Table 2.
Metabolites that were significantly associated with odds of developing type 2 diabetes in the present study and in studies reported in the literature, metabolite changes at the 10 year follow-up among controls and cases, and effect of medication in the present study
| MetaMetabolite | Association with risk of developing type 2 diabetes at baseline | Changes in metabolites over time | Medication | ||||
|---|---|---|---|---|---|---|---|
| Directiona | Pathophysiologyb | Referencesc | ICC (95% CI)d | Cases vs controlse | Baseline vs follow-upf | ||
| LysoPC(18:2) | – | HOMA-IR | [6, 10, 15] | 0.38 (0.26, 0.50) | Lower | ||
| LysoPC(18:1) | – | HOMA-IR | [10, 15] | 0.51 (0.40, 0.61) | Lower | ||
| LysoPC(p-16:0) | – | HOMA-IR | 0.42 (0.31, 0.48) | Lower | Lower | ||
| LysoPC(17:0) | – | HOMA-IR | [10, 30] | 0.22 (0.11, 0.38) | Lower | Lower | |
| LysoPC(19:1) | – | HOMA-IR, HOMA-%B | 0.5 (0.40, 0.61) | Lower | Lower | ||
| LysoPC(20:1) | – | HOMA-IR | [10] | 0.27 (0.17, 0.41) | Lower | ||
| PC(16:0/16:1) | + | HOMA-IR | [48] | 0.25 (0.14, 0.40) | Higher | Affectedg | |
| PC 583.3792@10.75 | – | HOMA-IR | 0.10 (0.03, 0.31) | Lower | |||
| PC(16:1/14:0)h | + | 0.25 (0.14, 0.40) | Higher | ||||
| PC(15:1/18:2)h | – | HOMA-IR, HOMA-%B | [10] | 0.45 (0.34, 0.56) | Lower | Lower | |
| PC(17:0/18:2) | – | HOMA-IR | 0.21 (0.11, 0.38) | Lower | |||
| DAG(16:1/16:1)h | + | HOMA-IR, HOMA-%B | 0.28 (0.16, 0.42) | Higher | Affectedg | ||
| DAG(14:0/16:0)h | + | HOMA-IR, HOMA-%B | 0.31 (0.20, 0.45) | Higher | Affectedg | ||
| DAG 531.4484@13.29h | + | HOMA-IR, HOMA-%B | 0.36 (0.25, 0.49) | Higher | Affectedg | ||
| DAG 571.4437@13.30h | + | HOMA-IR, HOMA-%B | 0.40 (0.29, 0.53) | Higher | Affectedg | ||
| DAG(14:0/18:1)h | + | HOMA-IR, HOMA-%B | 0.37 (0.25, 0.49) | Higher | Affectedg | ||
| DAG(16:0/18:1)h | + | HOMA-IR, HOMA-%B | 0.43 (0.32, 0.55) | Higher | Affectedg | ||
| Fatty acid 364.333@10.46 | + | HOMA-IRi | 0.35 (0.24, 0.48) | Higher | |||
| Fatty acid 259.1608@7.63 | + | HOMA-IR, HOMA-%B | 0.49 (0.38, 0.59) | Higher | |||
| 2-Methylbutyroylcarnitine | + | HOMA-IRi | [9, 39] | 0.54 (0.44, 0.64) | Higher | ||
| 3-Hydroxyisovalerylcarnitine | + | [9, 39] | 0.41 (0.30, 0.53) | Higher | |||
| Phenylalanine | + | HOMA-IRi | [11, 38] | 0.62 (0.53, 0.70) | Higher | Affectedg | |
| Leucine | + | HOMA-IR, HOMA-%B | [10, 15, 38] | 0.65 (0.57, 0.73) | Higher | Higher | |
| Isoleucine | + | HOMA-IR, HOMA-%B | [10, 15, 38] | 0.68 (0.59, 0.75) | Higher | Higher | |
| Valine | + | HOMA-IR, HOMA-%B | [10, 15, 16, 38] | 0.50 (0.37, 0.58) | Higher | Higher | |
| Tryptophan | + | HOMA-IR, HOMA-B%i | [48] | 0.46 (0.35, 0.57) | Higher | Affectedg | |
| l-Tyrosine | + | HOMA-IR | [9, 11, 38] | 0.50 (0.39, 0.60) | Higher | ||
| Alanine | + | [11, 49] | 0.32 (0.21, 0.45) | Higher | |||
| Citrulline | + | HOMA-IRi | [40] | 0.43 (0.32, 0.54) | – | ||
| N-Acetylglycineh | – | HOMA-IR, HOMA-%Bi | [6] | 0.39 (0.28, 0.51) | Lower | Affectedg | |
| 2-Hydroxyethanesulfonate | – | HOMA-IR, HOMA-%Bi | 0.34 (0.23, 0.47) | Lower | Affectedg | ||
| Glutamate | + | HOMA-IR, HOMA-%B | [49] | 0.39 (0.28, 0.52) | Higher | Higher | |
