Beneficial effects of exendin-4 on experimental polyneuropathy in diabetic mice

Tatsuhito Himeno, Hideki Kamiya, Keiko Naruse, Norio Harada, Nobuaki Ozaki, Yusuke Seino, Taiga Shibata, Masaki Kondo, Jiro Kato, Tetsuji Okawa, Ayako Fukami, Yoji Hamada, Nobuya Inagaki, Yutaka Seino, Daniel J. Drucker, Yutaka Oiso, Jiro Nakamura

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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. RESEARCH DESIGN AND 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 animalmodel 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 HbA1c 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.

Original languageEnglish
Pages (from-to)2397-2406
Number of pages10
JournalDiabetes
Volume60
Issue number9
DOIs
Publication statusPublished - 09-2011

All Science Journal Classification (ASJC) codes

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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  • Cite this

    Himeno, T., Kamiya, H., Naruse, K., Harada, N., Ozaki, N., Seino, Y., Shibata, T., Kondo, M., Kato, J., Okawa, T., Fukami, A., Hamada, Y., Inagaki, N., Seino, Y., Drucker, D. J., Oiso, Y., & Nakamura, J. (2011). Beneficial effects of exendin-4 on experimental polyneuropathy in diabetic mice. Diabetes, 60(9), 2397-2406. https://doi.org/10.2337/db10-1462