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. 2020 Nov 30;21(23):9144. doi: 10.3390/ijms21239144

Figure 1.

Figure 1

In the insulin-OCN-feed-forward-loop the binding of insulin to its receptor causes an Insulin receptor phosphorylation and activation which in turn causes the phosphorylation of Forkhead Box Protein O-1 (FoxO-1) and its inactivation. This reduces FoxO-1 levels, which otherwise would have inhibited Gla-OCN production and promoted osteosprotegrin (OPG) synthesis. At the same time, insulin signaling activates Runt-related transcription factor 2 (RUNX 2) which leads to a further increase in the expression and secretion of bio-inactive Gla-OCN. Insulin-dependent OPG reduction causes an increase in Receptor Activator of NF-κB/Receptor Activator of NF-κB-Ligand (RANK/RANKL) interaction and thus osteoclast differentiation and activation. This in turn leads to higher levels of bone resorption in acid resorption lacunae causing an increase in the pH dependent transformation of inactive Gla-OCN into under- or un-γ-carboxylated Glu-OCN and its release from the extracellular matrix (ECM). In its soluble and bioactive form Glu-OCN causes an improved peripheral insulin sensitivity as well as further β-cell activation and a consequent drop in blood glucose thus multiplying insulin’s physiological effects [13,14].