Novel regulators of islet function identified from genetic variation in mouse islet Ca 2+ oscillations.

Autor:	Emfinger CH; Department of Biochemistry, University of Wisconsin-Madison, Madison, United States., Clark LE; Department of Biochemistry, University of Wisconsin-Madison, Madison, United States., Yandell B; Department of Statistics, University of Wisconsin-Madison, Madison, United States., Schueler KL; Department of Biochemistry, University of Wisconsin-Madison, Madison, United States., Simonett SP; Department of Biochemistry, University of Wisconsin-Madison, Madison, United States., Stapleton DS; Department of Biochemistry, University of Wisconsin-Madison, Madison, United States., Mitok KA; Department of Biochemistry, University of Wisconsin-Madison, Madison, United States., Merrins MJ; Department of Medicine, Division of Endocrinology, University of Wisconsin-Madison, Madison, United States.; William S. Middleton Memorial Veterans Hospital, Madison, United States., Keller MP; Department of Biochemistry, University of Wisconsin-Madison, Madison, United States., Attie AD; Department of Biochemistry, University of Wisconsin-Madison, Madison, United States.; Department of Medicine, Division of Endocrinology, University of Wisconsin-Madison, Madison, United States.; Department of Chemistry, University of Wisconsin-Madison, Madison, United States.
Jazyk:	angličtina
Zdroj:	ELife [Elife] 2023 Oct 03; Vol. 12. Date of Electronic Publication: 2023 Oct 03.
DOI:	10.7554/eLife.88189
Abstrakt:	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. Competing Interests: CE, LC, BY, KS, SS, DS, KM, MM, MK, AA No competing interests declared (© 2023, Emfinger, Clark et al.)
Databáze:	MEDLINE
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