Pathophysiological and genetic characterization of the major diabetes locus in GK rats

Genetic studies of the type 2 diabetes-like GK rat have revealed several su sceptibility loci for the compound diabetes phenotype, Congenic strains wer e established for Niddm1, the major quantitative trait locus (QTL) for post prandial glucose levels, by transfer of GK alleles onto the genome of the n ormoglycemic F344 rat. Despite the polygenic nature of diabetes in GK, the locus-specific diabetes phenotype was retained in the congenic strain Niddm 1a, containing a GK-derived genomic fragment of 52 cM from the Niddm1 locus . Furthermore, Niddm1 was divided into two nonoverlapping loci, physically separated in the two congenic strains Niddm1b and Niddm1i with distinct met abolic phenotypes, Both strains displayed postprandial hyperglycemia and re duced insulin action in isolated adipose cells. Furthermore, Niddm1i alread y exhibits a pronounced in vivo insulin secretion defect at 65 days, while Niddm1b develops a relative insulin secretory defect at 95 days. This sugge sts that Niddm1i impairs mechanisms common to insulin secretion in pancreat ic B-cells and insulin action in adipocytes, Niddm1b rats show signs of inc reasing insulin resistance with age associated with obesity, hyperinsulinem ia, and dyslipidemia, Moreover, the data indicated nonallelic interaction ( epistasis) between Niddm1b and Niddm1i on the postprandial glucose levels. These data emphasize the pathophysiological complexity of diabetes, even wi thin an apparently single QTL, and demonstrate the potential of the GK mode l in transforming the multifactorial diabetes phenotype into single traits, suitable for positional cloning.