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.

Abstract

A backcross model of New Zealand obese mice (NZO) with the lean, atherosclerosis-resistant SJL strain was established to locate genes responsible for obesity, insulin resistance, and type 2 diabetes-like hyperglycemia. In male NZO ؋ F1 backcross mice, a major susceptibility locus for the development of hyperglycemia and hypoinsulinemia (Nidd/SJL) was identified on chromosome 4 between the markers D4Mit278 and D4Mit232, 10-28 cM distal of the previously described Nidd1 locus. The diabetogenic allele has presumably been contributed by the SJL genome, and it appeared to be responsible for ~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 associated with reduced weight gain or weight loss, presumably as a consequence of decompensated hyperglycemia. In all male backcross mice, the prevalence of hyperglycemia at week 22 increased with the body weight at week 12, suggesting 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 the 12-week weight was <45 and 45-50 g, respectively. These data are consistent with the conclusion that Nidd/SJL represents a diabetes gene that lowers the obesity threshold for the development of hyperglycemia and hypoinsulinemia. Diabetes 49:1590-1596, 2000 N ew Zealand obese (NZO) mice exhibit a polygenic syndrome of hyperphagia, obesity, and insulin resistance (1-5). In the course of the syndrome, some NZO mice develop islet cell failure, hypoinsulinemia, and overt hyperglycemia. Thus, the NZO strain is an ideal model for the identification of the genes that are responsible for aberrations of glucose metabolism and insulin action in mice. Recently, a cross between NZO and NON mice was established, and it was shown that susceptibility loci derived from both NON (Nidd1 and Nidd2) and NZO genomes (Nidd3) contributed to the development of hyperglycemia and hypoinsulinemia (6). Furthermore, it has been shown that leptin resistance might be the primary cause of obesity in NZO mice (7,8). Interestingly, a leptin receptor variant with several amino acid exchanges (Lepr A720T/T1044I ), including 2 nonconservative substitutions (A720T; T1044l), was found in the NZO strain (7). However, the contribution of Lepr A720T/T1044I to the metabolic syndrome of the NZO mouse was unclear, because the allele was also present in the related nonobese New Zealand Black (NZB) strain.To assess the contribution of Lepr A720T/T1044I and identify other susceptibility loci for obesity and insulin resistance, we established a backcross model of NZO mice with the lean and atherosclerosis-resistant SJL strain (9,10). Surprisingly, we found that the prevalence of hyperglycemia and hypoinsulinemia in the male NZO ϫ F1 backcross mice was higher than expected and that this effect was due to a diabetogenic ...

The Diabetes-Prone NZO/HlLt Strain. I. Immunophenotypic Comparison to the Related NZB/BlNJ and NZW/LacJ Strains

“…However, outcross of NZO/Hl to SWR, another Swiss-derived strain, suppressed diabetogenesis (Plum et al, 2000). As noted previously, the NZB genome synergizes with the related NZW genome to exacerbate lupus-like symptoms in F1 hybrids (Theofilopoulos and Kono, 1998).…”

“…Thus, an immunophenotype assumed to be H2 z -controlled in NZW can now be compared in NZO to establish the extent to which interactions with non-MHC loci are required to produce the phenotype. Genetic outcrosses between NZO and other (unrelated) inbred strains (NON/Lt, SJL/J) have not shown an MHC requirement for "diabesity" (Leiter et al, 1998;Plum et al, 2000). Hence, there is no basis for assuming that there is a primary role for autoimmunity in diabetes pathogenesis in NZO mice as there clearly is in the NOD mouse model for T cell-mediated type 1 diabetes (Serreze and Leiter, 2001).…”

Development of diabetes in obese, insulin-resistant mice: essential role of dietary carbohydrate in beta cell destruction

“…With outcross populations, a threshold body weight (45 g at 12 weeks) is required for the development of diabetes [8,12,28,29]. In the presence of dietary carbohydrate, an increase of dietary fat accelerated the development of diabetes (Fig.…”

Genetic regulation of hypothalamic cocaine and amphetamine-regulated transcript (CART) in BxD inbred mice

“…A series of QTL related to body weight, food intake, energy balance and other metabolic parameters map to Chr 4 and 11 in the exact same regions as the CARTta QTL (Bevova et al, 2006;Moody et al, 1999;Plum et al, 2000;Ueda et al, 1999;Allan et al, 2005;Rocha et al, 2004).…”