Changing Metabolic Signatures of Amino Acids and Lipids During the Prediabetic Period in a Pig Model With Impaired Incretin Function and Reduced β-Cell Mass

  1. Eckhard Wolf1
  1. 1Chair for Molecular Animal Breeding and Biotechnology, and Laboratory for Functional Genome Analysis, Gene Center, Ludwig-Maximilians-Universität München, Munich, Germany
  2. 2Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
  3. 3Institute of Experimental Genetics, Genome Analysis Center, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
  4. 4Institute of Experimental Genetics, Life and Food Science Center Weihenstephan, Technische Universität München, Freising-Weihenstephan, Germany
  5. 5Medical Clinic II, Klinikum Grosshadern, Ludwig-Maximilians-Universität München, Munich, Germany
  6. 6Faculty of Biology, Ludwig-Maximilians-Universität München, Planegg-Martinsried, Germany
  7. 7Department of Physiology and Biophysics, Weill Cornell Medical College in Qatar, Education City-Qatar Foundation, Doha, Qatar
  8. 8Children’s Research Center, Dr. von Hauner Children’s Hospital, Ludwig-Maximilians-Universität München, Munich, Germany
  1. Corresponding author: Eckhard Wolf, ewolf{at}lmb.uni-muenchen.de.

Abstract

Diabetes is generally diagnosed too late. Therefore, biomarkers indicating early stages of β-cell dysfunction and mass reduction would facilitate timely counteraction. Transgenic pigs expressing a dominant-negative glucose-dependent insulinotropic polypeptide receptor (GIPRdn) reveal progressive deterioration of glucose control and reduction of β-cell mass, providing a unique opportunity to study metabolic changes during the prediabetic period. Plasma samples from intravenous glucose tolerance tests of 2.5- and 5-month-old GIPRdn transgenic and control animals were analyzed for 163 metabolites by targeted mass spectrometry. Analysis of variance revealed that 26 of 163 parameters were influenced by the interaction Genotype × Age (P ≤ 0.0001) and thus are potential markers for progression within the prediabetic state. Among them, the concentrations of seven amino acids (Phe, Orn, Val, xLeu, His, Arg, and Tyr) were increased in 2.5-month-old but decreased in 5-month-old GIPRdn transgenic pigs versus controls. Furthermore, specific sphingomyelins, diacylglycerols, and ether phospholipids were decreased in plasma of 5-month-old GIPRdn transgenic pigs. Alterations in plasma metabolite concentrations were associated with liver transcriptome changes in relevant pathways. The concentrations of a number of plasma amino acids and lipids correlated significantly with β-cell mass of 5-month-old pigs. These metabolites represent candidate biomarkers of early phases of β-cell dysfunction and mass reduction.

Footnotes

  • Received September 5, 2011.
  • Accepted February 21, 2012.

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  1. Diabetes vol. 61 no. 8 2166-2175
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