REV-ERB in GABAergic neurons controls diurnal hepatic insulin sensitivity

Systemic insulin sensitivity shows a diurnal rhythm with a peak upon waking(1,2). The molecular mechanism that underlies this temporal pattern is unclear. Here we show that the nuclear receptors REV-ERB-alpha and REV-ERB-beta (referred to here as 'REV-ERB') in the GABAergic (gamma-aminobutyric acid-producing) neurons in the suprachiasmatic nucleus (SCN) (SCNGABA neurons) control the diurnal rhythm of insulin-mediated suppression of hepatic glucose production in mice, without affecting diurnal eating or locomotor behaviours during regular light-dark cycles. REV-ERB regulates the rhythmic expression of genes that are involved in neurotransmission in the SCN, and modulates the oscillatory firing activity of SCNGABA neurons. Chemogenetic stimulation of SCNGABA neurons at waking leads to glucose intolerance, whereas restoration of the temporal pattern of either SCNGABA neuron firing or REV-ERB expression rescues the time-dependent glucose metabolic phenotype caused by REV-ERB depletion. In individuals with diabetes, an increased level of blood glucose after waking is a defining feature of the 'extended dawn phenomenon'(3,4). Patients with type 2 diabetes with the extended dawn phenomenon exhibit a differential temporal pattern of expression of REV-ERB genes compared to patients with type 2 diabetes who do not have the extended dawn phenomenon. These findings provide mechanistic insights into how the central circadian clock regulates the diurnal rhythm of hepatic insulin sensitivity, with implications for our understanding of the extended dawn phenomenon in type 2 diabetes. REV-ERB in GABAergic neurons orchestrates the rhythmic sensitivity of hepatic glucose production to insulin-mediated suppression that peaks at wakening, with implications in the extended dawn phenomenon.

Automated summary

The nuclear receptors REV-ERB-alpha and REV-ERB-beta in GABAergic neurons control the diurnal rhythm of insulin-mediated suppression of hepatic glucose production, peaking at waking. This mechanism is crucial for understanding the extended dawn phenomenon in type 2 diabetes.