{"doi":"10.1002/cphy.c220031","title":"Noncanonical Regulation of cAMP‐Dependent Insulin Secretion and Its Implications in Type 2 Diabetes","abstract":"Impaired glucose tolerance (IGT) and β-cell dysfunction in insulin resistance associated with obesity lead to type 2 diabetes (T2D). Glucose-stimulated insulin secretion (GSIS) from β-cells occurs via a canonical pathway that involves glucose metabolism, ATP generation, inactivation of K ATP channels, plasma membrane depolarization, and increases in cytosolic concentrations of [Ca 2+ ] c . However, optimal insulin secretion requires amplification of GSIS by increases in cyclic adenosine monophosphate (cAMP) signaling. The cAMP effectors protein kinase A (PKA) and exchange factor activated by cyclic-AMP (Epac) regulate membrane depolarization, gene expression, and trafficking and fusion of insulin granules to the plasma membrane for amplifying GSIS. The widely recognized lipid signaling generated within β-cells by the β-isoform of Ca 2+ -independent phospholipase A 2 enzyme (iPLA 2 β) participates in cAMP-stimulated insulin secretion (cSIS). Recent work has identified the role of a G-protein coupled receptor (GPCR) activated signaling by the complement 1q like-3 (C1ql3) secreted protein in inhibiting cSIS. In the IGT state, cSIS is attenuated, and the β-cell function is reduced. Interestingly, while β-cell-specific deletion of iPLA 2 β reduces cAMP-mediated amplification of GSIS, the loss of iPLA 2 β in macrophages (MØ) confers protection against the development of glucose intolerance associated with diet-induced obesity (DIO). In this article, we discuss canonical (glucose and cAMP) and novel noncanonical (iPLA 2 β and C1ql3) pathways and how they may affect β-cell (dys)function in the context of impaired glucose intolerance associated with obesity and T2D. In conclusion, we provide a perspective that in IGT states, targeting noncanonical pathways along with canonical pathways could be a more comprehensive approach for restoring β-cell function in T2D. © 2023 American Physiological Society. Compr Physiol 13:5023-5049, 2023.","journal":"Comprehensive physiology","year":2023,"id":391867,"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":6,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9491,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":160348,"name":"John Turk","orcid":null,"position":1,"is_corresponding":false},{"id":310762,"name":"Sushant Bhatnagar","orcid":"0000-0002-2917-8588","position":2,"is_corresponding":false},{"id":427977,"name":"Sasanka Ramanadham","orcid":"0000-0002-1664-0657","position":0,"is_corresponding":true}],"reference_count":410,"raw_metadata":null,"created_at":"2026-07-19T01:18:52.232318Z","pmid":"37358504","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":[]}