contributed equally to the work
Diabetic polyneuropathy (DPN) renders progressive sensory neurodegeneration linked to hyperglycemia and its associated metabolopathy. Here we hypothesized that there may be additive impacts of direct insulin signaling, independent of glycemia and PTEN (phosphatase and tensin homolog deleted on chromosome 10) knockdown on neuropathy. Our targets for combined interventions were neurons and Schwann cells in vitro and chronic Type 1 DPN in mice. IR (insulin receptor) expression was not altered by high glucose conditions in neurons or SCs and insulin promoted survival of neurons and proliferation of SCs in vitro. There were additive impacts between insulin signaling and PTEN knockdown in sensory neuron outgrowth and in axon myelination by SCs. In a chronic long term mouse model of experimental DPN unilateral intra-hindpaw injections of a PTEN siRNA and local insulin had additive impacts on correcting key features of chronic experimental DPN independent of glycemia, including motor axon conduction, thermal and mechanical sensory loss. Moreover, combined interventions improved sural and tibial nerve myelin thickness, hindpaw epidermal innervation and pAkt expression in dorsal root ganglia sensory neurons. We conclude that local PTEN inhibition or knockdown and insulin provide additive trophic support for sensory neurons and SCs whilst reversing key abnormalities of experimental DPN but without requiring metabolic correction.
