Novel regulators of islet function identified from genetic variation in mouse islet Ca 2+ oscillations.
Christopher H EmfingerLauren E ClarkBrian YandellKathryn L SchuelerShane P SimonettDonnie S StapletonKelly A MitokMatthew J MerrinsMark P KellerAlan D AttiePublished in: eLife (2023)
Insufficient insulin secretion to meet metabolic demand results in diabetes. The intracellular flux of Ca 2+ into β-cells triggers insulin release. Since genetics strongly influences variation in islet secretory responses, we surveyed islet Ca 2+ 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 glucose-dependent insulinotropic polypeptide (GIP); and (4) 2 mM glucose. These stimuli interrogate β-cell function, α- to β-cell signaling, and incretin responses. We then correlated components of the Ca 2+ waveforms to islet protein abundances in the same strains used for the Ca 2+ measurements. To focus on proteins relevant to human islet function, we identified human orthologues of correlated mouse proteins that are proximal to glycemic-associated single-nucleotide polymorphisms in human genome-wide association studies. 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 nominate novel regulators of islet Ca 2+ 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.
Keyphrases
- endothelial cells
- type diabetes
- induced pluripotent stem cells
- escherichia coli
- amino acid
- pluripotent stem cells
- blood glucose
- cardiovascular disease
- transcription factor
- metabolic syndrome
- high throughput
- protein kinase
- blood pressure
- small molecule
- electronic health record
- bone marrow
- deep learning
- induced apoptosis
- skeletal muscle
- cell proliferation
- climate change
- reactive oxygen species
- binding protein
- cell cycle arrest