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Inositol-1,4,5-trisphosphate receptor regulates hepatic gluconeogenesis in fasting and diabetes

Abstract

In the fasted state, increases in circulating glucagon promote hepatic glucose production through induction of the gluconeogenic program. Triggering of the cyclic AMP pathway increases gluconeogenic gene expression via the de-phosphorylation of the CREB co-activator CRTC2 (ref. 1). Glucagon promotes CRTC2 dephosphorylation in part through the protein kinase A (PKA)-mediated inhibition of the CRTC2 kinase SIK2. A number of Ser/Thr phosphatases seem to be capable of dephosphorylating CRTC2 (refs 2, 3), but the mechanisms by which hormonal cues regulate these enzymes remain unclear. Here we show in mice that glucagon stimulates CRTC2 dephosphorylation in hepatocytes by mobilizing intracellular calcium stores and activating the calcium/calmodulin-dependent Ser/Thr-phosphatase calcineurin (also known as PP3CA). Glucagon increased cytosolic calcium concentration through the PKA-mediated phosphorylation of inositol-1,4,5-trisphosphate receptors (InsP3Rs), which associate with CRTC2. After their activation, InsP3Rs enhanced gluconeogenic gene expression by promoting the calcineurin-mediated dephosphorylation of CRTC2. During feeding, increases in insulin signalling 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 downregulation of InsP3Rs and calcineurin improved circulating glucose levels in insulin resistance, these results demonstrate how interactions between cAMP and calcium pathways at the level of the InsP3R modulate hepatic glucose production under fasting conditions and in diabetes.

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Figure 1: Calcineurin promotes CRTC2 activation during fasting.
Figure 2: Glucagon stimulates CRTC2 dephosphorylation via activation of InsP 3 Rs.
Figure 3: Glucagon stimulates CRTC2 activity via PKA-dependent phosphorylation of InsP 3 Rs.
Figure 4: InsP 3 R activity is upregulated in diabetes.

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Acknowledgements

This work was supported by National Institutes of Health grants R01-DK049777, R01-DK083834 and R01-DK091618 (M.M.), HL087123 (I.T.), the Kieckhefer Foundation, The Clayton Foundation for Medical Research, and the Leona M. and Harry B. Helmsley Charitable Trust.

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Y.W., I.T. and M.M. designed and interpreted the experiments. Y.W., G.L., J.C.P., R.S. and J.G. carried out the experimental work. Y.W., K.O. and J.C. characterized glucose metabolism in Insp3r2 knockout mice. W.H.F. performed proteomic studies, and Y.W. and M.M. wrote the paper.

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Correspondence to Marc Montminy.

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The authors declare no competing financial interests.

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Wang, Y., Li, G., Goode, J. et al. Inositol-1,4,5-trisphosphate receptor regulates hepatic gluconeogenesis in fasting and diabetes. Nature 485, 128–132 (2012). https://doi.org/10.1038/nature10988

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