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Abstract. Sensory neurons in diabetes may be primarily targeted by diabetes and their involvement may account for prominent sensory loss and pain in diabetic patients. Previous studies demonstrating evidence of excessive polyol flux, microangiopathy, and oxidative stress involving sensory axons and ganglia have been joined by more recent work demonstrating altered neuron phenotype, mitochondrial dysfunction, ion channel alterations, and abnormal growth factor signaling. As such, an interesting and unique panoply of molecular changes in primary sensory neurons has been identified in diabetic models. Insulin deficiency and subsequent changes in second messenger signaling may also play an important role in how sensory neurons respond to diabetes. Applying approaches to support sensory neurons in diabetes may be an important therapeutic direction in diabetic patients.
Key Words: Diabetes; Dorsal root ganglion; Neuron; Neuropathy.
INTRODUCTION
Human diabetes mellitus is associated with "endstage" complications involving the retina, kidney, and peripheral nerve. Although exceptional control of diabetes-related hyperglycemia may attenuate, delay, or prevent development of diabetic complications, reversal of complications does not occur. Among these complications, diabetes selectively targets the peripheral nervous system in a widespread or diffuse fashion leading to polyneuropathy or selectively causing focal neuropathies. In patients with polyneuropathy, sensory and perhaps autonomic neurons appear to be involved early. Unfortunately, polyneuropathy is also not really an "endstage complication" but may, for example, develop in diabetic children.
A number of hypotheses have been proposed to explain the targeting of peripheral nerves by diabetes (Fig. 1). We will emphasize, however, those changes that are particularly directed toward the cell body or perikaryon of the sensory neuron. In the past, the direct targeting of perikarya in ganglia has not been emphasized as much as changes in distal axons. The perikaryon is an important target to consider, however, since loss of sensory neurons may be an irretrievable consequence, limiting options for repair. Alternatively, specific and early approaches that would support the sensory neuron may provide options to prevent such loss. This might be accomplished by better understanding of the potential role of neuron growth factors, including insulin.
Why would disease of perikarya account for the features of diabetic polyneuropathy? The innervation of the most distal target organs is the first to be disrupted by early diabetic polyneuropathy. This causes clinical symptoms...