SUPPLEMENTARY DATA Supplementary Table 1. Effects Of

Home , Aldehyde dehydrogenase, Aldehyde oxidase, Aldehyde oxidase 1, Retinal oxidase

SUPPLEMENTARY DATA

Supplementary Table 1. Effects of 43 risk SNPs for type 2 diabetes or hyperglycemia on the levels of eight amino acids in non‐diabetic METSIM participants.

SNP Gene Alleles T2D and/or MAF N HWE Alanine Glutamine Valine Leucine Isoleucine Phenylalanine Tyrosine Histidine maj/min GLU SNP total P-val % B P % B P % B P % B P % B P % B P % B P % B P

rs780094 GCKR G/A GLU, T2D 37.7 5227 1.00 1.9 1.6E-11 -1.2 1.0E-05 0.2 0.719 1.2 0.001 2.3 3.1E-06 0.1 0.763 -1.1 0.001 -0.8 0.003 rs8042680 PRC1 A/G T2D 31.3 5735 0.09 0.3 0.386 0.0 0.888 1.2 0.001 1.2 0.002 1.7 0.001 0.6 0.088 0.4 0.419 0.5 0.097 rs11708067 ADCY5 G/T GLU, T2D 15.8 5086 0.42 -1.2 0.001 -1.0 0.003 0.1 0.881 -0.3 0.607 0.5 0.548 -0.3 0.471 -1.1 0.032 -0.2 0.722 rs7578326 IRS1 G/A T2D 34.7 5819 1.00 0.1 0.936 -0.4 0.202 -0.7 0.047 -0.8 0.019 -1.5 0.003 -0.1 0.701 -0.7 0.037 -0.5 0.039 rs10811661 CDKN2B A/G T2D 14.8 6708 0.98 -0.6 0.082 -1.0 0.004 0.5 0.262 -0.2 0.889 0.4 0.579 0.6 0.079 0.1 0.713 -0.2 0.612 rs10885122 ADRA2A G/C GLU 15.5 5100 0.44 -0.8 0.034 -0.2 0.666 -0.1 0.893 0.1 0.920 0.7 0.396 -0.3 0.400 -0.4 0.530 -1.0 0.013 rs864745 JAZF1 A/G T2D 48.4 6713 0.34 -0.6 0.029 0.3 0.212 -0.3 0.324 -0.6 0.109 -1.1 0.008 -0.3 0.225 0.4 0.302 0.3 0.114 rs7501939 HNF1B A/C T2D 32.9 6426 0.86 0.0 0.856 -0.6 0.021 -0.1 0.873 0.9 0.082 1.2 0.009 0.0 0.998 0.4 0.264 0.4 0.120 rs13292136 CHCHD9 C/T T2D 13.8 5951 0.85 0.2 0.663 -0.1 0.790 0.7 0.132 0.3 0.694 0.8 0.329 0.5 0.171 1.3 0.012 0.4 0.294 rs896854 TP53INP1 A/C T2D 46.0 5796 0.88 0.6 0.013 0.0 0.843 0.0 0.853 0.3 0.327 -0.1 0.848 0.0 0.874 0.1 0.650 -0.5 0.059 rs10923931 NOTCH2 G/T T2D 14.0 6712 0.89 -0.3 0.304 0.3 0.423 -0.2 0.802 0.1 0.974 -0.6 0.174 -0.8 0.014 0.2 