Multiple beta cell-independent mechanisms drive hypoglycemia in Timothy syndrome
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 path...
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Nature Portfolio
2024-10-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-52885-3 |
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| author | 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 Geoffrey S. Pitt |
| author_facet | 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 Geoffrey S. Pitt |
| author_sort | Maiko Matsui |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-c69ae191aabc414ca794e63e3df33805 |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-10-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-c69ae191aabc414ca794e63e3df338052025-08-20T02:17:53ZengNature PortfolioNature Communications2041-17232024-10-0115111410.1038/s41467-024-52885-3Multiple beta cell-independent mechanisms drive hypoglycemia in Timothy syndromeMaiko Matsui0Lauren E. Lynch1Isabella Distefano2Allison Galante3Aravind R. Gade4Hong-Gang Wang5Nicolas Gómez-Banoy6Patrick Towers7Daniel S. Sinden8Eric Q. Wei9Adam S. Barnett10Kenneth Johnson11Renan Lima12Alfonso Rubio-Navarro13Ang K. Li14Steven O. Marx15Timothy E. McGraw16Paul S. Thornton17Katherine W. Timothy18James C. Lo19Geoffrey S. Pitt20Cardiovascular Research Institute, Weill Cornell MedicineCardiovascular Research Institute, Weill Cornell MedicineCardiovascular Research Institute, Weill Cornell MedicineCardiovascular Research Institute, Weill Cornell MedicineCardiovascular Research Institute, Weill Cornell MedicineCardiovascular Research Institute, Weill Cornell MedicineCardiovascular Research Institute, Weill Cornell MedicineCardiovascular Research Institute, Weill Cornell MedicineCardiovascular Research Institute, Weill Cornell MedicineDepartment of Medicine, MSRB II, 2 Genome Ct, Duke University Medical CenterDepartment of Medicine, MSRB II, 2 Genome Ct, Duke University Medical CenterCardiovascular Research Institute, Weill Cornell MedicineWeill Center for Metabolic Health, Weill Cornell MedicineCardiovascular Research Institute, Weill Cornell MedicineCardiovascular Research Institute, Weill Cornell MedicineDivision of Cardiology, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia UniversityDepartment of Biochemistry, Weill Cornell Medical CollegeDivision of Endocrinology and Diabetes, Cook Children’s Medical CenterChildren’s Hospital Boston, Harvard Medical SchoolCardiovascular Research Institute, Weill Cornell MedicineCardiovascular Research Institute, Weill Cornell MedicineAbstract 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.https://doi.org/10.1038/s41467-024-52885-3 |
| spellingShingle | 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 Geoffrey S. Pitt Multiple beta cell-independent mechanisms drive hypoglycemia in Timothy syndrome Nature Communications |
| title | Multiple beta cell-independent mechanisms drive hypoglycemia in Timothy syndrome |
| title_full | Multiple beta cell-independent mechanisms drive hypoglycemia in Timothy syndrome |
| title_fullStr | Multiple beta cell-independent mechanisms drive hypoglycemia in Timothy syndrome |
| title_full_unstemmed | Multiple beta cell-independent mechanisms drive hypoglycemia in Timothy syndrome |
| title_short | Multiple beta cell-independent mechanisms drive hypoglycemia in Timothy syndrome |
| title_sort | multiple beta cell independent mechanisms drive hypoglycemia in timothy syndrome |
| url | https://doi.org/10.1038/s41467-024-52885-3 |
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