192-OR: T-Type Calcium Channel Cav3.2 in GABAergic Neurons Regulates Rhythmic Glucose Metabolism

Abstract

Systemic insulin sensitivity shows a diurnal rhythm with a peak upon waking. The GABAergic (γ-aminobutyric acid-producing) neurons in the suprachiasmatic nucleus (SCN) (SCNGABA neurons) were reported to control the diurnal rhythm of insulin-mediated suppression of hepatic glucose production in mice in earlier work1. SCNGABA neural firing activity displays a diurnal rhythm, with the intrinsic ionic mechanism underlying this temporal pattern not completely understood. Here we provided evidence supporting a role of the T type voltage-gated calcium ion channel subunit 3.2 (Cav3.2) in SCNGABA neurons in regulating rhythmic neural firing and glucose homeostasis. We found that Cav3.2 global knockout (Cav3.2KO) mice displayed disrupted diurnal rhythm of blood glucose levels. Selective deletion of Cav3.2 in the SCNGABA neurons abolished the oscillatory firing activity of SCNGABA neurons and led to glucose intolerance. Furthermore, our real-time calcium imaging data in freely moving mice showed that SCN GABA neuronal activity displayed a circadian rhythm pattern in WT control mice but not Cav3.2KO mice or mice with Cav3.2 selectively deleted in the SCNGABA neurons. These findings provide insights into how the calcium ion channel regulates the central circadian clock and glucose metabolism, with implications in the extended dawn phenomenon in type 2 diabetes. Keywords: Type 2 diabetes, calcium channel, Cav3.2, GABA neurons, circadian rhythm Reference: 1 Ding, G. et al. REV-ERB in GABAergic neurons controls diurnal hepatic insulin sensitivity. Nature 592, 763-767, doi:10.1038/s41586-021-03358-w (2021) . Disclosure P. Xu: None. W. Zhou: None. Z. Sun: None. Y. He: None. Funding NIH (P20 GM135002)