0.912 -0.1 0.934 rs1552224 CENTD2 T/C T2D 24.8 5906 0.05 0.7 0.016 -0.1 0.731 0.0 0.813 0.7 0.144 0.8 0.162 0.2 0.529 -0.1 0.800 0.1 0.842 rs7961581 TSPAN8 A/G T2D 19.7 6707 0.40 0.6 0.066 0.2 0.737 0.6 0.103 0.6 0.257 1.4 0.018 0.4 0.274 0.8 0.034 0.4 0.197 rs13266634 SLC30A8 T/A T2D, GLU 39.3 6712 0.94 -0.6 0.020 -0.4 0.061 -0.4 0.107 -0.3 0.486 -0.9 0.035 0.3 0.232 -0.5 0.103 -0.3 0.202 rs560887 G6PC2 C/T GLU 27.8 4983 0.01 -0.3 0.316 -0.2 0.711 0.8 0.032 1.2 0.024 1.3 0.037 0.5 0.081 0.5 0.295 -0.1 0.730 rs10423928 GIPR G/A GLU 21.7 5711 0.80 -0.7 0.026 0.5 0.136 -0.3 0.569 -0.4 0.429 -0.4 0.638 -0.6 0.071 0.3 0.580 0.2 0.412 rs7944584 MADD C/T GLU 18.0 5082 0.33 -0.3 0.410 0.1 0.868 -0.8 0.087 -1.1 0.029 -0.8 0.121 0.0 0.835 -0.3 0.675 0.2 0.690 rs9939609 FTO T/A T2D 40.0 6707 0.98 -0.3 0.429 -0.3 0.155 -0.1 0.819 0.0 0.948 0.4 0.394 0.0 0.950 -0.2 0.670 0.5 0.027 rs174550 FADS1 C/A GLU 42.7 5073 0.85 0.0 0.931 0.3 0.218 0.6 0.068 -0.4 0.434 0.9 0.070 0.5 0.048 0.4 0.176 0.1 0.639 rs2191349 DGBK C/T GLU, T2D 43.1 5019 0.76 -0.5 0.080 -0.2 0.722 -0.7 0.051 -0.2 0.538 -0.3 0.506 -0.1 0.621 -0.5 0.128 -0.1 0.564 rs4457053 ZBED3 G/C T2D 21.2 5901 0.57 0.6 0.055 0.4 0.314 0.0 0.926 -0.6 0.269 0.1 0.559 -0.1 0.868 0.4 0.457 0.1 0.686 rs7034200 GLIS3 C/T GLU 48.8 4929 0.01 0.2 0.370 0.5 0.085 0.6 0.059 0.2 0.637 0.2 0.731 0.2 0.421 0.1 0.866 0.3 0.338 rs2283228 KCNQ1 C/A T2D 6.1 6714 0.57 0.9 0.072 -0.2 0.740 -0.6 0.443 -0.2 0.716 -0.4 0.567 0.3 0.492 -0.2 0.836 -0.2 0.489 rs12779790 CDC123 A/G T2D 21.3 6700 0.44 0.0 0.846 -0.2 0.609 -0.3 0.323 0.1 0.893 -0.5 0.474 0.6 0.073 0.4 0.295 0.1 0.876 rs4402960 IGF2BP2 A/G T2D 31.9 6709 0.42 0.4 0.148 0.3 0.304 0.0 0.740 0.2 0.499 0.7 0.082 0.1 0.734 0.0 0.940 0.2 0.370 rs11605924 CRY2 G/A GLU 47.0 4765 0.43 -0.1 0.764 -0.3 0.353 -0.3 0.348 -0.7 0.097 -0.6 0.177 0.0 0.926 0.5 0.121 -0.5 0.133

