Introduction
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- Price 3rd., J.W.
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- Rabinovitch P.S.
- Szeto H.H.
- Houmard J.A.
- Cortright R.N.
- Wasserman D.H.
- Neufer P.D.
Results
Metabolic heterogeneity between strains


113 metabolites significantly correlated with metabolic parameters

Metabolites changed with insulin resistance, diet, and between strains

Phenotypes | IR | Diet | Strain | |||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Low IRI | High IRI | p value | Chow | HFD | p value | #50 | #89 | #97 | p value 50 vs. 89 | p value 50 vs. 97 | p value 89 vs. 97 | |
Body weight (g) | 24.7 | 25.0 | 0.8123 | 24.5 | 25.1 | 0.5759 | 25.3 | 27.2 | 22.2 | 0.1061 | 0.0022 | 0.0002 |
Adiposity (%) | 16.1 | 22.7 | 0.0057 | 14.5 | 22.0 | 0.0007 | 17.9 | 17.1 | 20.0 | 0.7985 | 0.4815 | 0.3455 |
GTT AUC | 1058 | 1345 | 0.0041 | 1018 | 1286 | 0.0050 | 1321 | 1104 | 1039 | 0.1212 | 0.0314 | 0.3980 |
GTT iAUC | 360 | 624 | 0.0002 | 354 | 542 | 0.0085 | 541 | 379 | 427 | 0.1251 | 0.2140 | 0.5400 |
Fasting glucose (mm) | 7.6 | 7.2 | 0.3816 | 7.4 | 7.6 | 0.6647 | 7.2 | 8.6 | 6.7 | 0.0080 | 0.2447 | 0.0014 |
Fasting insulin (ng/ml) | 0.52 | 0.91 | 0.0003 | 0.51 | 0.79 | 0.0093 | 0.66 | 0.58 | 0.72 | 0.4673 | 0.6900 | 0.3449 |
IRI (1000×) | 177 | 537 | 0.0000 | 173 | 420 | 0.0013 | 392 | 225 | 277 | 0.1736 | 0.2825 | 0.4572 |
HOMA-IR | 4.3 | 7.5 | 0.0029 | 4.1 | 6.7 | 0.0153 | 5.4 | 5.4 | 5.5 | 0.9811 | 0.9795 | 0.9604 |



Insulin resistance classification analysis and novel signature
- Chaudhuri R.
- Khoo P.S.
- Tonks K.
- Junutula J.R.
- Kolumam G.
- Modrusan Z.
- Samocha-Bonet D.
- Meoli C.C.
- Hocking S.
- Fazakerley D.J.
- Stöckli J.
- Hoehn K.L.
- Greenfield J.R.
- Yang J.Y.H.
- James D.E.
- Raichur S.
- Wang S.T.
- Chan P.W.
- Li Y.
- Ching J.
- Chaurasia B.
- Chaurasia B.
- Dogra S.
- Öhman M.K.
- Takeda K.
- Sugii S.
- Pewzner-Jung Y.
- Futerman A.H.
- Summers S.A.
- Turpin S.M.
- Nicholls H.T.
- Willmes D.M.
- Mourier A.
- Brodesser S.
- Wunderlich C.M.
- Mauer J.
- Xu E.
- Hammerschmidt P.
- Brönneke H.S.
- Trifunovic A.
- LoSasso G.
- Wunderlich F.T.
- Kornfeld J.W.
- Blüher M.
- Krönke M.
- Brüning J.C.

