Genetic analysis of obesity-induced diabetes associated with a limited capacity to synthesize insulin in C57BL/KS mice: evidence for polygenic control.

Expression of obesity-induced diabetes associated with the diabetes or db mutation in mice varies in inbred strains. This study utilized a genetic analysis to evaluate the number of genes responsible for the difference in diabetes responses between mice of the susceptible C57BL/KsJ (BL/Ks) and resistant 129/J inbred strains. BL/Ks (db/+) males and 129/J (+/+) females were bred to generate F1 hybrids, and the F1 females (db/+ and +/+, distinguished by progeny testing) were backcrossed to BL/Ks (db/+) males. A total of 252 backcrossed males were obtained, of which 31 were db/db and obese. While the plasma glucose of all the fed backcrossed mice was greater than 22 mmol/l, the expression of diabetes varied considerably, as measured by fasting plasma glucose, fed plasma insulin, and pancreatic insulin and proinsulin mRNA content. That proinsulin mRNA content was a good indicator of diabetes severity and islet dysfunction was seen in the inverse correlation between proinsulin mRNA content and fasting plasma glucose (r = 0.69, p less than 0.001), and a direct correlation between proinsulin mRNA and plasma insulin (r = 0.86, p less than 0.001), and pancreatic insulin content (r = 0.61, p less than 0.01). If a single gene were responsible for severe islet dysfunction, one-half of the backcrossed mice would develop low proinsulin mRNA levels like the BL/Ks parent, and one-half would be resistant to islet destruction. Statistical evaluation (SKUMIX) of the distribution of these parameters in backcrossed mice rejected with a high degree of probability a bimodal distribution.(ABSTRACT TRUNCATED AT 250 WORDS)