Diabetic peripheral neuropathy (DPN) is a common complication affecting more than one third of diabetes mellitus (DM) patients. Although all cellular components participating in peripheral nerve function are exposed to and affected by the metabolic consequences of DM, nodal regions, areas of intense interactions between Schwann cells and axons, may be particularly sensitive to DM-induced alterations. Nodes are enriched in insulin receptors, glucose transporters, Na⁺ and K⁺ channels, and mitochondria, all implicated in the development and progression of DPN. Latest results particularly reinforce the idea that changes in ion-channel function and energy metabolism, both of which depend on axon–glia crosstalk, are among the important contributors to DPN. These insights provide a basis for new therapeutic approaches aimed at delaying or reversing DPN.