Some plasma metabolites in the urea cycle were reportedly associated with DKD, although results were inconsistent among studies. Also, few studies examined the association between urea cycle metabolites and DKD in community dwellers. To address this, we used the metabolite database from the Tsuruoka Metabolomics Cohort Study, which had global metabolomics in Japan, using capillary electrophoresis-mass spectrometry. Among 10,933 participants, cross-sectionally analyzed were 1,005 who had diabetes mellitus (DM) defined by HbA1c ≥6.5%, and/or fasting blood glucose ≥126 mg/dl and/or antidiabetic drug use. Of these 231 had DKD, which was defined by eGFR <60 ml/min and/or test-strip positive proteinuria. Individuals with DKD (163 men, 68 women, mean age 66 y, mean HbA1c 6.8±1.2%, mean BMI 25.4±4.0) were significantly older than those without (508 men, 266 women, mean age 64 y, mean HbA1c 6.8±0.9%, mean BMI 25.0±3.7). Univariate and multivariate logistic regression models were used to identify the association between plasma metabolites (aspartic acid [Asp], citrulline, symmetric dimethylarginine [SDMA] and ornithine) and DKD in DM patients. We found that urea cycle metabolites were associated with DKD even after adjustment for possible confounders: age, sex, BMI, alcohol intake, smoking habit, energy intake and history of hypertension or dyslipidemia. Odds ratios (ORs) per 1 SD increase in Asp, citrulline, SDMA and ornithine for DKD were 1.24 (95% confidence interval [CI], 1.01-1.53), 1.80 (1.53-2.13), 1.52 (1.30-1.79) and 1.09 (0.95-1.25) as continuous variables, respectively. For sensitivity analyses, participants were divided into quartile groups for each metabolite. Multivariate logistic regression analyses between each metabolite quartile group and DKD showed similar results as above. These results may enable early detection of DKD or clarify the pathophysiology of DKD although a prospective study remains necessary.


M. Yamamoto: None. S. Harada: None. T. Okamura: None. K. Fujihara: None. Y. Yaguchi: None. T. Komatsu: None. T. Sato: None. M. Kitazawa: None. M.H. Yamada: None. M. Kaneko: None. T. Osawa: None. Y. Matsubayashi: None. T. Yamada: None. S. Kodama: None. H. Sone: Research Support; Self; Kyowa Hakko Kirin Co., Ltd., Novartis AG, Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co. T. Takebayashi: None.

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