l-Carnosine, a Substrate of Carnosinase-1, Influences Glucose Metabolism

  1. Sibylle Sauerhöfer123,
  2. Gang Yuan12,
  3. Gerald Stefan Braun2,
  4. Martina Deinzer4,
  5. Michael Neumaier4,
  6. Norbert Gretz5,
  7. Jürgen Floege2,
  8. Wilhelm Kriz1,
  9. Fokko van der Woude3 and
  10. Marcus Johannes Moeller12
  1. 1Institute for Anatomy and Cell Biology 1, University of Heidelberg, Heidelberg, Germany
  2. 2Division of Nephrology and Immunology, RWTH University, Aachen, Germany
  3. 3Med. Klinik V, University of Heidelberg/Mannheim, Mannheim, Germany
  4. 4Institute for Clinical Chemistry, University of Heidelberg/Mannheim, Mannheim, Germany
  5. 5Center for Medical Research (ZMF), University of Heidelberg/Mannheim, Mannheim, Germany
  1. Address correspondence and reprint requests to Dr. Marcus J. Moeller, Division of Nephrology and Immunology, RWTH-Aachen, D-52074 Aachen, Germany. E-mail: mmoeller{at}ukaachen.de

Abstract

OBJECTIVE—Carnosinase 1 (CN1) is a secreted dipeptidase that hydrolyzes l-carnosine. Recently, we have identified an allelic variant of human CN1 (hCN1) that results in increased enzyme activity and is associated with susceptibility for diabetic nephropathy in human diabetic patients. We therefore hypothesized that l-carnosine in the serum represents a critical protective factor in diabetic patients.

RESEARCH DESIGN AND METHODS—l-carnosine serum levels were manipulated in db/db mice, a model of type 2 diabetes. In a transgenic approach, hCN1 cDNA was expressed under the control of a liver-specific promoter in db/db mice, mimicking the expression pattern of hCN1 in humans.

RESULTS—Fasting plasma glucose as well as A1C levels rose significantly earlier and remained higher in transgenic animals throughout life. Body weights were reduced as a result of significant glucosuria. In an opposite approach, nontransgenic db/db mice were supplemented with l-carnosine. In these latter mice, diabetes manifested significantly later and milder. In agreement with the above data, serum fasting insulin levels were low in the transgenic mice and elevated by l-carnosine feeding. Insulin resistance and insulin secretion were not significantly affected by l-carnosine serum levels. Instead, a significant correlation of l-carnosine levels with β-cell mass was observed.

CONCLUSIONS—hCN1-dependent susceptibility to diabetic nephropathy may at least in part be mediated by altered glucose metabolism in type 2 diabetic patients.

Footnotes

  • Published ahead of print at http://diabetes.diabetesjournals.org on 29 June 2007. DOI: 10.2337/db07-0177.

    Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db07-0177.

    S.S. and G.Y. contributed equally to this work.

  • Deceased.

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Accepted June 22, 2007.
    • Received February 9, 2007.
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  1. Diabetes vol. 56 no. 10 2425-2432
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