Metabolite Profiling of LADA Challenges the View of a Metabolically Distinct Subtype
Article Figures & Tables
Figures
- Figure 1
Analysis of low–molecular weight metabolites suggests a metabolic continuum extending from T1D via LADA to T2D. OPLS-DA accurately classifies T2D and T1D (A) and LADA and T1D (B) based on the low–molecular weight metabolome. C: Loadings, scaled as correlations, from the OPLS-DA models combined in a SUS-plot reveals differences between LADA and T1D and differences between T2D and T1D to be shared. Hence, none of the low–molecular weight metabolites uniquely distinguish between the diabetes types. p(corr)[1], loadings for the predictive component scaled as correlations; t[1], predictive component; to[1], the first orthogonal component. T1D, n = 50; T2D, n = 50; and LADA, n = 49.
- Figure 2
Analysis of lipophilic and high–molecular weight metabolites suggests a metabolic continuum extending from T1D via LADA to T2D: a similar analysis, as depicted for the low–molecular weight metabolome in Fig. 1, was conducted for the lipophilic and high–molecular weight metabolome. This analysis revealed a perfect classification of T2D and T1D (A) and LADA and T1D (B). C: The SUS-plot derived from these models revealed that LADA and T2D share differences with T1D, with no unique metabolites associated with either LADA or T2D. Abbreviations are as explained in Fig. 1. T1D, n = 48; T2D, n = 50; and LADA, n = 49.
- Figure 3
LADA is a metabolic intermediate of T1D and T2D: A: The score scatter plot from a PCA calculated on the 123 identified metabolites reveals LADA to cluster in between T1D and T2D, with a significant overlap with the T1D and T2D clusters. B: Score scatter plot from a PCA calculated on C-peptide, HbA1c, and GADAb levels. L, average LADA score; t[1] and t[2], first and second principal component, respectively. 1, average T1D score; 2, average T2D score. Average scores ± SEM are shown to the right of the score plots. Differences were examined by ANOVA followed by post hoc Tukey test. **P < 0.01, ***P < 0.001. T1D, n = 48; T2D, n = 50; and LADA, n = 49.
Tables
- Table 1
Subject characteristics by diabetes type
T2D T1D LADA T2D vs. T1D T2D vs. LADA T1D vs. LADA Ketoacidosis† 1/31 28/16 5/29 *** NS *** Blood glucose, mmol/L 10.78 ± 0.75 25.19 ± 1.28 14.29 ± 1.36 *** NS *** HbA1c, % (mmol/mol) 7.02 (53) ± 0.32 (3.5) 11.34 (100) ± 0.44 (4.8) 7.98 (64) ± 0.40 (4.4) *** NS *** Sex§ 27/23 40/10 23/26 * NS ** Gestational diabetes mellitus† 2/15 0/8 2/20 NS NS NS Length, cm 169.06 ± 1.61 179.52 ± 1.03 170.17 ± 1.58 *** NS *** Weight, kg 90.17 ± 2.36 67.62 ± 1.69 82.23 ± 2.81 *** * *** Family history† 28/19 27/21 28/17 NS NS NS Debut age, years 63.74 ± 1.89 24.04 ± 0.62 55.94 ± 1.82 *** ** *** BMI, kg/m2 31.52 ± 0.71 20.98 ± 0.50 28.30 ± 0.86 *** ** *** GADAb, log nmol/L 0.076 ± 0.043 2.28 ± 0.090 2.24 ± 0.080 *** *** NS C-peptide, nmol/L 1.33 ± 0.068 0.14 ± 0.009 0.78 ± 0.063 *** *** *** Data are expressed as n or the mean ± SEM. Differences between groups were assessed by ANOVA followed by post hoc Tukey test. NS, not significant.
*P < 0.05,
**P < 0.01,
***P < 0.001;
†Yes/no;
§Male/female.
