,"position":5,"is_corresponding":false},{"id":1393065,"name":"Akira Nishiyama","orcid":"0000-0002-8802-3770","position":6,"is_corresponding":false},{"id":734886,"name":"Erin R. Okawa","orcid":"0000-0001-8407-5250","position":7,"is_corresponding":false},{"id":1050934,"name":"Tomohiko Tamura","orcid":"0000-0002-9664-1747","position":8,"is_corresponding":false},{"id":482586,"name":"Yasuo Terauchi","orcid":"0000-0002-8872-3697","position":9,"is_corresponding":false},{"id":269959,"name":"Rohit Kulkarni","orcid":"0000-0001-5029-6119","position":10,"is_corresponding":false},{"id":482583,"name":"Jun Shirakawa","orcid":"0000-0002-0822-8750","position":0,"is_corresponding":true}],"reference_count":51,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:49:49.198144Z","pmid":"41042627","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":[]}