Direct Insulin Signaling of Neurons Reverses Diabetic Neuropathy

Abstract

Diabetic polyneuropathy is the most common acquired diffuse disorder of the peripheral nervous system. It is generally assumed that insulin benefits human and experimental diabetic neuropathy indirectly by lowering glucose levels. Insulin also provides potent direct support of neurons and axons, and there is a possibility that abnormalities in direct insulin signaling on peripheral neurons relate to the development of this disorder. Here we report that direct neuronal (intrathecal) delivery of low doses of insulin (0.1-0.2 IU daily), insufficient to reduce glycemia or equimolar IGF-I but not intrathecal saline or subcutaneous insulin, improved and reversed slowing of motor and sensory conduction velocity in rats rendered diabetic using streptozotocin. Moreover, insulin and IGF-I similarly reversed atrophy in myelinated sensory axons in the sural nerve. That intrathecal insulin had the capability of signaling sensory neurons was confirmed by observing that fluorescein isothiocyanate-labeled insulin given intrathecally accessed and labeled individual lumbar dorsal root ganglion neurons. Moreover, we confirmed that such neurons express the insulin receptor, as previously suggested by Sugimoto et al. Finally, we sequestered intrathecal insulin in nondiabetic rats using an antiinsulin antibody. Conduction slowing and axonal atrophy resembling the changes in diabetes were generated by anti-insulin but not by an anti-rat albumin antibody infusion. Defective direct signaling of insulin on peripheral neurons through routes that include the cerebrospinal fluid may relate to the development of diabetic peripheral neuropathy.

New insights in diabetic autonomic neuropathy in children and adolescents

“…The local injections of insulin have no impact on changes of neuropathy in other territories of the same rat (contralateral side given carrier or in the caudal nerve) (27). Furthermore, low subhypoglycemic doses of insulin administered by an intrathecal infusion pump reversed motor and sensory nerve conduction slowing, myelinated axon atrophy and loss of skin innervations (26)(27)(28). Identical doses given subcutaneously did not improve neuropathy.…”

“…Several experimental studies have investigated direct insulin signaling of sensory neurons in diabetic or injury models (26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39): the administration of local lowdose subhypoglycemic near nerve insulin reversed ipsilateral slowing of motor conduction velocity in diabetic rats without lowering plasma glucose levels. The local injections of insulin have no impact on changes of neuropathy in other territories of the same rat (contralateral side given carrier or in the caudal nerve) (27).…”

Oxidative injury and neuropathy in diabetes and impaired glucose tolerance

“…Insulin and insulin-like growth factor reverse DN in models of type 1 diabetes (Brussee et al, 2004;Xu et al, 2004;Toth et al, 2006) and insulin receptors are located within peripheral nerves of healthy rats (Sugimoto et al, 2000). Therefore, a relative reduction in insulin, insulin-like growth factor levels, or insulin insensitivity may be associated with induction of an axonal neuropathy and is implicated in mitochondrial dysfunction in sensory neurons (Huang et al, 2003;Brussee et al, 2004). In this study, ZDF animals with IGT or diabetes are hyperinsulinemic and hyperglycemic, consistent with reduced insulin sensitivity and/or signaling.…”

SOD2 protects neurons from injury in cell culture and animal models of diabetic neuropathy

“…Current rodent models of DN fail to develop changes that closely resemble the human disease (Whiteley and Tomlinson, 1985;Brussee et al, 2004). The reasons for this failure are likely multiple, and include the absence of genetic susceptibility genes and a short life-span (Breyer et al, 2005).…”