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Journal of Neurology

, Volume 264, Issue 5, pp 839–847 | Cite as

Correlation of insulin resistance and motor function in spinal and bulbar muscular atrophy

  • Hideaki Nakatsuji
  • Amane Araki
  • Atsushi Hashizume
  • Yasuhiro Hijikata
  • Shinichiro Yamada
  • Tomonori Inagaki
  • Keisuke Suzuki
  • Haruhiko Banno
  • Noriaki Suga
  • Yohei Okada
  • Manabu Ohyama
  • Tohru Nakagawa
  • Ken Kishida
  • Tohru Funahashi
  • Iichiro Shimomura
  • Hideyuki Okano
  • Masahisa KatsunoEmail author
  • Gen SobueEmail author
Original Communication

Abstract

This study aimed to evaluate various metabolic parameters in patients with spinal and bulbar muscular atrophy (SBMA), to investigate the association between those indices and disease severity, and to explore the underlying molecular pathogenesis. We compared the degree of obesity, metabolic parameters, and blood pressure in 55 genetically confirmed SBMA patients against those in 483 age- and sex-matched healthy control. In SBMA patients, we investigated the correlation between these factors and motor functional indices. SBMA patients had lower body mass index, blood glucose, and Hemoglobin A1c, but higher blood pressure, homeostasis model assessment of insulin resistance (HOMA-IR, a marker of insulin resistance), total cholesterol, and adiponectin levels than the control subjects. There were no differences in visceral fat areas, high-density lipoprotein-cholesterol (HDL-C), or triglyceride levels in two groups. Revised amyotrophic lateral sclerosis functional rating scale (ALSFRS-R) correlated positively with HDL-C, but negatively with HOMA-IR. Through stepwise multiple regression analysis, we identified HOMA-IR as a significant metabolic determinant of ALSFRS-R. In biochemical analysis, we found that decreased expressions of insulin receptors, insulin receptor substrate-1 and insulin receptor-β, in autopsied muscles and fibroblasts of SBMA patients. This study demonstrates that SBMA patients have insulin resistance, which is associated with the disease severity. The expressions of insulin receptors are attenuated in the skeletal muscle of SBMA, providing a possible pathomechanism of metabolic alterations. These findings suggested that insulin resistance is a metabolic index reflecting disease severity and pathogenesis as well as a potential therapeutic target for SBMA.

Keywords

Spinal and bulbar muscular atrophy SBMA Insulin resistance Insulin receptor 

Notes

Compliance with ethical standards

Funding

This work was supported by the Grant-in-Aids (KAKENHI) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (Nos. 26293206, 26670440, 2667043, 15K15337, and 16K15480) and a Grant from the Japan Agency for Medical Research and Development (AMED) (No. 15ek0109025).

Conflicts of interest

Drs. Nakatsuji, Araki, Hashizume, Hijikata, Yamada, Inagaki, Suzuki, Banno, Suga, Ohyama, Nakagawa, and Shimomura report no disclosures.

Dr. Okada is supported by KAKENHI Grants from MEXT/JSPS, Japan (Nos. 25640038, 25110730, 15H04278, and 15H01568), a Grant from the Japan Agency for Medical Research and Development (AMED) (No. 15ek0109025, 15ek0109048, and 15ek0109165), and Grants from the Ministry of Welfare, Health, and Labor of Japan.

Dr. Kishida is supported in part by a Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area) “Molecular Basis and Disorders of Control of Appetite and Fat Accumulation” (No. 22126008).

Dr. Funahashi is supported in part by a Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area) “Molecular Basis and Disorders of Control of Appetite and Fat Accumulation” (No. 22126008). He is a member of the “Department of Metabolism and Atherosclerosis”, a sponsored course endowed by Kowa Co. Ltd. The company has a scientific officer who oversees the program.

Dr. Okano is a founder scientist of SanBio Co. Ltd and K Pharma Co. Ltd. He is supported by the Program for Intractable Disease Research Utilizing Disease-specific iPS Cells funded by the Japan Science and Technology Agency (JST)/Japan Agency for Medical Research and Development (AMED).

Dr. Katsuno is supported by KAKENHI Grants from MEXT/JSPS, Japan (Nos. 26293206, 26670440, 2667043, 15K15337, and 16K15480) and a Grant from the Japan Agency for Medical Research and Development (AMED) (No. 15ek0109025 and 15ek0109165).

Dr. Sobue serves as a scientific advisory board member for the Kanae Science Foundation for the Promotion of Medical Science, Naito Science Foundation; an advisory board member of Brain; and an editorial board member of Degenerative Neurological and Neuromuscular Disease, the Journal of Neurology, and Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration. He is supported by KAKENHI Grants from MEXT/JSPS, Japan (Nos. 26117001); Grants from the Japan Science and Technology Agency; Grants from the Japan Agency for Medical Research and Development (AMED) (Nos. 15ek0109025, 15ek0109048, and 15ek0109165); and Grants from the Ministry of Welfare, Health, and Labor of Japan.

Ethical standards

This study was performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.

Supplementary material

415_2017_8405_MOESM1_ESM.docx (19 kb)
Supplementary material 1 (DOCX 18 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Hideaki Nakatsuji
    • 1
  • Amane Araki
    • 1
    • 2
  • Atsushi Hashizume
    • 1
  • Yasuhiro Hijikata
    • 1
  • Shinichiro Yamada
    • 1
  • Tomonori Inagaki
    • 1
  • Keisuke Suzuki
    • 1
    • 3
  • Haruhiko Banno
    • 1
  • Noriaki Suga
    • 1
    • 4
  • Yohei Okada
    • 5
    • 6
  • Manabu Ohyama
    • 7
  • Tohru Nakagawa
    • 8
  • Ken Kishida
    • 9
    • 10
  • Tohru Funahashi
    • 9
    • 11
  • Iichiro Shimomura
    • 9
  • Hideyuki Okano
    • 6
  • Masahisa Katsuno
    • 1
    Email author
  • Gen Sobue
    • 1
    • 12
    Email author
  1. 1.Department of NeurologyNagoya University Graduate School of MedicineNagoyaJapan
  2. 2.Department of NeurologyKasugai Municipal HospitalKasugaiJapan
  3. 3.Department of Clinical Research, Innovation Center for Clinical ResearchNational Center for Geriatrics and GerontologyObuJapan
  4. 4.Department of NeurologySarashina Rehabilitation ClinicIchiharaJapan
  5. 5.Department of NeurologyAichi Medical University School of MedicineAichiJapan
  6. 6.Department of PhysiologyKeio University School of MedicineTokyoJapan
  7. 7.Department of DermatologyKeio University School of MedicineTokyoJapan
  8. 8.Hitachi, Ltd. Hitachi Health Care CenterHitachiJapan
  9. 9.Department of Metabolic Medicine, Graduate School of MedicineOsaka UniversityOsakaJapan
  10. 10.Kishida ClinicOsakaJapan
  11. 11.Department of Metabolism and Atherosclerosis, Graduate School of MedicineOsaka UniversityOsakaJapan
  12. 12.Research Division of Dementia and Neurodegenerative DiseaseNagoya University Graduate School of MedicineNagoyaJapan

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