rs243021 BCL11A A/C T2D 43.6 5837 0.92 -0.4 0.176 0.2 0.657 -0.3 0.334 0.2 0.703 -0.5 0.265 -0.2 0.352 -0.4 0.289 -0.4 0.089 rs10010131 WFS1 G/A T2D 44.6 6714 0.71 0.1 0.512 0.1 0.697 0.5 0.100 0.0 0.951 0.6 0.108 0.1 0.715 0.3 0.551 0.1 0.942 rs1801282 PPARG A/T T2D 15.3 6716 0.78 -0.1 0.798 -0.2 0.508 -0.6 0.159 -0.2 0.779 -1.0 0.134 0.3 0.439 -0.3 0.490 -0.6 0.132 rs10830963 MTNR1B C/G T2D, GLU 35.8 6701 0.32 0.1 0.601 0.2 0.342 0.4 0.213 0.0 0.894 -0.1 0.682 -0.4 0.108 -0.4 0.195 0.1 0.746 rs4607103 ADAMTS9 C/A T2D 25.8 6716 0.38 -0.1 0.597 -0.4 0.121 0.2 0.635 0.5 0.431 0.6 0.422 0.4 0.267 0.1 0.785 0.4 0.285 rs11071657 FAM148A C/G GLU 30.5 5078 0.18 0.2 0.476 -0.1 0.799 -0.2 0.390 0.7 0.125 0.0 0.912 0.2 0.674 0.2 0.707 0.2 0.603 rs7754840 CDKAL1 C/A T2D 36.9 6716 0.96 0.0 0.876 0.1 0.553 -0.2 0.454 -0.6 0.132 -0.5 0.248 0.1 0.425 0.0 0.889 -0.1 0.966 rs4607517 GCK T/C GLU, T2D 9.8 5114 1.00 0.6 0.197 -0.2 0.550 0.2 0.884 -0.2 0.822 -0.4 0.477 0.1 0.984 0.5 0.416 0.6 0.159 rs340874 PROX1 T/A GLU, T2D 39.7 5049 0.10 0.2 0.346 -0.4 0.185 -0.1 0.731 0.4 0.340 0.6 0.155 0.3 0.244 0.1 0.963 -0.2 0.549 rs7578597 THADA C/T T2D 5.1 6714 0.90 -0.3 0.501 -0.3 0.612 0.5 0.586 -0.3 0.678 1.2 0.202 0.3 0.598 0.1 0.907 -0.2 0.743 rs231362 KCNQ1 C/T T2D 47.9 5143 0.98 -0.4 0.225 0.0 0.895 0.0 0.822 0.1 0.626 0.5 0.282 0.2 0.539 0.0 0.858 0.2 0.856 rs11920090 SLC2A2 A/G GLU 13.1 5108 0.87 0.2 0.810 0.6 0.240 -0.3 0.477 0.5 0.525 -0.4 0.572 0.7 0.060 0.7 0.225 0.4 0.353 rs5219 KCNJ11 C/T T2D 47.4 6692 0.99 -0.2 0.684 0.2 0.594 0.4 0.120 0.2 0.377 -0.1 0.961 -0.2 0.461 0.0 0.792 0.3 0.257 rs1111875 HHEX A/G T2D 46.6 6716 0.59 0.2 0.484 0.0 0.998 0.2 0.462 0.3 0.421 -0.1 0.981 -0.1 0.842 0.3 0.311 0.1 0.497 rs7903146 TCF7L2 G/A T2D, GLU 17.5 6715 0.45 0.1 0.697 -0.3 0.417 -0.2 0.530 0.0 0.933 0.0 0.705 0.3 0.328 -0.1 0.681 -0.2 0.486 rs11634397 ZFAND6 A/G T2D 40.6 5837 0.98 0.1 0.709 -0.3 0.420 0.0 0.982 -0.2 0.638 -0.4 0.438 0.0 0.781 0.1 0.439 0.0 0.901 rs2612067 HMGA2 G/A T2D 6.8 5879 0.55 -0.4 0.519 -0.5 0.487 0.1 0.932 0.6 0.495 -0.3 0.733 -0.2 0.699 0.1 0.859 0.0 0.934 Major/minor alleles are shown. Risk alleles for type 2 diabetes or hyperglycemia are underlined. MAF –minor allele frequency. HWE – P‐ value for testing of Hardy‐Weinberg equilibrium. % effect sizes per minor allele (% of B of an untransformed variable from the mean) and P‐values were obtained from linear regression adjusted for age and BMI. Significant P‐values after Bonferroni correction for multiple testing (P<1.45x10‐4, assuming 344 tests for 43 SNPs and 8 traits) are bold and underlined, nominally significant P‐values (P<0.05) are bold.

