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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

Data files

Mar 27, 2023 version files 123.57 MB
Mar 28, 2023 version files 123.57 MB
Sep 26, 2023 version files 81.58 GB

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.