SummaryThe T lymphocytes mediating autoimmune destruction of pancreatic [3 cells in the nonobese diabetic (NOD) mouse model of insulin-dependent diabetes mellitus (IDDM) may be generated due to functional defects in hematopoietically derived antigen-presenting cells (APC). However, it has not been clear which particular subpopulations ofAPC (B lymphocytes, macrophages, and dendritic cells) contribute to the development and activation of diabetogenic T cells in NOD mice. In the current study we utilized a functionally inactivated immunoglobulin (Ig)l.* allele (Ig/x ''a) to generate a "speed congenic" stock of B lymphocyte-deficient NOD mice that are fixed for linkage markers delineating previously identified diabetes suscepnbility (Ida") genes, These B lymphocyte NOD.Igi.,, ''tt mice had normal numbers of T cells but were free of overt IDDM and insulitis resistant, while the frequency of disease in the B lymphocyte intact segregants was equivalent to that of standard NOD mice in our colony. Thus, B lymphocytes play a heretofore unrecogmzed role that is essential for the initial development and/or activation of [3 cell autoreactive T cells in NOD mice.

The C57BL/6J (B6/J) male mouse represents a standard for diet‐induced obesity (DIO) and is unique in expressing a loss‐of‐function nicotinamide nucleotide transhydrogenase (Nnt) gene. This mutation was associated with a marked reduction in glucose‐stimulated insulin secretion from B6/J islets in vitro and moderately impaired glucose clearance in vivo. To assess the contribution of this Nnt mutation, we compared DIO responsiveness of Nnt‐mutant B6/J males to Nnt wild‐type C57BL/6NJ (B6/NJ) males over a 14‐week period of feeding a high‐fat (60% of calories) diet. Initial mean body weights at 6 weeks did not distinguish the substrains and both substrains were DIO‐sensitive. However, B6/J males outgained the B6/NJ males, with a significant 3 g higher mean body weight at 20 weeks accompanied by significant increases in both lean and fat mass. Mean nonfasting serum glucose over time was also significantly higher in B6/J males, as was impairment of glucose tolerance assessed at 8 and 20 weeks of age. Serum leptin, but not insulin, was significantly higher in B6/J males over time. Potential contributions of the wild‐type Nnt gene were demonstrable on a lower fat diet (10% of calories) where a significantly greater weight gain over time by B6/NJ males was correlated with a significantly higher serum insulin. In conclusion, DIO developed in response to 60% fat feeding regardless of Nnt allele status. Contribution of the B6/J‐unique Nnt mutation was most evident in response to 10% fat feeding that resulted in reduced serum insulin and weight gain compared to B6/NJ males.

Obesity, a major risk factor for type II diabetes, is becoming more prevalent in Western populations consuming high calorie diets while expending less energy both at the workplace and at home. Most human obesity, and probably most type II diabetes as well, reflects polygenic rather than monogenic inheritance. We have genetically dissected a polygenic mouse model of obesity-driven type II diabetes by outcrossing the obese, diabetes-prone, NZO (New Zealand Obese)/HlLt strain to the relatively lean NON (Nonobese Nondiabetic)/Lt strain, and then reciprocally backcrossing obese F1 mice to the lean NON/Lt parental strain. A continuous distribution of body weights was observed in a population of 203 first backcross males. The 22% of first backcross males developing overt diabetes showed highest peripubertal weight gains and earliest development of hyperinsulinemia. We report a complex diabetes-predisposing ("diabesity") QTL (Quantitative Trait Loci) on chromosome 1 contributing significant main effects to increases in body weight, plasma insulin, and plasma glucose. NZO contributed QTL with significant main effects on adiposity parameters on chromosomes 12 and 5. A NON QTL on chromosome 14 interacted epistatically with the NZO obesity QTL on chromosome 12 to increase adiposity. Although the main effect of the diabetogenic QTL on chromosome 1 was on rapid growth rather than adiposity, it interacted epistatically with the obesity QTL on chromosome 12 to increase plasma glucose levels. Additional complex epistatic interactions eliciting significant increases in body weight and/or plasma glucose were found between the NZO-contributed QTL on chromosome 1 and other NZO-contributed QTL on chromosomes 15 and 17, as well as with an NON-contributed QTL on chromosome 2. We further show that certain of these intergenic interactions are predicated on, or enhanced by, the maternal postparturitional environment. We show by cross-fostering experiments that the maternal environmental influence in part is because of the presence of early obesity-inducing factors in the milk of obese F1 dams. We also discuss a strategy for using recombinant congenic strains to separate and reassemble interacting QTL for future study.

SummaryInsulin-dependent diabetes meUitus (IDDM) in NOD/Lt mice represents a complex polygenic disease. NOR/Lt is a recombinant congenic strain (RCS) in which limited regions of the NOD/Lt genome have been replaced by genome from the C57BL/KsJ strain. NOR. mice are insulitis resistant and diabetes free despite genetic identity with NOD at numerous chromosomal regions containing previously described insulin-dependent diabetes (Idd) genes, including the strongly diabetogenic H2g 7 major histocompatibility complex (MHC) haplotype. The present study revealed BKs-derived genome on segments of chromosomes (Chr) 1, 2, 4, 5, 7, 11, 12, and 18, approximating 11.6% of the total NOR genome analyzed. (NOD x NOR)F2 segregation analysis was employed to identify chromosomal regions in NOR containing Idd resistance alleles. IDDM developed in 33% (10/30) of F1 females, and 29.3% (36/123) of F2 females aged to 1 yr. A previously unrecognized diabetes resistance locus (designated Idcl13") strongly protective in homozygous state was identified on NOR Chr 2 in linkage with the Illcr structural gene. The existence of this locus was confirmed by construction of a NOD stock congenic for NORderived markers on Chr 2. Our analysis shows the utility of RCS and congenic stocks for the identification and isolation of non-MHC genes with strong antidiabetogenic functions.

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