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

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.