Upregulation of axonal HCN current by methylglyoxal: Potential association with diabetic polyneuropathy

Abstract

Objective: To describe functional changes of axonal ion channels by a metabolic derivative of glucose, methylglyoxal (MGO), and its potential contribution to diabetic neuropathy.

Methods: (1) In wild-type male mice, multiple excitability measurements of sensory nerves were performed at baseline and 1week after serial administration of MGO (50mg/kg). (2) Excitability testing in patients with diabetic neuropathy (N=17) and healthy controls (N=12) were also conducted, and data were interpreted using mathematical modeling.

Results: In the animal study, there was a decrease in threshold changes by long hyperpolarization and in superexcitability after administration of MGO. In the preliminary human study, the threshold changes by long hyperpolarizing current were decreased in patients with diabetes. Mathematical modeling showed increased hyperpolarization-activated cation current (Ih) in the MGO-treated mice and in patients with diabetes.

Conclusion: Ih was upregulated after MGO administration in normal mice.

Significance: MGO is associated with abnormal axonal excitability. Hyperexcitability in diabetic polyneuropathy may, at least in part, be caused by dysfunctional axonal hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. A future study with a large sample size of the diabetic patients would clarify this hypothesis.

Keywords: Axonal excitability; Diabetic neuropathy; HCN channel; Ih; Methylglyoxal.