Identification of serum metabolome signatures associated with retinal and renal complications of type 2 diabetes

Yoshihiko Tomofuji; Ken Suzuki; Toshihiro Kishikawa; Nobuhiro Shojima; Jun Hosoe; Kyoko Inagaki; Sunao Matsubayashi; Hisamitsu Ishihara; Hirotaka Watada; Yasushi Ishigaki; BioBank Japan Project; Hidenori Inohara; Yoshinori Murakami; Koichi Matsuda; Yukinori Okada; Toshimasa Yamauchi; Takashi Kadowaki

doi:10.1038/s43856-022-00231-3

Identification of serum metabolome signatures associated with retinal and renal complications of type 2 diabetes

Commun Med (Lond). 2023 Jan 9;3(1):5. doi: 10.1038/s43856-022-00231-3.

Authors

Yoshihiko Tomofuji^#^{1

2}, Ken Suzuki^#^{1

3

4}, Toshihiro Kishikawa^{1

5

6}, Nobuhiro Shojima³, Jun Hosoe³, Kyoko Inagaki⁷, Sunao Matsubayashi⁸, Hisamitsu Ishihara⁹, Hirotaka Watada¹⁰, Yasushi Ishigaki¹¹; BioBank Japan Project; Hidenori Inohara⁵, Yoshinori Murakami¹², Koichi Matsuda¹³, Yukinori Okada^{14

15

16

17

18}, Toshimasa Yamauchi^{19

20}, Takashi Kadowaki^{21

22

23}

Collaborators

Affiliations

¹ Department of Statistical Genetics, Osaka University Graduate School of Medicine, Osaka, Japan.
² Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Osaka, Japan.
³ Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
⁴ Centre for Genetics and Genomics Versus Arthritis, Centre for Musculoskeletal Research, Division of Musculoskeletal and Dermatological Sciences, University of Manchester, Manchester, England, UK.
⁵ Department of Otorhinolaryngology-Head and Neck Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
⁶ Department of Head and Neck Surgery, Aichi Cancer Center Hospital, Aichi, Japan.
⁷ Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Nippon Medical School, Tokyo, Japan.
⁸ Fukuoka Tokushukai Hospital, Fukuoka, Japan.
⁹ Division of Diabetes and Metabolism, Nihon University School of Medicine, Tokyo, Japan.
¹⁰ Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan.
¹¹ Division of Diabetes, Metabolism and Endocrinology, Iwate Medical University, Iwate, Japan.
¹² Division of Molecular Pathology, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
¹³ Department of Computational Biology and Medical Sciences, Graduate school of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
¹⁴ Department of Statistical Genetics, Osaka University Graduate School of Medicine, Osaka, Japan. yokada@sg.med.osaka-u.ac.jp.
¹⁵ Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Osaka, Japan. yokada@sg.med.osaka-u.ac.jp.
¹⁶ Laboratory of Statistical Immunology, Immunology Frontier Research Center (WPI-IFReC), Osaka University, Osaka, Japan. yokada@sg.med.osaka-u.ac.jp.
¹⁷ Laboratory for Systems Genetics, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan. yokada@sg.med.osaka-u.ac.jp.
¹⁸ Department of Genome Informatics, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan. yokada@sg.med.osaka-u.ac.jp.
¹⁹ Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. tyamau@m.u-tokyo.ac.jp.
²⁰ AMED-CREST, Japan Agency for Medical Research and Development, Tokyo, Japan. tyamau@m.u-tokyo.ac.jp.
²¹ Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. t-kadowaki@toranomon.kkr.or.jp.
²² Toranomon Hospital, Tokyo, Japan. t-kadowaki@toranomon.kkr.or.jp.
²³ Department of Prevention of Diabetes and Life-style Related Diseases, The University of Tokyo, Tokyo, Japan. t-kadowaki@toranomon.kkr.or.jp.

^# Contributed equally.

Abstract

Background: Type 2 diabetes is a common disease around the world and its major complications are diabetic retinopathy (DR) and diabetic kidney disease (DKD). Persons with type 2 diabetes with complications, especially who have both DR and DKD, have poorer prognoses than those without complications. Therefore, prevention and early identification of the complications of type 2 diabetes are necessary to improve the prognosis of persons with type 2 diabetes. The aim of this study is to identify factors associated with the development of multiple complications of type 2 diabetes.

Methods: We profiled serum metabolites of persons with type 2 diabetes with both DR and DKD (N = 141) and without complications (N = 159) using a comprehensive non-targeted metabolomics approach with mass spectrometry. Based on the serum metabolite profiles, case-control comparisons and metabolite set enrichment analysis (MSEA) were performed.

Results: Here we show that five metabolites (cyclohexylamine, P = 4.5 × 10^-6; 1,2-distearoyl-glycero-3-phosphocholine, P = 7.3 × 10^-6; piperidine, P = 4.8 × 10^-4; N-acetylneuraminic acid, P = 5.1 × 10^-4; stearoyl ethanolamide, P = 6.8 × 10^-4) are significantly increased in those with the complications. MSEA identifies fatty acid biosynthesis as the type 2 diabetes complications-associated biological pathway (P = 0.0020).

Conclusions: Our metabolome analysis identifies the serum metabolite features of the persons with type 2 diabetes with multiple complications, which could potentially be used as biomarkers.

Plain language summary

In the management of type 2 diabetes, prevention and early identification of diabetes complications are important. In particular, people with type 2 diabetes with diabetic retinopathy (DR), affecting the eye, and diabetic kidney disease (DKD), have poorer outcomes than those without complications and need early intervention. Here, we comprehensively profiled blood metabolites, or breakdown products of the biological processes occurring in the body, of people with type 2 diabetes with both DR and DKD and those without complications. We found that five metabolites were significantly increased in those with complications, and we identified a specific metabolic pathway associated with having complications. Our analysis identified the blood metabolite features of people with type 2 diabetes with multiple complications, which could potentially be used as markers in the future.