Type 2 diabetes-like hyperglycemia in a backcross model of NZO and SJL mice - Characterization of a susceptibility locus on chromosome 4 and its relation with obesity

A backcross model of New Zealand obese mice (NZO) with the lean, atheroscle rosis-resistant SJL strain was established to locate genes responsible for obesity, insulin resistance, and type 2 diabetes-like hyperglycemia, In mal e NZO X F1 backcross mice, a major susceptibility locus for the development of hyperglycemia and hypoinsulinemia (Nidd/SJL) was identified on chromoso me 4 between the markers D4Mit278 and D4Mit232, 10-28 cM distal of the prev iously described Nidd1 locus, The diabetogenic allele has presumably been c ontributed by the SJL genome, and it appeared to be responsible for similar to 60% of the total prevalence of hyperglycemia, The presence of Nidd/SJL did not alter body weight or weight gain by week 12, Thereafter, it was ass ociated with reduced weight gain or weight loss, presumably as a consequenc e of decompensated hyperglycemia, In all male backcross mice, the prevalenc e of hyperglycemia at week 22 increased with the body weight at week 12, su ggesting that the development of hyperglycemia was dependent on the degree of obesity, In the absence of Nidd/SJL, mice weighing <50 g at week 12 did not develop hyperglycemia by week 22, In contrast, in animals carrying the diabetogenic allele, the prevalence of hyperglycemia was 20 and 64% when th e 12-week weight was <45 and 45-50 g, respectively. These data are consiste nt with the conclusion that Nidd/SJL represents a diabetes gene that lowers the obesity threshold for the development of hyperglycemia and hypoinsulin emia.