A role for mitogen-activated protein kinases in the etiology of diabetic neuropathy

The onset of diabetic neuropathy, a complication of diabetes mellitus, has been linked to poor glycemic control. We tested the hypothesis that the mit ogen-activated protein kinases (MAPK) form transducers for the damaging eff ects of high glucose. In cultures of adult rat sensory neurons, high glucos e activated JNK and p38 MAPK but did not result in cell damage. However, ox idative stress activated ERK and p38 MAPKs and resulted in cellular damage. In the dorsal root ganglia of streptozotocin-induced diabetic rats (a mode l of type I diabetes), ERK and p38 were activated at 8 wk duration, followe d by activation of JNK at 12 wk duration. We report activation of JNK and i ncreases in total levels of p38 and JNK in sural nerve of type I and II dia betic patients. These data implicate MAPKs in the etiology of diabetic neur opathy both via direct effects of glucose and via glucose-induced oxidative stress.