Novel regulators of islet function identified from genetic variation in mouse islet Ca2+ oscillations
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...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2023-10-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/88189 |
| _version_ | 1797667205316345856 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Christopher H Emfinger |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T20:09:54Z |
| format | Article |
| id | doaj.art-de0ff10cf88640b2b8b46a53e15528a6 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-03-11T20:09:54Z |
| publishDate | 2023-10-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-de0ff10cf88640b2b8b46a53e15528a62023-10-03T12:28:43ZengeLife Sciences Publications LtdeLife2050-084X2023-10-011210.7554/eLife.88189Novel regulators of islet function identified from genetic variation in mouse islet Ca2+ oscillationsChristopher H Emfinger0https://orcid.org/0000-0002-9130-4194Lauren E Clark1https://orcid.org/0000-0002-0209-9716Brian Yandell2Kathryn L Schueler3Shane P Simonett4https://orcid.org/0000-0002-9359-7808Donnie S Stapleton5Kelly A Mitok6https://orcid.org/0000-0002-0167-3990Matthew J Merrins7https://orcid.org/0000-0003-1599-9227Mark P Keller8https://orcid.org/0000-0002-7405-5552Alan D Attie9https://orcid.org/0000-0002-0568-2261Department of Biochemistry, University of Wisconsin-Madison, Madison, United StatesDepartment of Biochemistry, University of Wisconsin-Madison, Madison, United StatesDepartment of Statistics, University of Wisconsin-Madison, Madison, United StatesDepartment of Biochemistry, University of Wisconsin-Madison, Madison, United StatesDepartment of Biochemistry, University of Wisconsin-Madison, Madison, United StatesDepartment of Biochemistry, University of Wisconsin-Madison, Madison, United StatesDepartment of Biochemistry, University of Wisconsin-Madison, Madison, United StatesDepartment of Medicine, Division of Endocrinology, University of Wisconsin-Madison, Madison, United States; William S. Middleton Memorial Veterans Hospital, Madison, United StatesDepartment of Biochemistry, University of Wisconsin-Madison, Madison, United StatesDepartment 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 StatesInsufficient 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.https://elifesciences.org/articles/88189isletcalcium imaginginsulin secretionmouse geneticsdiabetesβ-cell |
| spellingShingle | 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 Novel regulators of islet function identified from genetic variation in mouse islet Ca2+ oscillations eLife islet calcium imaging insulin secretion mouse genetics diabetes β-cell |
| title | Novel regulators of islet function identified from genetic variation in mouse islet Ca2+ oscillations |
| title_full | Novel regulators of islet function identified from genetic variation in mouse islet Ca2+ oscillations |
| title_fullStr | Novel regulators of islet function identified from genetic variation in mouse islet Ca2+ oscillations |
| title_full_unstemmed | Novel regulators of islet function identified from genetic variation in mouse islet Ca2+ oscillations |
| title_short | Novel regulators of islet function identified from genetic variation in mouse islet Ca2+ oscillations |
| title_sort | novel regulators of islet function identified from genetic variation in mouse islet ca2 oscillations |
| topic | islet calcium imaging insulin secretion mouse genetics diabetes β-cell |
| url | https://elifesciences.org/articles/88189 |
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