| Glutamate derivate 316.0887@6.19 | + | HOMA-IR, HOMA-%B | 0.41 (0.30, 0.53) | Higher | Higher | ||
| Bile acid386.2455 @8.21 | + | HOMA-IR, HOMA-%B | 0.65 (0.56, 0.72) | Higher | Higher | ||
| 3-Methyl-2-oxovaleric acid | + | HOMA-IRi | [6, 39] | 0.61 (0.48, 0.67) | Higher | Higher | |
| 161.0062@2.7 | – | HOMA-IR, HOMA-%B | 0.45 (0.35, 0.57) | Lower | Affectedg | ||
| 88.0162@1.71 | + | HOMA-IR | 0.23 (0.12, 0.38) | Higher | |||
| 198.0142 @1.71 | + | HOMA-IR | 0.24 (0.13, 0.40) | Higher | |||
| 491.1196@6.19 | – | HOMA-IR | 0.52 (0.42, 0.62) | Lower | |||
| 518.4333@12.07 | + | HOMA-IR, HOMA-%B | 0.40 (0.28, 0.52) | Higher | |||
| 590.4876@14.11 | + | HOMA-IR, HOMA-%B | 0.35 (0.24, 0.48) | Higher | |||
| 428.2242@7.98 | + | HOMA-IR, HOMA-%B | 0.76 (0.70, 0.82) | Higher | Affectedg | ||
| 566.3105@8.28 | + | HOMA-IR, HOMA-%B | 0.54 (0.44, 0.64) | Higher | |||
| 614.3679@8.60 | + | 0.63 (0.54, 0.71) | Higher | ||||
| 665.2645@9.87 | – | 0.50 (0.40, 0.61) | Lower | ||||
| 597.4023@10.93 | – | HOMA-IRi | 0.22 (0.12, 0.38) | Lower | Affectedg | ||
aDirection: + denotes a higher concentration of metabolite present in cases, while − denotes a lower concentration of metabolites compared with cases
bMetabolites at baseline correlated significantly (Bonferroni-adjusted p < 0.05) with HOMA-IR and/or HOMA-%B
cPrevious findings reported in the literature from 2013 to the present. For each metabolite, the list of papers is not exhaustive. Reviews are not considered. For lipids, reference is made only to publications that report fatty acid constituents
dICC represents long-term reproducibility of metabolites among healthy controls (n = 187) over 10 years. ICC ≥0.4 denotes good to excellent reproducibility
eDifference between cases (n = 187) and their matched controls, independent of BMI, age, sex and time to diagnosis stratification. ‘Higher’ means metabolite level is higher in the case than in the matched control, and vice versa
fThe difference between baseline and the 10 year follow-up among cases, independent of BMI, age, sex and time to diagnosis stratification. ‘Higher’ means metabolite level is higher at follow-up than at baseline, and vice versa
gGroup-specific difference in metabolites between baseline and 10 year follow-up in 187 cases. Four groups were created according to medication: no medication (n = 19), only glucose-lowering medication (n = 13), other medication (n = 48), and glucose-lowering and other medication (n = 107). ‘Affected’ means that medication affected changes in metabolite levels between baseline and 10 year follow-up among cases
hGroup-specific differences in metabolites between baseline and 10 year follow-up in 187 cases. Three groups were created depending on when type 2 diabetes diagnosis occurred in relation to the 10 year follow-up (group A: repeated sampling before diagnosis; group B: repeated sampling close to diagnosis; group C: repeated sampling after diagnosis)
iPartial Spearman correlations of metabolites with HOMA-%B and/or HOMA-IR were affected by time to diagnosis, and significant correlations were only found a median time of 6 years before type 2 diabetes onset