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

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.