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Genetic variation in mouse islet Ca2+ oscillations reveals novel regulators of islet function

Emfinger, Christopher1; Clark, Lauren1; Yandell, Brian1; Schueler, Kathryn1; Simonett, Shane1; Stapleton, Donnie2; Mitok, Kelly2; Merrins, Matthew2; Keller, Mark2; Attie, Alan2

Research facility: University of Wisconsin–Madison
Published Mar 27, 2023; Updated Sep 26, 2023 on Dryad. https://doi.org/10.5061/dryad.j0zpc86jc

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Abstract

Insufficient insulin secretion to meet metabolic demand results in diabetes. The intracellular flux of Ca2+ into β-cells triggers insulin release. Since genetics strongly influences variation in islet secretory responses, we surveyed islet Ca2+ dynamics in eight genetically diverse mouse strains. We found high strain variation in response to four conditions: 1) 8 mM glucose; 2) 8 mM glucose plus amino acids; 3) 8 mM glucose, amino acids, plus 10nM GIP; and 4) 2 mM glucose. These stimuli interrogate β-cell function, α-cell to β-cell signaling, and incretin responses. We then correlated components of the Ca2+ waveforms to islet protein abundances in the same strains used for the Ca2+ measurements. To focus on proteins relevant to human islet function, we identified human orthologues of correlated mouse proteins that are proximal to glycemic-associated SNPs in human GWAS. Several orthologues have previously been shown to regulate insulin secretion (e.g. ABCC8, PCSK1, and GCK), supporting our mouse-to-human integration as a discovery platform. By integrating these data, we nominated novel regulators of islet Ca2+ oscillations and insulin secretion with potential relevance for human islet function. We also provide a resource for identifying appropriate mouse strains in which to study these regulators.