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

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 10 nM 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.