Abstract
BackgroundThe precise mechanisms of the neuroprotective effects of insulin in streptozotocin (STZ)-induced diabetic animals remain unknown, but altered peripheral nerve insulin receptor signaling due to insulin deficiency might be one cause.Methodology and Principal FindingsDiabetes was induced in 10-week-old, male Wistar rats by injecting them with STZ (45 mg/kg). They were assigned to one group that received half of an insulin implant (∼1 U/day; I-group, n = 11) or another that remained untreated (U-group, n = 10) for 6 weeks. The controls were age- and sex-matched, non-diabetic Wistar rats (C-group, n = 12). Low-dose insulin did not change haemoglobin A1c, which increased by 136% in the U-group compared with the C-group. Thermal hypoalgesia and mechanical hyperalgesia developed in the U-group, but not in the I-group. Sensory and motor nerve conduction velocities decreased in the U-group, whereas sensory nerve conduction velocity increased by 7% (p = 0.0351) in the I-group compared with the U-group. Western blots showed unaltered total insulin receptor (IR), but a 31% decrease and 3.1- and 4.0-fold increases in phosphorylated IR, p44, and p42 MAPK protein levels, respectively, in sciatic nerves from the U-group compared with the C-group. Phosphorylated p44/42 MAPK protein decreased to control levels in the I-group (p<0.0001).Conclusions and SignificanceLow-dose insulin deactivated p44/42 MAPK and ameliorated peripheral sensory nerve dysfunction in rats with STZ-induced diabetes. These findings support the notion that insulin deficiency per se introduces impaired insulin receptor signaling in type 1 diabetic neuropathy.
Highlights
Insulin acts as a potent neurotrophic factor that stimulates neurite outgrowth and regeneration of sensory neurons [1,2]
Low-dose insulin deactivated p44/42 mitogen-activated protein kinase (MAPK) and ameliorated peripheral sensory nerve dysfunction in rats with STZ-induced diabetes. These findings support the notion that insulin deficiency per se introduces impaired insulin receptor signaling in type 1 diabetic neuropathy
We have demonstrated that the high-affinity insulin receptor is expressed preferentially in small-to-medium-sized sensory neurons in rats [11,12] and that impaired peripheral nerve insulin receptor signaling, as indicated by decreased expression of phosphorylated insulin receptor, occurs during the early course of altered pain sensation in STZ-induced diabetic rats [13]
Summary
Insulin acts as a potent neurotrophic factor that stimulates neurite outgrowth and regeneration of sensory neurons [1,2]. In streptozotocin (STZ)-induced diabetic rats, which is the most extensively studied animal model of type 1 diabetic neuropathy, low-dose insulin insufficient to affect systemic glycemia reverses abnormal peripheral nerve function and structure [5,6,7,8,9]. The effects of low-dose insulin on impaired peripheral nerve insulin receptor signaling in association with altered nociception in type 1 diabetic neuropathy remain to be explored. The precise mechanisms of the neuroprotective effects of insulin in streptozotocin (STZ)-induced diabetic animals remain unknown, but altered peripheral nerve insulin receptor signaling due to insulin deficiency might be one cause
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