- Table 2
Low–molecular weight metabolites differing in levels between LADA, T1D, and T2D
Metabolite q P LADA vs. T1D LADA vs. T2D T1D vs. T2D T1D LADA T2D Alanine 5.86E-18 8.02E-20 **** * **** 1 ± 0.040 1.41 ± 0.042 1.60 ± 0.036 Uric acid 5.03E-15 1.38E-16 **** ** **** 1 ± 0.077 1.66 ± 0.079 2.13 ± 0.082 Tyrosine 8.06E-12 3.31E-13 **** ** **** 1 ± 0.047 1.33 ± 0.047 1.64 ± 0.065 Isocitrate 7.55E-11 4.13E-12 **** * **** 1 ± 0.067 1.30 ± 0.050 1.57 ± 0.052 C16:0 1.10E-10 7.53E-12 **** NS **** 1 ± 0.065 1.45 ± 0.077 1.76 ± 0.087 Myo-inositol 1.48E-10 1.42E-11 **** ** **** 1 ± 0.038 1.26 ± 0.043 1.45 ± 0.045 Phenylalanine 1.48E-10 1.42E-11 **** ** **** 1 ± 0.040 1.35 ± 0.067 1.56 ± 0.058 C18:0 2.51E-10 2.76E-11 **** NS **** 1 ± 0.033 1.18 ± 0.029 1.26 ± 0.030 Lysine 7.09E-10 8.74E-11 **** * **** 1 ± 0.045 1.25 ± 0.036 1.45 ± 0.044 Ornithine2 1.94E-09 2.66E-10 **** NS **** 1 ± 0.068 1.37 ± 0.057 1.55 ± 0.056 Anthranilic acid 2.16E-09 3.26E-10 **** NS **** 1 ± 0.059 1.80 ± 0.133 1.96 ± 0.154 C22:6 1.09E-08 1.79E-09 **** NS **** 1 ± 0.090 1.69 ± 0.147 1.96 ± 0.124 C17/0 1.57E-08 2.80E-09 **** NS **** 1 ± 0.068 1.38 ± 0.071 1.58 ± 0.076 Quinic acid 4.12E-08 7.91E-09 **** NS **** 1 ± 0.201 2.69 ± 0.328 2.62 ± 0.376 Citric acid 1.02E-07 2.10E-08 *** * **** 1 ± 0.042 1.29 ± 0.067 1.47 ± 0.058 2-hydroxyglutarate 1.99E-07 4.35E-08 **** NS **** 1 ± 0.027 1.24 ± 0.049 1.32 ± 0.044 Pyroglutamic acid 2.42E-07 5.64E-08 *** NS **** 1 ± 0.024 1.15 ± 0.025 1.22 ± 0.030 C18:1 3.88E-07 9.56E-08 *** NS **** 1 ± 0.092 1.29 ± 0.066 1.51 ± 0.071 Cholesterol 6.97E-07 1.81E-07 *** NS **** 1 ± 0.039 1.14 ± 0.043 1.36 ± 0.048 Hypoxanthine 1.30E-06 3.56E-07 *** NS **** 1 ± 0.148 1.89 ± 0.249 2.28 ± 0.218 Proline 1.66E-06 4.78E-07 *** NS **** 1 ± 0.059 1.34 ± 0.069 1.44 ± 0.052 C14:0 5.66E-06 1.71E-06 ** NS **** 1 ± 0.151 1.28 ± 0.114 1.53 ± 0.094 Glycerol 2-phosphate 6.68E-06 2.10E-06 * * **** 1 ± 0.049 1.13 ± 0.041 1.34 ± 0.040 Malic acid 7.27E-06 2.39E-06 * * **** 1 ± 0.051 1.28 ± 0.090 1.57 ± 0.088 C20:4 9.67E-06 3.31E-06 * * **** 1 ± 0.053 1.15 ± 0.045 1.39 ± 0.062 Homocysteine 1.05E-05 3.75E-06 ** NS **** 1 ± 0.056 1.23 ± 0.057 1.44 ± 0.072 Cysteine 1.14E-05 4.23E-06 *** NS **** 1 ± 0.095 1.44 ± 0.133 1.56 ± 0.112 Fumaric acid 1.64E-05 6.29E-06 NS * **** 1 ± 0.039 1.15 ± 0.053 1.36 ± 0.059 C18:2 1.68E-05 6.69E-06 ** NS **** 1 ± 0.074 