Supplementary Table 2. Effect of different adjustments on the relationship between amino acid levels and FPG or 2hPG glucose categories.

FPG categories 2hPG categories P PISI PInsSec P PISI PInsSec Alanine 4.3E‐42 0.008 6.4E‐70 2.3E‐46 0.094 6.8E‐72 Phenylalanine 1.1E‐09 1.5E‐08 6.3E‐20 1.1E‐13 0.020 2.1E‐25 Valine 0.030 1.0E‐08 1.2E‐05 0.093 1.7E‐04 3.8E‐05 Leucine 4.2E‐04 0.010 9.7E‐10 1.0E‐18 0.063 6.5E‐29 Isoleucine 6.7E‐10 1.2E‐15 8.3E‐35 2.7E‐58 0.383 1.0E‐102 Tyrosine 1.8E‐15 0.368 1.8E‐30 1.1E‐10 0.010 4.1E‐23 Glutamine 1.9E‐48 5.4E‐28 3.2E‐51 1.4E‐31 3.5E‐13 5.2E‐34 Histidine 3.3E‐04 4.2E‐05 0.015 9.1E‐06 3.9E‐07 9.9E‐04 P values are adjusted for age and BMI in a general linear model. PISI values are adjusted for age, BMI, and Matsuda ISI. PInsSec values are adjusted for age, BMI, and InsAUC0‐30/GluAUC0‐30.

Supplementary Table 3. Differences in amino acid levels between METSIM participants who maintained normal glucose tolerance (NGT) in follow‐up study and those participants who progressed from NGT at baseline to abnormal glucose tolerance (AGT) during the follow‐up period.

NGT at baseline&follow‐ NGT at baseline, up AGT at follow‐up Amino acid levels at N 375 440 baseline Mean SD Mean SD PT‐test P* Alanine 815 125.09 ± 15.96 127.87 ± 18.10 0.032 0.101 Leucine 815 28.54 ± 6.04 29.57 ± 6.86 0.029 0.087 Isoleucine 814 17.25 ± 4.10 17.95 ± 4.42 0.025 0.182 Phenylalanine 815 23.18 ± 3.33 23.32 ± 3.05 0.447 0.995 Tyrosine 802 17.11 ± 2.94 17.40 ± 3.04 0.200 0.565 Valine 815 65.61 ± 11.49 67.16 ± 11.06 0.034 0.146 Glutamine 716 159.60 ± 20.77 155.55 ± 18.07 0.009 0.019 Histidine 815 19.70 ± 2.65 19.66 ± 2.48 0.901 0.631 Data are shown as unadjusted means, SD. P‐values were calculated using log‐transformed variables due to their skewed distribution. P* values were adjusted for age and BMI in general linear model.

Supplementary Table 4. Pearson correlation between adipose tissue gene expression levels of genes implicated in metabolism of different amino acids and Matsuda index of insulin sensitivity in 200 METSIM participants (only significant genes are listed, highlighted are key enzymes in the respective pathway).

Valine, leucine, and isoleucine degradation Matsuda ISI Valine Leucine Isoleucine

