Abnormal Muscle Spindle Innervation and Large-Fiber Neuropathy in Diabetic Mice

Abstract

OBJECTIVE-Large-fiber diabetic polyneuropathy (DPN) leads to balance and gait abnormalities, placing patients at risk for falls. Large sensory axons innervating muscle spindles provide feedback for balance and gait and, when damaged, can cause altered sensorimotor function. This study aimed to determine whether symptoms of large-fiber DPN in type 1 and type 2 diabetic mouse models are related to alterations in muscle spindle innervation. In addition, diabetic mice were treated with insulin to assess whether sensorimotor and spindle deficits were reversible.RESEARCH DESIGN AND METHODS-Behavioral assessments were performed in untreated and treated streptozotocin (STZ)-injected C57BL/6 mice to quantitate diabetes-induced deficits in balance and gait. Quantification of Ia axon innervation of spindles was carried out using immunohistochemistry and confocal microscopy on STZ-injected C57BL/6 and db/db mice.RESULTS-STZ-injected C57BL/6 mice displayed significant and progressive sensorimotor dysfunction. Analysis of Ia innervation patterns of diabetic C57BL/6 spindles revealed a range of abnormalities suggestive of Ia axon degeneration and/or regeneration. The multiple abnormal Ia fiber morphologies resulted in substantial variability in axonal width and inter-rotational distance (IRD). Likewise, db/db mice displayed significant variability in their IRDs compared with db ϩ mice, suggesting that damage to Ia axons occurs in both type 1 and type 2 diabetes models. Insulin treatment improved behavioral deficits and restored Ia fiber innervation in comparison with nondiabetic mice.CONCLUSIONS-Similar to small fibers, Ia axons are vulnerable to diabetes, and their damage may contribute to balance and gait deficits. In addition, these studies provide a novel method to assay therapeutic interventions designed for diabetes-induced large-fiber dysfunction. Diabetes 57:1693-1701, 2008 E stimates from the Centers for Disease Control and Prevention suggest that 60 -70% of diabetic patients develop neuropathy. In addition, diabetes is the leading cause of neuropathy in the U.S. and Western countries (1). Sensorimotor diabetic polyneuropathy (DPN) affects both large and small sensory afferent nerve fibers. The majority of research focuses on small-fiber neuropathy leading to increased or decreased pain and temperature sensations (2-5). Consequently, there is a shortage of animal model research exploring large-fiber DPN, which can cause deficits in lower-limb proprioception, decreased tactile sensitivity and vibration sense, and incoordination due to balance abnormalities (1,6).The sensorimotor deficits resulting from large-fiber DPN, while sometimes subtle in nature, can lead to significant impairment. Numerous human studies report that patients with DPN are at increased risk for falls due to decreased postural control, altered gait and balance, and increased body sway (7-9). The underlying neurologic mechanisms involved in large-fiber DPN remain poorly understood. It has been hypothesized that large-fiber DPN instability could be ca...

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Regulation of hepatic pyruvate dehydrogenase phosphorylation in offspring glucose intolerance induced by intrauterine hyperglycemia

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