Running title: L-carnosine influences glucose metabolism. To whom correspondence should be addressed:

Objective: Carnosinase 1 (CN1) is a secreted dipeptidase that hydrolyses L-carnosine. Recently, we have identified an allelic variant of hCN1, which results in increased enzyme activity and which is associated with susceptibility for diabetic nephropathy (DN) in human 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, the human CN1 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 HbA1c 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, non-transgenic db/db mice were substituted with L