1.21 ± 0.062 1.37 ± 0.058 Aspartic acid 2.18E-05 8.96E-06 * NS **** 1 ± 0.070 1.28 ± 0.075 1.55 ± 0.084 Histidine 3.19E-05 1.37E-05 *** NS **** 1 ± 0.046 1.19 ± 0.033 1.27 ± 0.047 Succinic acid 3.19E-05 1.40E-05 NS * **** 1 ± 0.034 1.11 ± 0.038 1.32 ± 0.057 Erythritol 4.99E-05 2.26E-05 ** NS **** 1 ± 0.039 0.81 ± 0.043 0.73 ± 0.037 Taurine 9.78E-05 4.56E-05 ** NS **** 1 ± 0.049 1.33 ± 0.073 1.35 ± 0.058 Glycerol 1.75E-04 8.38E-05 * NS **** 1 ± 0.083 1.19 ± 0.080 1.43 ± 0.077 Tryptophane 1.97E-04 9.73E-05 ** NS **** 1 ± 0.048 1.18 ± 0.042 1.29 ± 0.048 Arginine product 2.18E-04 1.11E-04 ** NS *** 1 ± 0.045 1.20 ± 0.042 1.24 ± 0.047 Ornithine 1 3.96E-04 2.06E-04 ** NS *** 1 ± 0.045 1.19 ± 0.038 1.21 ± 0.044 Methyl malate 6.65E-04 3.55E-04 NS NS *** 1 ± 0.173 1.27 ± 0.170 1.83 ± 0.255 Glutamic acid 6.86E-04 3.76E-04 NS NS *** 1 ± 0.099 1.29 ± 0.111 1.62 ± 0.135 Threonine 9.42E-04 5.29E-04 * NS *** 1 ± 0.039 1.13 ± 0.035 1.23 ± 0.044 Creatinine 1.38E-03 7.94E-04 ** NS ** 1 ± 0.050 1.20 ± 0.048 1.25 ± 0.057 Beta-alanine 1.65E-03 9.97E-04 NS NS *** 1 ± 0.060 1.16 ± 0.061 1.35 ± 0.073 Valine 1.65E-03 9.90E-04 * NS ** 1 ± 0.058 1.14 ± 0.043 1.18 ± 0.036 Glyceric acid 1.80E-03 1.11E-03 NS NS *** 1 ± 0.054 1.18 ± 0.064 1.28 ± 0.050 Xylose 2.66E-03 1.68E-03 NS NS ** 1 ± 0.072 1.64 ± 0.223 2.17 ± 0.327 Leucine 3.56E-03 2.29E-03 * NS ** 1 ± 0.048 1.11 ± 0.038 1.17 ± 0.036 Asparagine 3.94E-03 2.59E-03 * NS ** 1 ± 0.076 1.25 ± 0.066 1.32 ± 0.079 Isoleucine 6.39E-03 4.29E-03 NS NS * 1 ± 0.064 1.12 ± 0.051 1.13 ± 0.039 Indole 3-acetic acid 9.31E-03 6.38E-03 * NS ** 1 ± 0.083 1.48 ± 0.221 1.53 ± 0.154 Hippuric acid 1 2.14E-02 1.49E-02 * NS * 1 ± 0.137 1.29 ± 0.133 1.34 ± 0.159 Glycine 3.39E-02 2.42E-02 NS NS * 1 ± 0.031 1.09 ± 0.025 1.09 ± 0.026 Hippuric acid 2 3.74E-02 2.71E-02 NS NS * 1 ± 0.153 1.40 ± 0.143 1.51 ± 0.191 Glycerol 3-phosphate 4.20E-02 3.16E-02 NS * NS 1 ± 0.042 0.96 ± 0.037 1.10 ± 0.040 Xylitol 6.03E-02 4.62E-02 NS NS NS 1 ± 0.082 1.08 ± 0.070 1.13 ± 0.064 Data are expressed as the mean fold to T1D ± SEM. Differences were assessed by ANOVA followed by post hoc Tukey test on log2-transformed data. P values were corrected for multiple comparisons using the false discovery rate method. When more than one derivative of the same metabolite are detected, this is indicated by a number after the name. NS, not significant.