r P PFDR r P PFDR r P PFDR r P PFDR HIBADH 3-hydroxyisobutyrate dehydrogenase 0.524 2.4E-15 7.7E-12 -0.153 3.2E-02 0.142 -0.134 6.0E-02 0.205 -0.354 3.0E-07 3.1E-05 HADH Hydroxyacyl-Coenzyme A dehydrogenase 0.511 1.4E-14 2.9E-11 -0.187 8.4E-03 0.063 -0.179 1.2E-02 0.079 -0.334 1.5E-06 1.1E-04 PCCA Propionyl Coenzyme A carboxylase, alpha polypeptide 0.510 1.7E-14 3.4E-11 -0.271 1.1E-04 0.003 -0.185 9.0E-03 0.066 -0.390 1.3E-08 2.4E-06 ACAT1 Acetyl-Coenzyme A acetyltransferase 1 0.498 8.0E-14 1.2E-10 -0.209 3.1E-03 0.033 -0.129 7.0E-02 0.224 -0.401 4.9E-09 1.1E-06 ACADM Acyl-CoA dehydrogenase, C-4 to C-12 straight chain 0.494 1.5E-13 2.0E-10 -0.267 1.4E-04 0.004 -0.217 2.2E-03 0.026 -0.419 8.0E-10 2.3E-07 MCCC1 Methylcrotonoyl-Coenzyme A carboxylase 1 (alpha) 0.488 3.0E-13 3.5E-10 -0.281 6.1E-05 0.002 -0.212 2.7E-03 0.030 -0.401 4.6E-09 1.0E-06 MUT Methylmalonyl Coenzyme A mutase 0.482 6.4E-13 6.2E-10 -0.265 1.6E-04 0.004 -0.132 6.5E-02 0.214 -0.386 1.9E-08 3.3E-06 BCAT1 Branched chain aminotransferase 1, cytosolic -0.452 2.3E-11 1.3E-08 0.136 5.6E-02 0.197 0.072 3.1E-01 0.463 0.293 2.8E-05 0.001 BCKDHA Branched chain keto acid dehydrogenase E1, alpha polypeptide 0.452 2.3E-11 1.3E-08 -0.146 4.0E-02 0.163 -0.147 3.9E-02 0.160 -0.335 1.4E-06 1.1E-04 ALDH6A1 Aldehyde dehydrogenase 6 family, member A1 0.451 2.6E-11 1.4E-08 -0.269 1.3E-04 0.003 -0.232 1.0E-03 0.015 -0.404 3.6E-09 8.5E-07 AOX1 Aldehyde oxidase 1 -0.450 3.0E-11 1.6E-08 0.288 4.0E-05 0.001 0.081 2.6E-01 0.428 0.330 2.1E-06 1.4E-04 AUH AU RNA binding protein/enoyl-Coenzyme A hydratase 0.432 2.1E-10 7.7E-08 -0.245 5.0E-04 0.009 -0.203 4.1E-03 0.039 -0.370 8.3E-08 1.1E-05 Hydroxyacyl-Coenzyme A dehydrogenase/3-ketoacyl-Coenzyme A HADHA thiolase/enoyl-Coenzyme A hydratase (trifunctional protein), alpha 0.387 1.8E-08 3.2E-06 -0.148 3.8E-02 0.159 -0.064 3.7E-01 0.498 -0.227 1.3E-03 0.018 subunit ACAD8 Acyl-Coenzyme A dehydrogenase family, member 8 0.363 1.5E-07 1.8E-05 -0.245 5.1E-04 0.009 -0.210 3.0E-03 0.032 -0.389 1.5E-08 2.8E-06 Hydroxyacyl-Coenzyme A dehydrogenase/3-ketoacyl-Coenzyme A HADHB thiolase/enoyl-Coenzyme A hydratase (trifunctional protein), beta 0.362 1.5E-07 1.9E-05 -0.242 5.9E-04 0.010 -0.033 6.5E-01 0.617 -0.320 4.4E-06 2.6E-04 subunit PCCB Propionyl Coenzyme A carboxylase, beta polypeptide 0.362 1.6E-07 1.9E-05 -0.127 7.4E-02 0.231 -0.132 6.4E-02 0.213 -0.305 1.2E-05 5.7E-04 BCAT2 Branched chain aminotransferase 2, mitochondrial 0.358 2.2E-07 2.5E-05 -0.194 6.3E-03 0.052 -0.126 7.6E-02 0.234 -0.286 4.3E-05 0.002 BCKDHB Branched chain keto acid dehydrogenase E1, beta polypeptide 0.355 2.9E-07 3.0E-05 -0.222 1.7E-03 0.021 -0.202 4.3E-03 0.041 -0.312 7.7E-06 4.0E-04 ALDH7A1 Aldehyde dehydrogenase 7 family, member A1 0.347 5.3E-07 5.0E-05 -0.142 4.5E-02 0.176 -0.164 2.1E-02 0.110 -0.320 4.3E-06 2.5E-04 HSD17B10 Hydroxysteroid (17-beta) dehydrogenase 10 0.346 6.0E-07 5.5E-05 -0.168 1.8E-02 0.102 -0.125 8.0E-02 0.240 -0.268 1.4E-04 0.004 ALDH2 Aldehyde dehydrogenase 2 family (mitochondrial) 0.276 8.2E-05 0.002 0.026 7.2E-01 0.641 -0.059 4.1E-01 0.518 -0.154 3.1E-02 0.140 OXCT1 3-oxoacid CoA transferase 1 0.245 4.9E-04 0.009 -0.063 3.8E-01 0.503 -0.070 3.3E-01 0.475 -0.191 6.9E-03 0.056 MCEE Methylmalonyl CoA epimerase 0.231 1.0E-03 0.015 -0.005 9.4E-01 0.699 -0.064 3.7E-01 0.499 -0.173 1.5E-02 0.090 IVD Isovaleryl Coenzyme A dehydrogenase 0.225 1.4E-03 0.019 -0.160 2.4E-02 0.121 -0.112 1.2E-01 0.293 -0.176 1.3E-02 0.084 Alanine, aspartate, and glutamate metabolism Matsuda ISI Alanine Glutamine

