{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T11:22:41Z","timestamp":1785410561350,"version":"3.56.0"},"reference-count":40,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004329","name":"The Slovenian Research and Innovation Agency","doi-asserted-by":"publisher","award":["P1-0055"],"award-info":[{"award-number":["P1-0055"]}],"id":[{"id":"10.13039\/501100004329","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004329","name":"The Slovenian Research and Innovation Agency","doi-asserted-by":"publisher","award":["J3-60062"],"award-info":[{"award-number":["J3-60062"]}],"id":[{"id":"10.13039\/501100004329","id-type":"DOI","asserted-by":"publisher"}]},{"award":["P1-0055"],"award-info":[{"award-number":["P1-0055"]}],"id":[{"id":"https:\/\/ror.org\/059bp8k51","id-type":"ROR","asserted-by":"publisher"}]},{"award":["J3-60062"],"award-info":[{"award-number":["J3-60062"]}],"id":[{"id":"https:\/\/ror.org\/059bp8k51","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Metabolites"],"abstract":"<jats:p>Background\/Objectives: Gamma-aminobutyric acid (GABA) is increasingly recognized as an important modulator of pancreatic beta-cell function, but the mechanisms by which it regulates intracellular Ca2+ oscillations and coordinated beta-cell activity remain insufficiently understood. The aim of this study was to investigate how GABA influences the amplitude, frequency, phase adjustment, entrainment, and synchronization of beta-cell Ca2+ oscillations. Methods: We developed a reduced ATP\u2013Ca2+ oscillation model, based on established beta-cell oscillatory frameworks, and coupled it to the GABA-shunt subsystem derived from our previously established Dual Anaplerotic Model. The model incorporates explicit dynamics of cytosolic Ca2+, endoplasmic reticulum Ca2+, ATP, and a regulatory variable controlling Ca2+ influx, while the interstitial GABA signal is represented as a delayed feedback signal acting on cellular excitability. Single-cell and two-cell simulations were performed to analyze GABA-dependent oscillatory regulation and intercellular coupling. Results: The model reproduced key experimental observations under both control and GABA-deficient conditions, including reduced Ca2+-oscillation amplitude and a prolonged oscillation period when GABA production was suppressed. Mechanistically, GABA affected single-cell oscillations through two complementary pathways: metabolically, by modulating ATP production through PEP-related and TCA-related contributions linked to the GABA shunt, and as an interstitial\/paracrine signal, by adjusting the phase of Ca2+ influx through fast and delayed inhibitory feedback. In the reduced two-cell model, delayed interstitial GABA signaling could phase-lock non-identical oscillators over finite ranges of parameter mismatch. When included as an additional weak effective term, electrical coupling broadened these ranges, consistent with a complementary interaction between GABA-mediated phase adjustment and established electrical coupling. Conclusions: GABA acts as a dual regulator of beta-cell dynamics, linking intracellular metabolism to Ca2+-oscillation patterning and promoting coordinated activity through intercellular phase adjustment. The model provides a mechanistic framework connecting GABA metabolism, ATP dynamics, Ca2+ signaling, and beta-cell synchronization in pancreatic islets.<\/jats:p>","DOI":"10.3390\/metabo16070462","type":"journal-article","created":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T16:50:33Z","timestamp":1782924633000},"page":"462","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["GABA Regulates Ca2+ Oscillations and Synchronization in Pancreatic Beta Cells"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4182-8520","authenticated-orcid":false,"given":"Vladimir","family":"Grubelnik","sequence":"first","affiliation":[{"name":"Faculty of Electrical Engineering and Computer Science, University of Maribor, Koro\u0161ka cesta 46, 2000 Maribor, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0387-1162","authenticated-orcid":false,"given":"Marko","family":"Marhl","sequence":"additional","affiliation":[{"name":"Faculty of Natural Sciences and Mathematics, University of Maribor, Koro\u0161ka cesta 160, 2000 Maribor, Slovenia"},{"name":"Faculty of Medicine, University of Maribor, Taborska ulica 8, 2000 Maribor, Slovenia"},{"name":"Faculty of Education, University of Maribor, Koro\u0161ka cesta 160, 2000 Maribor, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1152\/physrev.00008.2017","article-title":"Pancreatic \u03b2-cell electrical activity and insulin secretion: Of mice and men","volume":"98","author":"Rorsman","year":"2018","journal-title":"Physiol. 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