IR | Diet | Strain | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Low IRI | High IRI | q value | Chow | HFD | q value | #50 | #89 | #97 | q value 50 vs. 89 | q value 50 vs. 97 | q value 89 vs. 97 | |
IR classifiers | ||||||||||||
C22:1-CoA | 0.066 | 0.156 | 0.0484 | 0.071 | 0.122 | 0.2529 | 0.106 | 0.081 | 0.103 | 0.7102 | 0.9632 | 0.7709 |
C19:3-CoA | 1.51 | 2.19 | 0.0976 | 1.16 | 2.29 | 0.0001 | 1.99 | 1.73 | 1.52 | 0.7102 | 0.4138 | 0.7559 |
C2-carnitine | 76 | 58 | 0.1232 | 85 | 56 | 0.0024 | 75 | 70 | 64 | 0.8266 | 0.3178 | 0.8785 |
C16-Ceramide | 0.875 | 1.041 | 0.4172 | 0.880 | 0.980 | 0.4450 | 0.872 | 0.891 | 1.03 | 0.8833 | 0.2381 | 0.5277 |
Diet classifiers | ||||||||||||
C19:3-CoA | 1.514 | 2.193 | 0.0976 | 1.163 | 2.294 | 0.0001 | 1.99 | 1.73 | 1.52 | 0.7102 | 0.4138 | 0.7559 |
Free carnitine | 239 | 193 | 0.1673 | 270 | 179 | 0.0008 | 202 | 194 | 271 | 0.8710 | 0.1459 | 0.1697 |
Sum of SC-carnitines | 84 | 65 | 0.1325 | 93 | 63 | 0.0024 | 84 | 76 | 71 | 0.7102 | 0.2727 | 0.9323 |
C2-carnitine | 76 | 58 | 0.1232 | 85 | 56 | 0.0024 | 75 | 70 | 64 | 0.8266 | 0.3178 | 0.8785 |
Strain classifiers | ||||||||||||
Arg | 92 | 125 | 0.6844 | 98 | 108 | 0.9001 | 191 | 58 | 56 | 0.0171 | 0.0061 | 0.9567 |
Arg/(Orn + Cit) ratio | 0.660 | 0.770 | 0.8058 | 0.695 | 0.698 | 0.9812 | 1.206 | 0.465 | 0.395 | 0.0016 | 0.0002 | 0.1939 |
C12-OH/C10-DC-carnitine | 0.055 | 0.081 | 0.4172 | 0.060 | 0.068 | 0.7724 | 0.065 | 0.042 | 0.083 | 0.1848 | 0.4498 | 0.1892 |
Arg/Orn ratio | 2.698 | 3.719 | 0.6217 | 2.791 | 3.292 | 0.7473 | 4.878 | 1.928 | 2.232 | 0.0171 | 0.0183 | 0.6126 |
- Raichur S.
- Wang S.T.
- Chan P.W.
- Li Y.
- Ching J.
- Chaurasia B.
- Chaurasia B.
- Dogra S.
- Öhman M.K.
- Takeda K.
- Sugii S.
- Pewzner-Jung Y.
- Futerman A.H.
- Summers S.A.
- Turpin S.M.
- Nicholls H.T.
- Willmes D.M.
- Mourier A.
- Brodesser S.
- Wunderlich C.M.
- Mauer J.
- Xu E.
- Hammerschmidt P.
- Brönneke H.S.
- Trifunovic A.
- LoSasso G.
- Wunderlich F.T.
- Kornfeld J.W.
- Blüher M.
- Krönke M.
- Brüning J.C.
- Newgard C.B.
- An J.
- Bain J.R.
- Muehlbauer M.J.
- Stevens R.D.
- Lien L.F.
- Haqq A.M.
- Shah S.H.
- Arlotto M.
- Slentz C.A.
- Rochon J.
- Gallup D.
- Ilkayeva O.
- Wenner B.R.
- Yancy Jr., W.S.
- et al.
- Floegel A.
- Stefan N.
- Yu Z.
- Mühlenbruch K.
- Drogan D.
- Joost H.G.
- Fritsche A.
- Häring H.U.
- Hrabě de Angelis M.
- Peters A.
- Roden M.
- Prehn C.
- Wang-Sattler R.
- Illig T.
- Schulze M.B.
- Adamski J.
- Boeing H.
- Pischon T.
- Raichur S.
- Wang S.T.
- Chan P.W.
- Li Y.
- Ching J.
- Chaurasia B.
- Chaurasia B.
- Dogra S.
- Öhman M.K.
- Takeda K.
- Sugii S.
- Pewzner-Jung Y.
- Futerman A.H.
- Summers S.A.
- Turpin S.M.
- Nicholls H.T.
- Willmes D.M.
- Mourier A.
- Brodesser S.
- Wunderlich C.M.
- Mauer J.
- Xu E.
- Hammerschmidt P.
- Brönneke H.S.
- Trifunovic A.
- LoSasso G.
- Wunderlich F.T.
- Kornfeld J.W.
- Blüher M.
- Krönke M.
- Brüning J.C.
Signature | Ext 1 | Ext 2 | Ext 3 | Ext 4 | Ext 5 | Ext 6 | Ext 7 | Ext 8 | Ext 9 | Ext 10 | Ext 11 |
---|---|---|---|---|---|---|---|---|---|---|---|
Refs. | 35 ,
CerS2 haploinsufficiency inhibits β-oxidation and confers susceptibility to diet-induced steatohepatitis and insulin resistance. Cell Metab. 2014; 20: 687-695 36
Obesity-induced CerS6-dependent C16:0 ceramide production promotes weight gain and glucose intolerance. Cell Metab. 2014; 20: 678-686 | 44 | 38 | 45 | 37
A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance. Cell Metab. 2009; 9: 311-326 | 41 | 42 | 46 | 39 | 43
Identification of serum metabolites associated with risk of type 2 diabetes using a targeted metabolomic approach. Diabetes. 2013; 62: 639-648 | 40 |
