title: L-carnosine, a substrate of carnosinase-1, influences glucose metabolism.
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.
  
  
  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 beta-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.
authors.affiliation: Institute for Anatomy and Cell Biology 1, University of Heidelberg, Heidelberg, Germany.
authors.forename: Sibylle
authors.initials: S
authors.lastname: Sauerhöfer
authors.forename: Gang
authors.initials: G
authors.lastname: Yuan
authors.forename: Gerald Stefan
authors.initials: GS
authors.lastname: Braun
authors.forename: Martina
authors.initials: M
authors.lastname: Deinzer
authors.forename: Michael
authors.initials: M
authors.lastname: Neumaier
authors.forename: Norbert
authors.initials: N
authors.lastname: Gretz
authors.forename: Jürgen
authors.initials: J
authors.lastname: Floege
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Kriz
authors.forename: Fokko
authors.initials: F
authors.lastname: van der Woude
authors.forename: Marcus Johannes
authors.initials: MJ
authors.lastname: Moeller
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D002336:Carnosine / Q000097:blood* / Q000378:metabolism; D003001:Cloning, Molecular; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology / Q000235:genetics*; D003928:Diabetic Nephropathies / Q000201:enzymology / Q000235:genetics*; D004150:Dipeptidases / Q000235:genetics* / Q000378:metabolism*; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006442:Glycated Hemoglobin / Q000032:analysis; D006801:Humans; D051379:Mice; D008815:Mice, Inbred Strains; D017354:Point Mutation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013379:Substrate Specificity; D014162:Transfection
chemical_list: D001786:Blood Glucose; D002336:Carnosine; D004150:Dipeptidases; D006442:Glycated Hemoglobin; C522928:CNDP1 protein, human