Multiple beta cell-independent mechanisms drive hypoglycemia in Timothy syndrome

Maiko Matsui, Lauren E. Lynch, Isabella Distefano, Allison Galante, Aravind R. Gade, Hong-Gang Wang, Nicolas Gómez-Banoy, Patrick Towers, Daniel S. Sinden, Eric Q. Wei, Adam S. Barnett, Kenneth Johnson, Renan Lima, Alfonso Rubio-Navarro, Ang K. Li, Steven O. Marx, Timothy E. McGraw, Paul S. Thornton, Katherine W. Timothy, James C. Lo and Geoffrey S. Pitt ()
Additional contact information
Maiko Matsui: Weill Cornell Medicine
Lauren E. Lynch: Weill Cornell Medicine
Isabella Distefano: Weill Cornell Medicine
Allison Galante: Weill Cornell Medicine
Aravind R. Gade: Weill Cornell Medicine
Hong-Gang Wang: Weill Cornell Medicine
Nicolas Gómez-Banoy: Weill Cornell Medicine
Patrick Towers: Weill Cornell Medicine
Daniel S. Sinden: Weill Cornell Medicine
Eric Q. Wei: Duke University Medical Center
Adam S. Barnett: Duke University Medical Center
Kenneth Johnson: Weill Cornell Medicine
Renan Lima: Weill Cornell Medicine
Alfonso Rubio-Navarro: Weill Cornell Medicine
Ang K. Li: Weill Cornell Medicine
Steven O. Marx: Columbia University
Timothy E. McGraw: Weill Cornell Medical College
Paul S. Thornton: Cook Children’s Medical Center
Katherine W. Timothy: Harvard Medical School
James C. Lo: Weill Cornell Medicine
Geoffrey S. Pitt: Weill Cornell Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract The canonical G406R mutation that increases Ca2+ influx through the CACNA1C-encoded CaV1.2 Ca2+ channel underlies the multisystem disorder Timothy syndrome (TS), characterized by life-threatening arrhythmias. Severe episodic hypoglycemia is among the poorly characterized non-cardiac TS pathologies. While hypothesized from increased Ca2+ influx in pancreatic beta cells and consequent hyperinsulinism, this hypoglycemia mechanism is undemonstrated because of limited clinical data and lack of animal models. We generated a CaV1.2 G406R knockin mouse model that recapitulates key TS features, including hypoglycemia. Unexpectedly, these mice do not show hyperactive beta cells or hyperinsulinism in the setting of normal intrinsic beta cell function, suggesting dysregulated glucose homeostasis. Patient data confirm the absence of hyperinsulinism. We discover multiple alternative contributors, including perturbed counterregulatory hormone responses with defects in glucagon secretion and abnormal hypothalamic control of glucose homeostasis. These data provide new insights into contributions of CaV1.2 channels and reveal integrated consequences of the mutant channels driving life-threatening events in TS.

Date: 2024
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-024-52885-3 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-52885-3

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-024-52885-3

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().