title: 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.
  
  
  CONCLUSIONS
  Ih was upregulated after MGO administration in normal mice.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Neurology, Tokushima University, Tokushima, Japan.
authors.forename: Yoshimitsu
authors.initials: Y
authors.lastname: Shimatani
authors.affiliation: Department of Neurology, Tokushima University, Tokushima, Japan. Electronic address: hnodera@tokushima-u.ac.jp.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nodera
authors.affiliation: Department of Neurology, Tokushima University, Tokushima, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Osaki
authors.affiliation: Department of Neurology, Tokushima University, Tokushima, Japan.
authors.forename: Chimeglkham
authors.initials: C
authors.lastname: Banzrai
authors.affiliation: Department of Neurology, Tokushima University, Tokushima, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Takayasu
authors.affiliation: Department of Neurology, Tokushima University, Tokushima, Japan.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Endo
authors.affiliation: Department of Neurology, Tokushima University, Tokushima, Japan; Department of Neurology, National Hospital Organization Takamatsu Medical Center, Takamatsu, Japan.
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Shibuta
authors.affiliation: Department of Neurology, Tokushima University, Tokushima, Japan.
authors.forename: Ryuji
authors.initials: R
authors.lastname: Kaji
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001369:Axons / Q000187:drug effects* / Q000502:physiology; D015415:Biomarkers / Q000378:metabolism; D016022:Case-Control Studies; D003929:Diabetic Neuropathies / Q000378:metabolism / Q000503:physiopathology*; D004195:Disease Models, Animal; D005260:Female; D005947:Glucose / Q000378:metabolism; D006801:Humans; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / Q000187:drug effects* / Q000502:physiology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008875:Middle Aged; D008962:Models, Theoretical; D011765:Pyruvaldehyde / Q000378:metabolism / Q000494:pharmacology*; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects* / Q000502:physiology
chemical_list: D015415:Biomarkers; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D011765:Pyruvaldehyde; D005947:Glucose
keywords: Axonal excitability; Diabetic neuropathy; HCN channel; Ih; Methylglyoxal