Deficiency of glucagon gene-derived peptides induces peripheral polyneuropathy in mice

Biochem Biophys Res Commun. 2020 Oct 29;532(1):47-53. doi: 10.1016/j.bbrc.2020.08.007. Epub 2020 Aug 19.


Although diabetic polyneuropathy (DPN) is the commonest diabetic complication, its pathology remains to be clarified. As previous papers have suggested the neuroprotective effects of glucagon-like peptide-1 in DPN, the current study investigated the physiological indispensability of glucagon gene-derived peptides (GCGDPs) including glucagon-like peptide-1 in the peripheral nervous system (PNS). Neurological functions and neuropathological changes of GCGDP deficient (gcg-/-) mice were examined. The gcg-/- mice showed tactile allodynia and thermal hyperalgesia at 12-18 weeks old, followed by tactile and thermal hypoalgesia at 36 weeks old. Nerve conduction studies revealed a decrease in sensory nerve conduction velocity at 36 weeks old. Pathological findings showed a decrease in intraepidermal nerve fiber densities. Electron microscopy revealed a decrease in circularity and an increase in g-ratio of myelinated fibers and a decrease of unmyelinated fibers in the sural nerves of the gcg-/- mice. Effects of glucagon on neurite outgrowth were examined using an ex vivo culture of dorsal root ganglia. A supraphysiological concentration of glucagon promoted neurite outgrowth. In conclusion, the mice with deficiency of GCGDPs developed peripheral neuropathy with age. Furthermore, glucagon might have neuroprotective effects on the PNS of mice. GCGDPs might be involved in the pathology of DPN.

Keywords: Demyelination; Diabetic polyneuropathy; Glucagon; Glucagon-gene derived peptides.

MeSH terms

  • Animals
  • Diabetic Neuropathies / etiology*
  • Diabetic Neuropathies / genetics
  • Diabetic Neuropathies / pathology
  • Disease Models, Animal
  • Ganglia, Spinal / metabolism
  • Ganglia, Spinal / pathology
  • Glucagon / deficiency
  • Glucagon / genetics
  • Glucagon / metabolism
  • Glucagon-Like Peptide 1 / deficiency
  • Glucagon-Like Peptide 1 / genetics
  • Glucagon-Like Peptide 1 / metabolism
  • Glucagon-Like Peptides / deficiency*
  • Glucagon-Like Peptides / genetics
  • Glucagon-Like Peptides / metabolism
  • Hyperalgesia / etiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nerve Fibers, Myelinated / pathology
  • Neural Conduction
  • Neuronal Outgrowth
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, Glucagon / genetics
  • Receptors, Glucagon / metabolism


  • RNA, Messenger
  • Receptors, Glucagon
  • Glucagon-Like Peptides
  • Glucagon-Like Peptide 1
  • Glucagon