Sensory Neurodegeneration in Diabetes: Beyond Glucotoxicity

Diabetic polyneuropathy in humans is of gradual, sometimes insidious onset, and is more likely to occur if glucose control is poor. Arguments that the disorder arises chiefly from glucose toxicity however ignore the greater complexity of a unique neurodegenerative disorder. For example, sensory neurons regularly thrive in media with levels of glucose at or exceeding those of poorly controlled diabetic persons. Also, all of the linkages between hyperglycemia and neuropathy develop in the setting of altered insulin availability or sensitivity. Insulin itself is recognized as a potent growth, or trophic factor for adult sensory neurons. Low doses of insulin, insufficient to alter blood glucose levels, reverse features of diabetic neurodegeneration in animal models. Insulin resistance, as occurs in diabetic adipose tissue, liver, and muscle, also develops in sensory neurons, offering a mechanism for neurodegeneration in the setting of normal or elevated insulin levels. Other interventions that "shore up" sensory neurons prevent features of diabetic polyneuropathy from developing despite persistent hyperglycemia. More recently evidence has emerged that a series of subtle molecular changes in sensory neurons can be linked to neurodegeneration including epigenetic changes in the control of gene expression. Understanding the new complexity of sensory neuron degeneration may give rise to therapeutic strategies that have a higher chance of success in the clinical trial arena.