Table 5. Serum and urine metabolites that significantly changed among DN-III, DN-IV and DN-V groups.
| Sample | Class | Name | DN-III | DN-IV | DN-V | III vs. IV P value | III vs. V P value | IV vs. V P value | VIP | Pathway |
|---|---|---|---|---|---|---|---|---|---|---|
| Serum | Alcohols | Glycerol | 554,871 (405,622–718,374) | 530,712 (378,659–783,090) | 1,356,328 (692,536–1,598,110.75)*# | 0.8835416 | 0.0197352 | 0.048111 | 1.22482 | Galactose metabolism, glycerolipid metabolism |
| Amino acid | N-Acetyl-L-aspartic acid | 7,770 (5,369–12,691) | 23,028 (16,692–60,100)*** | 357,297 (179,723.5–535,292)***### | 0.0006474 | 4.71E-05 | 0.0003343 | 1.52243 | Aspartate metabolism | |
| Alpha-ketoisovaleric acid | 6,586 (4,220–8,518) | 3,687 (2,928–5,151)** | 1,770 (1,290–2,491.75)***## | 0.0061593 | 0.0003789 | 0.0061593 | 1.48702 | Valine, Leucine and Isoleucine Degradation | ||
| L-Glutamic acid | 398,915 (323,825–470,549) | 256,626 (199,139–396,871)* | 139,187 (90,730.25–23,7134.5)**## | 0.0225532 | 0.0024392 | 0.0072421 | 1.62093 | Alanine metabolism, amino sugar metabolism, ammonia recycling, arginine and proline metabolism, cysteine metabolism, folate metabolism, glucose-alanine cycle, glutamate metabolism, glutathione metabolism, glycine and serine metabolism, histidine metabolism, malate-aspartate shuttle, transcription/translation, urea cycle | ||
| 1-Methylhistidine | 6,977 (5,963–7,954) | 9,821 (8,354–21,290)* | 43,756.5 (38,094.25–57,711)***### | 0.0251514 | 3.77E-05 | 0.0003343 | 1.98778 | Histidine metabolism | ||
| L-Proline | 593,489 (374,549–952,896) | 831,689 (525,705–1,032,912) | 1,219,261 (1,048,785.5–1,424,675.75)**## | 0.2673994 | 0.0038324 | 0.0038324 | 1.54998 | Arginine and proline metabolism, transcription/translation | ||
| Creatinine | 242,432 (224,664–286,246) | 312,233 (190,620–447,288) | 158,3951.5 (1,255,862.5–2,448,715.75)***### | 0.3909141 | 4.71E-05 | 9.14E-05 | 1.95035 | Arginine and proline metabolism; Metabolic pathways | ||
| Alpha-ketoisovaleric acid/L-Valine | 0.0096 (0.0063–0.0113) | 0.0061 (0.0037–0.0067) | 0.0034 (0.0027–0.005)** | 0.1165453 | 0.0024392 | 0.1017904 | 1.15383 | Valine, leucine and isoleucine degradation; pantothenate and CoA biosynthesis | ||
| Carbohydrate metabolism | L-Arabinose/L-Arabitol | 0.4219 (0.2254–0.5234) | 0.295 (0.1474–0.4964) | 0.1359 (0.0498–0.1827)**## | 0.4387786 | 0.004084 | 0.0081892 | 1.41058 | Pentose and glucuronate interconversions | |
| L-Glutamine/L-Glutamic acid | 5.9833 (4.2901–7.1692) | 8.0008 (7.1466–11.0582)* | 15.5129 (12.5254–27.2526)***## | 0.0201914 | 0.0006781 | 0.0033596 | 1.78315 | Glyoxylate and dicarboxylate metabolism; alanine, aspartate and glutamate metabolism | ||
| L-Arabitol | 62,868 (53,664–78,121) | 99,356 (73,143–184,132)** | 255,076 (232,777.25–322,292.5)***## | 0.0069457 | 9.01E-05 | 0.0014783 | 2.01299 | Pentose and glucuronate interconversions; metabolic pathways | ||
| D-Threitol | 8,982 (5,350–9,827) | 13,297 (10,258–18,161)** | 56,686 (48,846.5–74,620.5)***### | 0.0069457 | 3.02E-05 | 0.0003905 | 1.71417 | NA | ||
| Threonic acid | 30,265 (26,836–44,175) | 45,008 (34,548–78,503)* | 255,433.5 (183,747.75–337,353)***### | 0.0113404 | 3.02E-05 | 0.0002858 | 1.56505 | NA | ||
| D-Maltose | 11,284 (7,260–19,087) | 20,425 (12,039–60,104) | 138,927 (71,495.5–205,625.5)***### | 0.0983015 | 9.01E-05 | 0.0002858 | 1.86072 | Starch and sucrose metabolism | ||
| Erythritol | 52,721 (26,677–63,597) | 57,960 (45,451–93,530) | 178,694 (159,213.75–316,899.5)***## | 0.1873931 | 3.77E-05 | 0.0012827 | 1.56967 | NA | ||
| Galactonic acid | 18,020 (13,996–22,177) | 25,906 (10,121–66,028) | 164,484 (138,925.5–195,967.5)***### | 0.2169695 | 9.01E-05 | 9.14E-05 | 2.10123 | Galactose metabolism; metabolic pathways; microbial metabolism in diverse environments | ||
