Novel regulators of islet function identified from genetic variation in mouse islet Ca2+ oscillations

• DOI: 10.7554/elife.88189.3
• Publication Date: 2023-10-03T12:30:48Z
• Authors: Christopher H Emf...; Lauren E Clark; Brian Yandell; Kathryn L Schueler; Shane P Simonett; Donnie S Stapleton; Kelly A Mitok; Matthew J Merrins; Mark P Keller; Alan D Attie
• Keywords: Incretin

Insufficient insulin secretion to meet metabolic demand results in diabetes. The intracellular flux of Ca 2+ into β-cells triggers release. Since genetics strongly influences variation islet secretory responses, we surveyed dynamics eight genetically diverse mouse strains. We found high strain response four conditions: (1) 8 mM glucose; (2) glucose plus amino acids; (3) glucose, acids, 10 nM glucose-dependent insulinotropic polypeptide (GIP); and (4) 2 glucose. These stimuli interrogate β-cell function, α- signaling, incretin responses. then correlated components the waveforms protein abundances same strains used for measurements. To focus on proteins relevant human identified orthologues that are proximal glycemic-associated single-nucleotide polymorphisms genome-wide association studies. Several have previously been shown regulate (e.g. ABCC8, PCSK1, GCK), supporting our mouse-to-human integration as a discovery platform. By integrating these data, nominate novel regulators oscillations with potential relevance function. also provide resource identifying appropriate which study regulators.