*P/q < 0.05;
**P/q < 0.01;
***P/q < 0.001;
****P/q < 0.0001.
- Table 3
Lipophilic and high–molecular weight metabolites differing in levels between LADA, T1D, and T2D
Metabolite q P LADA vs. T1D LADA vs. T2D T1D vs. T2D T1D LADA T2D LPC(20:3) 1.44E-12 2.44E-14 **** NS **** 1 ± 0.093 1.82 ± 0.105 2.13 ± 0.104 LPC(16:1) 3.07E-12 1.04E-13 **** NS **** 1 ± 0.073 1.98 ± 0.170 2.59 ± 0.211 Phe/Phe 7.83E-12 3.98E-13 **** * **** 1 ± 0.072 1.71 ± 0.105 2.22 ± 0.154 LPC(20:5) 1.11E-10 7.52E-12 **** NS **** 1 ± 0.129 2.67 ± 0.346 2.89 ± 0.282 LPC(14:0) 2.63E-10 2.23E-11 **** NS **** 1 ± 0.083 1.96 ± 0.181 2.43 ± 0.231 PC(36:5) 3.07E-10 3.13E-11 **** NS **** 1 ± 0.092 1.83 ± 0.129 2.07 ± 0.113 PC(40:6) 4.18E-08 5.48E-09 **** NS **** 1 ± 0.091 1.77 ± 0.168 1.88 ± 0.123 Uric acid 1.39E-07 2.13E-08 *** NS **** 1 ± 0.103 1.67 ± 0.144 2.20 ± 0.159 LPC(20:2) 1.40E-07 2.38E-08 **** NS **** 1 ± 0.073 1.49 ± 0.085 1.58 ± 0.076 LPC(17:1) 3.47E-07 6.47E-08 **** NS **** 1 ± 0.061 1.67 ± 0.157 1.71 ± 0.126 LPC(20:4) 5.78E-07 1.18E-07 *** NS **** 1 ± 0.065 1.35 ± 0.073 1.49 ± 0.058 C14:1 carnitine 8.25E-07 1.82E-07 **** NS **** 1 ± 0.176 1.97 ± 0.239 2.92 ± 0.421 Tyrosine 9.54E-07 2.26E-07 ** NS **** 1 ± 0.064 1.26 ± 0.054 1.51 ± 0.067 C16 carnitine 1.79E-06 4.55E-07 *** NS **** 1 ± 0.123 1.75 ± 0.181 2.36 ± 0.245 Hypoxanthine 2.26E-06 6.14E-07 *** NS **** 1 ± 0.313 3.26 ± 0.775 4.80 ± 0.924 PC(34:3) 2.44E-06 7.02E-07 **** NS **** 1 ± 0.057 1.37 ± 0.064 1.45 ± 0.065 LPC(16:0) 2.82E-06 8.62E-07 *** NS **** 1 ± 0.033 1.14 ± 0.026 1.20 ± 0.021 C14 carnitine 5.72E-06 1.84E-06 *** NS **** 1 ± 0.149 2.17 ± 0.275 3.19 ± 0.439 C18:1 carnitine 1.58E-05 5.36E-06 ** NS **** 1 ± 0.136 1.62 ± 0.171 2.12 ± 0.218 PC(38:6) 3.30E-05 1.18E-05 *** NS **** 1 ± 0.070 1.35 ± 0.067 1.36 ± 0.050 C8 carnitine 4.97E-05 1.85E-05 *** NS **** 1 ± 0.171 2.05 ± 0.270 2.75 ± 0.432 C12 carnitine 8.76E-05 3.45E-05 *** NS **** 1 ± 0.137 1.90 ± 0.240 2.52 ± 0.336 Prothionamide 8.76E-05 3.56E-05 ** NS **** 1 ± 0.201 3.47 ± 0.549 4.48 ± 0.618 LPC(15:0) 