Altered distribution of juxtaparanodal K _v1.2 subunits mediates peripheral nerve hyperexcitability in type 2 diabetes mellitus

Peripheral nerve hyperexcitability (PNH) is one of the distal peripheral neuropathy phenotypes often present in patients affected by type 2 diabetes mellitus (T2DM). Through in vivo and ex vivo electrophysiological recordings in db/db mice, a model of T2DM, we observed that, in addition to reduced nerve conduction velocity, db/db mice also develop PNH. By using pharmacological inhibitors, we demonstrated that the PNH is mediated by the decreased activity of K _v1-channels. In agreement with these data, we observed that the diabetic condition led to a reduced presence of the K _v1.2-subunits in juxtaparanodal regions of peripheral nerves in db/db mice and in nerve biopsies fromT2DMpatients. Together, these observations indicate that theT2DMcondition leads to potassium channel-mediated PNH, thus identifying them as a potential drug target to treat some of the DPN related symptoms.