Biology and mechanism of action:
Mitochondrial signalling is essential for activation of insulin receptor in the brain
Neuronal insulin receptor isoform IR-A is widely distributed in the brain and binds insulin and insulin like growth factor 2 (IGF2) with a high affinity.
We discovered that mitochondrial signalling is an integral part of the insulin stimulated IR-A autophosphorylation. This signal occurs at times preceding autophosphorylation.
Neurons produce a 20 s spike of H2O2 release in response to insulin.
H2O2 signal generates all-or-nothing condition for IR-A autophosphorylation: autophosphorylation occurs, if H2O2 exceeds a certain threshold or NO autophosphorylation occurs even at highest insulin dose if H2O2 signal does not exceed the threshold. Mitochondrial H2O2 is key for IR-A autophosphorylation.
Mitochondrial complex II is the only source of H2O2 signal. Succinate is the only substrate that supports generation of signalling H2O2 in response to insulin.