Type 2 diabetes is a polygenic disease resulting from a combination of different disease alleles reflecting obesity, insulin resistance, and hyperglycemia. Using a positional cloning strategy with different inbred strains of mice, we mapped a disease locus for obesity-associated diabetes on chromosome 4. We analyzed all genes in this region and identified distinct differences in the expression levels of the transcription factor Zfp69. The expression of this gene mediated diabetes progression in a leptin-deficient congenic mouse line. The animals developed a disease pattern of hyperglycemia, reduced gonadal fat mass, and increased plasma and liver triglycerides, resembling a potential defect in triglyceride storage . In order to elucidate the impact of the human ortholog of Zfp69 in the development of type 2 diabetes, we tested its mRNA expression in human white adipose tissue. Consistent with the mouse data, mRNA-expression was significantly higher in diabetic subjects than in unaffected controls.