The Impact of Low-Dose Insulin on Peripheral Nerve Insulin Receptor Signaling in Streptozotocin-Induced Diabetic Rats

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.

Continuous subcutaneous insulin infusion preserves axonal function in type 1 diabetes mellitus

“…However, the present study failed to establish differences in glycaemic control between the two treatment groups or to find correlations between HbA 1c % and nerve excitability parameters. Previous work has provided evidence of changes in nerve conduction velocity and intraepidermal nerve fibre with alterations in insulin dosing, independent of changes in glucose levels . However, there were no significant differences between the two treatment groups in terms of total insulin requirement in the present study.…”

Cutaneous microangiopathy in patients with type 2 diabetes: Impaired vascular endothelial growth factor expression and its correlation with neuropathy, retinopathy and nephropathy

“…Sections were cover‐slipped with Prolong Gold antifade reagent (Molecular Probes, Eugene, OR, USA) to avoid photo‐bleaching, and were examined using a Zeiss LSM510 confocal laser scanning microscope (Carl Zeiss, Oberkochen, Germany) at identical settings including contrast, brightness level and pinhole size. The linear density of PGP9.5‐immunoreactive IENF was determined using a ×40 water immersion objective lens and appropriate filters at a resolution of 1,024 × 1,024 pixels, as described previously. In brief, 16 confocal images were captured at 2‐μm intervals, and image stacks were superimposed to produce a layered image for quantitation in three dimensions.…”

A Role for Insulin in Diabetic Neuropathy

“…Subcutaneous insulin delivery within these same experimental paradigms did not alter the investigated neuronal parameters. Studies in diabetic rats also reported positive actions of subcutaneous low dose insulin on reducing peripheral nerve dysfunction and MAP kinase activity (Sugimoto et al, 2013). This is in contrast to the results from Hoybergs and Meert, which demonstrated that low-dose insulin delivered through subcutaneous insulin pellet can nearly normalize diabetes-induced tactile allodynia and mechanical hyperalgesia, despite persistent hyperglycemia (blood glucose levels dropped from 600 mg/dl to approximately 400 mg/dl 2 weeks after insulin pellet insertion; Hoybergs and Meert, 2007).…”