InsP3 Receptor Regulates Hepatic Gluconeogenesis in Fasting and Diabetes

In the fasted state, increases in circulating glucagon promote hepatic glucose production through induction of the gluconeogenic program. Triggering of the cAMP pathway increases gluconeogenic gene expression via the de-phosphorylation of the CREB coactivator CRTC2 (1). Glucagon promotes CRTC2 dephosphorylation in part through the PKA-mediated inhibition of the CRTC2 kinase SIK2. A number of Ser/Thr phosphatases appear capable of dephosphorylating CRTC2 (2,3), but the mechanisms by which hormonal cues regulate these enzymes remain unclear. Here we show that glucagon stimulates CRTC2 dephosphorylation in hepatocytes by mobilizing intracellular calcium stores and activating the calcium/calmodulin dependent Ser/Thr phosphatase calcineurin/PP2B. Glucagon increased cytosolic calcium through the PKA-mediated phosphorylation of inositol 1,4,5-trisphosphate receptors (InsP3Rs), which we show here associate with CRTC2. Following their activation, InsP3Rs enhanced gluconeogenic gene expression by promoting the calcineurin-mediated dephosphorylation of CRTC2. During feeding, increases in insulin signaling reduced CRTC2 activity via the AKT-mediated inactivation of InsP3Rs. InsP3R activity was increased in diabetes, leading to upregulation of the gluconeogenic program. As hepatic down-regulation of InsP3Rs and calcineurin improved circulating glucose levels in insulin resistance, these results demonstrate how cross-talk between cAMP and calcium pathways at the level of the InsP3 receptor modulates hepatic glucose production under fasting conditions and in diabetes.