Multiple beta cell-independent mechanisms drive hypoglycemia in Timothy syndrome.

ABSTRACT: The canonical G406R mutation that increases Ca²⁺ influx through the CACNA1C-encoded Ca_V1.2 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 Ca_V1.2 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 func

SUBMITTER: Matsui M 

PROVIDER: S-EPMC11487186 | biostudies-literature | 2024 Oct

REPOSITORIES: biostudies-literature