| Isomaltose | 3,297 (1,953–7,873) | 6,234 (2,356–15,530) | 48,503.5 (17,205.25–61,323)***### | 0.3253535 | 0.0002542 | 0.0005304 | 1.86904 | NA | ||
| D-Glucuronic acid | 25,651 (14,313–74,686) | 58,577 (15,389–98,087) | 256,148 (163,050.5–440,611)***### | 0.4144377 | 0.0001769 | 0.0001769 | 1.77011 | Inositol metabolism, starch and sucrose metabolism | ||
| Ribonolactone | 23,058 (20,454–32,604) | 19,330 (9,341–35,691) | 92,405.5 (60,316.5–141,768.5)**## | 0.6303067 | 0.0085125 | 0.0085125 | 1.51333 | NA | ||
| Mannitol | 117,196 (75,382–313,193) | 203,909 (45,601–1,326,186) | 14,67,111.5 (989,205.5–2,226,217.75)***## | 0.753606 | 0.0009885 | 0.0038324 | 1.60645 | Fructose and mannose metabolism; ABC transporters; phosphotransferase system (PTS) | ||
| Hormone | Normetanephrine | 4,808 (3,706–6,685) | 4,142 (3,088–6,334) | 2,886 (2,356.25–3,741.5)* | 0.5165309 | 0.0348718 | 0.0530947 | 1.06807 | Tyrosine metabolism | |
| Lipid metabolism | Glycerol 3-phosphate/Glycerol | 0.1187 (0.0618–0.1576) | 0.0769 (0.0461–0.1311) | 0.0166 (0.0155–0.0419)***## | 0.2017864 | 0.0006781 | 0.0072421 | 1.42454 | Glycerolipid metabolism | |
| Metabolism of other amino acids | Beta-Alanine/L-Aspartic acid | 0.0685 (0.0478–0.0878) | 0.0826 (0.0493–0.104) | 0.1561 (0.1266–0.1976)**### | 0.7220354 | 0.0017235 | 0.0009109 | 1.49771 | Pantothenate and CoA biosynthesis; beta-alanine metabolism | |
| L-Glutamic acid/Pyroglutamic acid | 0.1722 (0.1365–0.2208) | 0.1541 (0.1187–0.1799) | 0.085 (0.0541–0.1064)***## | 0.2017864 | 0.0004611 | 0.0019551 | 1.53127 | Glutathione metabolism | ||
| Nucleotide | Cytidine | 497 (310–616) | 596 (380–956) | 3,504.5 (1,921.5–4,671.25)***### | 0.3463645 | 0.0006781 | 0.0009613 | 1.86751 | Pyrimidine metabolism | |
| Organic Acids | Vanillylmandelic acid | 315 (223–394) | 545 (332–991)* | 3,943.5 (2,513.5–6,400)***## | 0.0345568 | 0.000152 | 0.0011112 | 1.7413 | Tyrosine metabolism | |
| Taurine | 189,162 (163,813–268,372) | 177,816 (83,163–225,459) | 95,250.5 (59,044.5–196,355)* | 0.2497638 | 0.0303438 | 0.1210744 | 1.1412 | Bile acid biosynthesis, taurine and hypotaurine metabolism | ||
| Phenols | m-Cresol | 107,93 (5,845–32,654) | 14,797 (6,190–35,789) | 117,373 (63,152.5–169,724.25)**## | 0.600872 | 0.0028477 | 0.0028477 | 1.51486 | Toluene degradation; microbial metabolism in diverse environments; degradation of aromatic compounds | |
| Urine | Organic acids | 4-Hydroxybenzoic acid | 21,514 (13,167–26,186) | 56,709 (21,956–75,355) | 116,479.5 (50,411–577,073.5)*# | 0.051642 | 0.0125878 | 0.0287743 | 2.30879 | Ubiquinone biosynthesis |
| Carbohydrates | L-Arabinose | 353,611 (253,073–675,129) | 490,355 (408,902–728,241) | 417,832.5 (340,508.5–460,281)# | 0.206023 | 0.6623032 | 0.0415604 | 1.48153 | Pentose and glucuronate interconversions; ascorbate and aldarate metabolism; amino sugar and nucleotide sugar metabolism; metabolic pathways; ABC transporters | |
| Galactonic acid | 89,112 (50,457–104,671) | 58,110 (48,030–94,308) | 36,133 (23,138.75–43,421.75)**# | 0.3463645 | 0.0067036 | 0.0148147 | 1.89233 | Galactose metabolism; metabolic pathways; microbial metabolism in diverse environments | ||
| Amino acid metabolism | L-Asparagine/L-Aspartic acid | 20.8357 (11.5539–28.9061) | 9.155 (6.7247–18.4256) | 6.4576 (4.2255–9.2497)** | 0.0574455 | 0.0024392 | 0.0878498 | 1.65339 | Alanine, aspartate and glutamate metabolism | |
| Nucleotide metabolism | Inosine/Adenosine | 0.1917 (0.1556–0.3425) | 0.3472 (0.2507–0.5857) | 0.5713 (0.3275–1.2048)* | 0.107116 | 0.0107885 | 0.107116 | 1.9016 | Purine metabolism |
Differential metabolites were selected according to VIP >1 and P<0.05. Values are expressed as medians (IQRs). ANOVA test was conducted in the comparison among DN stages. T-test was performed in the comparison between two groups. *P<0.05; **P<0.01; ***P<0.001 when compared to DN-III, and #P<0.05; ##P<0.01; ###P<0.001 when compared to DN-IV.