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

Authors :
Christopher H Emfinger
Lauren E Clark
Brian Yandell
Kathryn L Schueler
Shane P Simonett
Donnie S Stapleton
Kelly A Mitok
Matthew J Merrins
Mark P Keller
Alan D Attie
Source :
eLife, Vol 12 (2023)
Publication Year :
2023
Publisher :
eLife Sciences Publications Ltd, 2023.

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 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 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 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 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.

Details

Language :
English
ISSN :
2050084X
Volume :
12
Database :
Directory of Open Access Journals
Journal :
eLife
Publication Type :
Academic Journal
Accession number :
edsdoj.0ff10cf88640b2b8b46a53e15528a6
Document Type :
article
Full Text :
https://doi.org/10.7554/eLife.88189