title: Beneficial effects of exendin-4 on experimental polyneuropathy in diabetic mice.
abstract: OBJECTIVE
  The therapeutic potential of exendin-4, an agonist of the glucagon-like peptide-1 receptor (GLP-1R), on diabetic polyneuropathy (DPN) in streptozotocin (STZ)-induced diabetic mice was investigated.
  
  
  METHODS
  The presence of the GLP-1R in lumbar dorsal root ganglion (DRG) was evaluated by immunohistochemical analyses. DRG neurons were dissected from C57BL6/J mice and cultured with or without Schwann cell-conditioned media in the presence or absence of GLP-1 (7-37) or exendin-4. Then neurite outgrowth was determined. In animal-model experiments, mice were made diabetic by STZ administration, and after 12 weeks of diabetes, exendin-4 (10 nmol/kg) was intraperitoneally administered once daily for 4 weeks. Peripheral nerve function was determined by the current perception threshold and motor and sensory nerve conduction velocity (MNCV and SNCV, respectively). Sciatic nerve blood flow (SNBF) and intraepidermal nerve fiber densities (IENFDs) also were evaluated.
  
  
  RESULTS
  The expression of the GLP-1R in DRG neurons was confirmed. GLP-1 (7-37) and exendin-4 significantly promoted neurite outgrowth of DRG neurons. Both GLP-1R agonists accelerated the impaired neurite outgrowth of DRG neurons cultured with Schwann cell-conditioned media that mimicked the diabetic condition. At the doses used, exendin-4 had no effect on blood glucose or HbA(1c) levels. Hypoalgesia and delayed MNCV and SNCV in diabetic mice were improved by exendin-4 without affecting the reduced SNBF. The decreased IENFDs in sole skins of diabetic mice were ameliorated by exendin-4.
  
  
  CONCLUSIONS
  Our findings indicate that exendin-4 ameliorates the severity of DPN, which may be achieved by its direct actions on DRG neurons and their axons.
authors.affiliation: Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Tatsuhito
authors.initials: T
authors.lastname: Himeno
authors.forename: Hideki
authors.initials: H
authors.lastname: Kamiya
authors.forename: Keiko
authors.initials: K
authors.lastname: Naruse
authors.forename: Norio
authors.initials: N
authors.lastname: Harada
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Ozaki
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Seino
authors.forename: Taiga
authors.initials: T
authors.lastname: Shibata
authors.forename: Masaki
authors.initials: M
authors.lastname: Kondo
authors.forename: Jiro
authors.initials: J
authors.lastname: Kato
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Okawa
authors.forename: Ayako
authors.initials: A
authors.lastname: Fukami
authors.forename: Yoji
authors.initials: Y
authors.lastname: Hamada
authors.forename: Nobuya
authors.initials: N
authors.lastname: Inagaki
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Seino
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Drucker
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Oiso
authors.forename: Jiro
authors.initials: J
authors.lastname: Nakamura
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D003929:Diabetic Neuropathies / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D000077270:Exenatide; D005727:Ganglia, Spinal / Q000378:metabolism; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D009431:Neural Conduction / Q000187:drug effects / Q000502:physiology; D010455:Peptides / Q000494:pharmacology / Q000627:therapeutic use*; D018027:Receptors, Glucagon / Q000819:agonists*; D012583:Schwann Cells / Q000187:drug effects / Q000378:metabolism; D012584:Sciatic Nerve / Q000098:blood supply / Q000187:drug effects / Q000503:physiopathology; D014688:Venoms / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D010455:Peptides; D018027:Receptors, Glucagon; D014688:Venoms; D000077270:Exenatide