Peripheral neuropathy is one of the main complications of diabetes. The pathogenesis of this affectation is not completely understood. Several studies refer to
hyperglycemia as the principal cause of
diabetic neuropathy. Nonetheless, there are changes in the expression of
insulin receptor during the progress of
diabetic neuropathy, suggesting that this disorder begins before high
glucose blood levels are established. In this study, we investigated
fructose-induced
insulin resistance as a model of
neuropathic pain.
Insulin resistance was induced by 15%
fructose in
drinking water for 16 weeks.
Fructose slightly enhanced
blood glucose levels. In contrast, chronic
fructose increased
insulin plasma levels and Homeostatic Model Assessment for
Insulin Resistance (HOMA-IR) index. Moreover,
fructose induced
hyperalgesia (to 0.5%
formalin) and
tactile allodynia. Interestingly,
gabapentin and
metformin, but not
diclofenac, reversed in a dose-dependent manner
fructose-induced
tactile allodynia.
Fructose enhanced activating
factor transcription 3 (ATF3), but not
caspase-3 and α2δ-1 subunit, in individual L4 and L5 dorsal root ganglia (DRG) and sciatic nerve. Chronic
fructose also increased
anoctamin-1 and ASIC3 whereas it reduced
insulin receptor-β, α5GABAA receptors and TASK-3 channels
protein expression in DRG and sciatic nerve. In contrast,
fructose did not change TRPV1 channel
protein expression. Treatment with
metformin for 4 weeks reversed some of the
fructose-induced changes in
protein expression. Taken together, these data suggest that
insulin resistance induced by
fructose reproduces several aspects of neuropathic-like
pain. Our data also suggest that nociceptive
hypersensitivity in this model is due to the modulation of several
ionic channels at the primary afferent neurons.