Gene Description r P PFDR r P PFDR r P PFDR GPT2 Glutamic pyruvate transaminase (alanine aminotransferase) 2 0.455 1.6E-11 9.7E-09 -0.177 1.3E-02 0.082 0.192 8.1E-03 0.062 GPT Glutamic-pyruvate transaminase (alanine aminotransferase) 0.454 1.7E-11 1.1E-08 -0.140 4.9E-02 0.183 0.214 3.2E-03 0.033 GLUL Glutamate-ammonia ligase (glutamine synthetase) 0.440 9.2E-11 4.0E-08 -0.220 1.8E-03 0.023 0.188 9.4E-03 0.068 GFPT1 Glutamine-fructose-6-phosphate transaminase 1 0.358 2.2E-07 2.5E-05 -0.116 1.0E-01 0.275 0.015 8.4E-01 0.674 ADSSL1 Adenylosuccinate synthase like 1 0.328 2.3E-06 1.5E-04 -0.194 6.2E-03 0.052 0.112 1.2E-01 0.302 ALDH4A1 Aldehyde dehydrogenase 4 family, member A1 -0.274 9.6E-05 0.003 0.212 2.7E-03 0.030 -0.053 4.7E-01 0.549 Glutamic-oxaloacetic transaminase 2, mitochondrial (aspartate GOT2 -0.202 4.3E-03 0.041 -0.082 2.5E-01 0.423 -0.064 3.8E-01 0.504 aminotransferase 2) Phenylalanine metabolism Matsuda ISI Phenylalanine

r P PFDR r P PFDR MIF Macrophage migration inhibitory factor (glycosylation-inhibiting factor) -0.470 2.7E-12 2.2E-09 0.230 1.2E-03 0.017 ALDH1A3 Aldehyde dehydrogenase 1 family, member A3 -0.418 8.6E-10 2.5E-07 0.276 8.6E-05 0.003 MAOA Monoamine oxidase A 0.400 5.3E-09 1.2E-06 -0.234 9.3E-04 0.014 ALDH3B1 Aldehyde dehydrogenase 3 family, member B1 -0.324 3.2E-06 2.0E-04 0.286 4.6E-05 0.002 AOC2 Amine oxidase, copper containing 2 (retina-specific) -0.285 4.8E-05 0.002 0.166 2.0E-02 0.108 Glutamic-oxaloacetic transaminase 2, mitochondrial (aspartate GOT2 -0.202 4.3E-03 0.041 0.036 6.2E-01 0.608 aminotransferase 2) Tyrosine metabolism Matsuda ISI Tyrosine

