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- W4381337287 abstract "Summary The canonical G406R gain of function mutation that reduces inactivation and increases Ca 2+ influx through the CACNA1C -encoded Ca V 1.2 voltage gated Ca 2+ channel underlies the multisystem disorder Timothy syndrome (TS), characterized by invariant Long QT syndrome and consequent life-threatening arrhythmias. Severe episodic hypoglycemia, which exacerbates arrhythmia risk, is among the myriad non-cardiac TS pathologies that are poorly characterized. While hypoglycemia is thought to result from increased Ca 2+ influx through Ca V 1.2 channels in pancreatic beta cells and consequent hyperinsulinism, this mechanism has never been demonstrated due to a lack of informative animal models, thus hampering development of preventive strategies. We generated a Ca V 1.2 G406R knockin mouse model that recapitulates key TS features including hypoglycemia. Unexpectedly, these mice did not show hyperactive beta cells or hyperinsulinism in the setting of normal intrinsic beta cell function, suggesting dysregulated glucose homeostasis. We discovered multiple alternative contributors to hypoglycemia, including perturbed counterregulatory hormone responses with defects in glucagon secretion and abnormal hypothalamic glucose sensing. Together, these data provide new insights into physiological contributions of the broadly expressed Ca V 1.2 channel and reveal integrated consequences of the mutant channel that underlie the life-threatening events in TS. Brief Summary Gain of function mutant Ca V 1.2 channels drive hypoglycemia through adverse effects on counterregulatory hormones and central nervous system glucose sensing" @default.
- W4381337287 created "2023-06-21" @default.
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- W4381337287 date "2023-06-19" @default.
- W4381337287 modified "2023-09-28" @default.
- W4381337287 title "Multiple beta cell-independent mechanisms drive hypoglycemia in Timothy syndrome" @default.
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- W4381337287 doi "https://doi.org/10.1101/2023.06.16.544987" @default.
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