A disrupted cholecystokinin A receptor gene induces diabetes in obese rats synergistically with ODB1 gene.

Otsuka Long-Evans Tokushima fatty (OLETF) rats develop hyperglycemia, hyperinsulinemia, and mild obesity, which are characteristic of human non-insulin-dependent diabetes mellitus. We have shown that two recessive genes, ODB1 mapped on the X chromosome and ODB2 mapped on chromosome 14, are involved in the induction of the diabetes in OLETF rats. Recently we found that OLETF rats are the naturally occurring cholecystokinin type A receptor (CCKAR) gene knockout rats. In this study, we focused on the genotype of CCKAR gene and the ODB1 gene in regulation of glucose homeostasis in the F2 cross of the OLETF rats. Relatively high plasma glucose levels were observed in the F2 offspring with the homozygously disrupted CCKAR gene. A synergistic effect for increasing plasma glucose levels in F2 rats between disrupted CCKAR gene and the ODB1 gene was shown. The CCKAR gene was found to map very close to ODB2 by a linkage analysis using microsatellite markers. These results suggest that CCKAR gene maintains normoglycemia in rats.