r P PFDR r P PFDR ADH1A Alcohol dehydrogenase 1A (class I), alpha polypeptide 0.507 2.5E-14 4.7E-11 -0.382 3.1E-08 4.9E-06 MIF Macrophage migration inhibitory factor (glycosylation-inhibiting factor) -0.470 2.7E-12 2.2E-09 0.333 1.7E-06 1.2E-04 AOX1 Aldehyde oxidase 1 -0.450 3.0E-11 1.6E-08 0.333 1.7E-06 1.2E-04 ALDH1A3 Aldehyde dehydrogenase 1 family, member A3 -0.418 8.6E-10 2.5E-07 0.240 6.7E-04 0.011 MAOA Monoamine oxidase A 0.400 5.3E-09 1.2E-06 -0.251 3.8E-04 0.007 ALDH3B1 Aldehyde dehydrogenase 3 family, member B1 -0.324 3.2E-06 2.0E-04 0.234 9.1E-04 0.014 COMT Catechol-O-methyltransferase -0.317 5.2E-06 2.9E-04 0.308 1.1E-05 5.1E-04 AOC2 Amine oxidase, copper containing 2 (retina-specific) -0.285 4.8E-05 0.002 0.275 9.4E-05 0.003 TRMT11 TRNA methyltransferase 11 homolog (S. cerevisiae) 0.258 2.4E-04 0.005 -0.161 2.4E-02 0.121 Glutamic-oxaloacetic transaminase 2, mitochondrial (aspartate GOT2 -0.202 4.3E-03 0.041 0.048 5.0E-01 0.563 aminotransferase 2) Histidine metabolism Matsuda ISI Histidine

r P PFDR r P PFDR

ALDH1A3 Aldehyde dehydrogenase 1 family, member A3 -0.418 8.6E-10 2.5E-07 0.099 1.6E-01 0.346 MAOA Monoamine oxidase A 0.400 5.3E-09 1.2E-06 -0.126 7.7E-02 0.235 ALDH7A1 Aldehyde dehydrogenase 7 family, member A1 0.347 5.3E-07 5.0E-05 -0.033 6.4E-01 0.616 ALDH3B1 Aldehyde dehydrogenase 3 family, member B1 -0.324 3.2E-06 2.0E-04 0.065 3.6E-01 0.493 ALDH2 Aldehyde dehydrogenase 2 family (mitochondrial) 0.276 8.2E-05 0.002 -0.024 7.3E-01 0.646 HDC Histidine decarboxylase -0.268 1.4E-04 0.004 0.083 2.4E-01 0.415 TRMT11 TRNA methyltransferase 11 homolog (S. cerevisiae) 0.258 2.4E-04 0.005 0.053 4.6E-01 0.545

Supplementary Figure 1. Required relative effect sizes and minor allele frequencies (MAFs) to achieve ≥80% statistical power for individual amino acids.

Supplementary Figure 2. Amino acid levels in categories of fasting and 2‐hour glucose levels across the entire range of glucose tolerance in lean (BMI<27 kg/m2) and obese (BMI≥27 kg/m2) individuals. Points represent unadjusted means of amino acid levels in each glucose category. P‐values were calculated using general linear model adjusted for age and BMI, and are coded as follows: *P<0.05, **P<10‐10, ***P<10‐20.

Supplementary Figure 3. Correlation of subcutaneous adipose tissue mRNA levels of genes involved in BCAA degradation with Matsuda ISI in 200 METSIM participants. Colours indicate the strength and direction of the correlation: red = positive correlation, blue = negative correlation, white = non‐ significant correlation (after FDR adjustment for multiple testing), grey = gene missing in the microarray. * several genes in the group (ALDH2, ALDH1B1, ALDH9A1, ALDH3A2, and ALDH7A1), box coloured by the strongest correlation. Modified from the KEGG "Valine, leucine and isoleucine degradation" pathway (hsa280).