Species | Mouse | Human | Human | Human | Human | Human | Human | Human | Human | Human | Human |
Sample | Adipose/Liver | Plasma | Plasma | Plasma | Serum | Muscle | Serum | Plasma | Plasma | Serum | Muscle |
Metabolites | C16-Cer | Val | Sum Cer | Val | Val | Sum Cer | Gly | Val | Sum Cer | Val | C18-Cer |
Leu/Ile | C18-Cer | Leu/Ile | Leu/Ile | C14-Cer | Leu/Ile | C14-Cer | Leu/Ile | ||||
Gly | C20-Cer | C3-carn | C3-carn | C16-Cer | Ala | C3-carn | |||||
Phe | C24-Cer | C5-carn | C5-carn | C24:1-Cer | Glx | Phe | |||||
Glx | C24:1-Cer | Ala | Phe | Tyr | |||||||
Glx | Tyr | ||||||||||
Met | Pyruvate | ||||||||||
Phe | Malonyl/hydroxy-butyryl-CoA | ||||||||||
Tyr |
Discussion
- Lotta L.A.
- Gulati P.
- Day F.R.
- Payne F.
- Ongen H.
- van de Bunt M.
- Gaulton K.J.
- Eicher J.D.
- Sharp S.J.
- Luan J.
- De Lucia Rolfe E.
- Stewart I.D.
- Wheeler E.
- Willems S.M.
- Adams C.
- et al.
- Kusunoki M.
- Tsutsumi K.
- Nakayama M.
- Kurokawa T.
- Nakamura T.
- Ogawa H.
- Fukuzawa Y.
- Morishita M.
- Koide T.
- Miyata T.
- Muoio D.M.
- Noland R.C.
- Kovalik J.P.
- Seiler S.E.
- Davies M.N.
- DeBalsi K.L.
- Ilkayeva O.R.
- Stevens R.D.
- Kheterpal I.
- Zhang J.
- Covington J.D.
- Bajpeyi S.
- Ravussin E.
- Kraus W.
- Koves T.R.
- Mynatt R.L.
- Raichur S.
- Wang S.T.
- Chan P.W.
- Li Y.
- Ching J.
- Chaurasia B.
- Chaurasia B.
- Dogra S.
- Öhman M.K.
- Takeda K.
- Sugii S.
- Pewzner-Jung Y.
- Futerman A.H.
- Summers S.A.
- Turpin S.M.
- Nicholls H.T.
- Willmes D.M.
- Mourier A.
- Brodesser S.
- Wunderlich C.M.
- Mauer J.
- Xu E.
- Hammerschmidt P.
- Brönneke H.S.
- Trifunovic A.
- LoSasso G.
- Wunderlich F.T.
- Kornfeld J.W.
- Blüher M.
- Krönke M.
- Brüning J.C.
- Turpin S.M.
- Nicholls H.T.
- Willmes D.M.
- Mourier A.
- Brodesser S.
- Wunderlich C.M.
- Mauer J.
- Xu E.
- Hammerschmidt P.
- Brönneke H.S.
- Trifunovic A.
- LoSasso G.
- Wunderlich F.T.
- Kornfeld J.W.
- Blüher M.
- Krönke M.
- Brüning J.C.
- Raichur S.
- Wang S.T.
- Chan P.W.
- Li Y.
- Ching J.
- Chaurasia B.
- Chaurasia B.
- Dogra S.
- Öhman M.K.
- Takeda K.
- Sugii S.
- Pewzner-Jung Y.
- Futerman A.H.
- Summers S.A.
- Turpin S.M.
- Nicholls H.T.
- Willmes D.M.
- Mourier A.
- Brodesser S.
- Wunderlich C.M.
- Mauer J.
- Xu E.
- Hammerschmidt P.
- Brönneke H.S.
- Trifunovic A.
- LoSasso G.
- Wunderlich F.T.
- Kornfeld J.W.
- Blüher M.
- Krönke M.
- Brüning J.C.
- Raichur S.
- Wang S.T.
- Chan P.W.
- Li Y.
- Ching J.
- Chaurasia B.
- Chaurasia B.
- Dogra S.
- Öhman M.K.
- Takeda K.
- Sugii S.
- Pewzner-Jung Y.
- Futerman A.H.
- Summers S.A.
- Turpin S.M.
- Nicholls H.T.
- Willmes D.M.
- Mourier A.
- Brodesser S.
- Wunderlich C.M.
- Mauer J.
- Xu E.
- Hammerschmidt P.
- Brönneke H.S.
- Trifunovic A.
- LoSasso G.
- Wunderlich F.T.
- Kornfeld J.W.
- Blüher M.
- Krönke M.
- Brüning J.C.
Experimental procedures
Animals and metabolic phenotypes
- Hoehn K.L.
- Turner N.
- Swarbrick M.M.
- Wilks D.
- Preston E.
- Phua Y.
- Joshi H.
- Furler S.M.
- Larance M.
- Hegarty B.D.
- Leslie S.J.
- Pickford R.
- Hoy A.J.
- Kraegen E.W.
- James D.E.
- Cooney G.J.
Metabolomics assessment
Computational analyses, correlation and hierarchical clustering
Computational analyses, classification studies
Statistical analysis
Author contributions
Acknowledgments
Supplementary Material
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Footnotes
This work was supported in part by National Health and Medical Research Council (NHMRC) Project Grants GNT1061122, GNT1086851, and GNT1086850 (to D. E. J.) and National Institutes of Health Grants 2R01DK089312 and 2P01-DK058398 (to D. M. M.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or NHMRC.
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