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The molecular pathogenesis of diabetes remains poorly understood because of the genetic complexity of the disease. One possibly effective approach to elucidate the pathogenesis is to study an animal model with a similar phenotype. The TSOD (Tsumura, Suzuki, Obese Diabetes) mouse, a newly developed animal model, exhibits both diabetes and obesity with marked hyperinsulinemia and hypertrophy of the pancreatic islets and might represent a common form of obese type 2 diabetes in humans. Phenotypic characterization revealed that the TSOD mouse had both insulin resistance and impaired glucose-stimulated insulin secretion. A comprehensive genetic dissection of diabetes and obesity has been performed using F1 and F2 progeny between the TSOD and control BALB/cA strains. A genome-wide screen for loci linked to glucose homeostasis and body weight allowed us to map three quantitative trait loci (QTLs) involved in this disorder. The major genetic determinant of blood glucose levels was identified on chromosome 11. Furthermore, two independent QTLs involved in controlling body weight were found on chromosomes 1 and 2. The QTL on chromosome 2 also affected insulin levels significantly. Each QTL has distinct effects on different traits and a different mode of inheritance. Our study indicates that hyperglycemia and obesity are clearly controlled by distinct combinations of genetic loci in this mouse model and provides insights into the genetic basis of common forms of human type 2 diabetes with obesity.

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The receptor-type protein tyrosine kinases in murine pancreatic islets were screened to identify possible growth/differentiation factors in pancreatic beta-cells. The analysis revealed that insulin receptor-related receptor (IRR) is highly expressed in the islets as well as in several highly differentiated beta-cell lines derived from transgenic mice. Islets predominantly contain IRR as uncleaved proreceptors compared with IRR as processed forms in the beta-cell lines, suggesting that the activity of IRR is regulated on the level of processing proteases in vivo. To examine the IRR signaling pathway, a chimeric receptor consisting of the extracellular domain of insulin receptor and the intracellular domain of IRR was expressed in Chinese hamster ovary cells. The hybrid receptor is functional because insulin is capable of tyrosine-phosphorylating the catalytic domain in these cells. It also stimulates the tyrosine phosphorylation of insulin receptor substrate (IRS)-1 and IRS-2, indicating that both proteins serve as substrates of IRR-protein tyrosine kinase in intact cells. The phenotype of the IRS-2 knockout mouse recently reported suggests that an IRS-2-mediated signaling pathway controls the compensatory increase in pancreatic beta-cell mass in insulin-resistant states. From our findings of the specific expression of IRR and its ability of signaling to IRS-2, we speculate that this receptor might play a role in the regulation of beta-cell mass.

We previously reported a quantitative trait locus for body weight, non-insulin-dependent diabetes 5 (Nidd5), on Chromosome 2 in the TSOD (Tsumura, Suzuki, Obese Diabetes) mouse, a model of polygenic obese type 2 diabetes. To find the gene responsible for a specific component of the pathogenesis, we used a marker-assisted selection protocol to produce congenic strains. These mice are designed to carry a control BALB/cA-derived genomic interval and a TSOD background to look for loss of phenotype. One of the strains with the widest congenic interval, D2Mit297-D2Mit304, showed reductions in both body weight and adiposity compared with TSOD mice. The phenotypic analyses of other congenic strains further narrowed the locus in a 9.4-Mb interval between D2Mit433 and D2Mit91, around which numerous loci for body weight and adiposity have been mapped previously. Although the locus showed a relatively modest effect on body weight, it had a major influence on fat mass that explains approximately 60% of the difference in the adipose index between parental TSOD and BALB/cA mice. Furthermore, the congenic strain with a minimal BALB/cA-derived region showed significantly smaller cell sizes of white and brown adipocytes compared with the control littermates. However, the locus did not primarily affect food consumption, general activity, or rectal temperature after cold exposure, although there are clear differences in these traits between the parental strains. The present work physically delineates the major locus for adiposity in the TSOD mouse.