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

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 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.

Network representation of multicellular activity in pancreatic islets: Technical considerations for functional connectivity analysis

“…Laboratory mice are a vital source of islets of Langerhans in beta cell physiology research; however, various laboratories employ various mouse models. Previous research has indicated that there is a considerable phenotypic variation between different mouse strains as well as substrains of the inbred strains [ 73 – 75 ] which manifest themselves also in beta cell responses to glucose and [Ca 2+ ] i signalling characteristics [ 33 , 76 ]. For that reason, we investigate here whether the functional beta cell network structure extracted from multicellular [Ca 2+ ] i recordings in tissue slices depends on the mouse strain.…”

“…In addition, during the plateau phase, the encoding mechanisms to enhance calcium activity in response to glucose differ quantitatively in all three groups [ 33 ]. Secretagogues other than glucose also cause [Ca 2+ ] i oscillations to vary greatly [ 76 ]. Generally, however, there are similarities between C57BL/6J, C57BL/6N, and NMRI mice in the sense that all three groups showed glucose-dependent activation and deactivation responses, as well as a 3% increase in relative active time per millimole of glucose [ 33 ].…”