8.93E-05 3.78E-05 ** NS **** 1 ± 0.072 1.40 ± 0.114 1.52 ± 0.097 Cinnamic acid 1.10E-04 4.86E-05 * NS **** 1 ± 0.065 1.25 ± 0.054 1.53 ± 0.077 C18 carnitine 2.05E-04 9.37E-05 ** NS **** 1 ± 0.100 1.37 ± 0.136 1.57 ± 0.126 LPC(18:0) 2.82E-04 1.34E-04 ** NS *** 1 ± 0.040 1.15 ± 0.034 1.20 ± 0.029 C10 carnitine 4.27E-04 2.10E-04 ** NS *** 1 ± 0.218 2.28 ± 0.460 3.06 ± 0.512 Inosine 6.32E-04 3.21E-04 NS NS *** 1 ± 0.321 2.65 ± 0.582 3.77 ± 0.665 PC(36:1) 7.00E-04 3.68E-04 NS NS *** 1 ± 0.069 0.78 ± 0.053 0.64 ± 0.042 C5 carnitine 1.00E-03 5.45E-04 * NS *** 1 ± 0.103 1.55 ± 0.148 1.79 ± 0.215 LPC(18:1) 1.32E-03 7.37E-04 * NS *** 1 ± 0.039 1.12 ± 0.030 1.15 ± 0.023 C18:2 carnitine 1.89E-03 1.09E-03 * NS *** 1 ± 0.132 1.39 ± 0.156 1.87 ± 0.220 C8:1 carnitine 2.19E-03 1.30E-03 ** NS **** 1 ± 0.136 1.62 ± 0.171 2.12 ± 0.218 Leu/Ile 3.62E-03 2.21E-03 NS NS NS 1 ± 0.121 1.22 ± 0.183 1.87 ± 0.248 3-amino 2-naphtoic acid 5.74E-03 3.60E-03 NS NS ** 1 ± 0.047 1.11 ± 0.039 1.23 ± 0.048 PC(32:1) 1.01E-02 6.48E-03 NS NS ** 1 ± 0.097 1.46 ± 0.169 1.80 ± 0.192 Tyr/Val 1.02E-02 6.73E-03 NS NS ** 1 ± 0.083 1.86 ± 0.157 2.10 ± 0.149 LPC(17:0) 1.13E-02 7.68E-03 * NS * 1 ± 0.067 1.24 ± 0.082 1.24 ± 0.062 C10:2 carnitine 1.42E-02 9.88E-03 NS NS ** 1 ± 0.076 1.13 ± 0.071 1.42 ± 0.162 C6 carnitine 2.22E-02 1.58E-02 NS * NS 1 ± 0.040 0.88 ± 0.031 1.04 ± 0.046 Pipecolic acid 3.68E-02 2.68E-02 * NS NS 1 ± 0.059 0.68 ± 0.042 0.60 ± 0.035 Glu/Phe 4.00E-02 2.98E-02 NS NS NS 1 ± 0.096 1.04 ± 0.090 1.25 ± 0.092 4-Acetamidobutanoate 4.03E-02 3.07E-02 NS NS * 1 ± 0.199 1.91 ± 0.484 2.52 ± 0.503 Betaine 4.47E-02 3.56E-02 NS NS *** 1 ± 0.052 1.14 ± 0.046 1.27 ± 0.056 Data are expressed as the mean fold to T1D ± SEM. Differences were assessed by ANOVA followed by post hoc Tukey test on log2-transformed data. P values were corrected for multiple comparison using the false discovery rate method. NS, not significant.
*P/q < 0.05;
**P/q < 0.01;
***P/q < 0.001;
****P/q < 0.0001.
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