Genetic Modifiers ofLeprfaAssociated with Variability in Insulin Production and Susceptibility to NIDDM

A Novel Model of Obesity-Related Diabetes: Introgression of the Leprfa Allele of the Zucker Fatty Rat into Nonobese Spontaneously Diabetic Torii (SDT) Rats

“…In contrast, ZF fa/fa rats of both sexes do not develop diabetes during their lifespan when fed a normal chow ad libitum in similar environmental conditions to those used in our investigations [3,15,23], although they show an impaired glucose tolerance and other signs of insulin resistance associated with obesity. We found that SDT fa/fa rats spontaneously developed hyperglycemia after 5 weeks of age in males and after 8 weeks of age in females, the onset of which is markedly earlier than in wild-type and heterozygous rats.…”

“…Further characterization of this congenic rat might be required not only to define a phenotypic difference among the several obese diabetes models but also to understand the heterogeneous pathology of obesity-related diabetes involved with genetic combinations of the SDT-background-derived defects and the Lepr gene mutation. It is well known that genetic background strongly influences susceptibility to diabetes [3,13,19]. Chung et al studied two rat models of diabetic and non-diabetic strains having the Lepr fa mutation [3] and determined three QTLs for the variability in the susceptibility to obese diabetes [3].…”

“…It is well known that genetic background strongly influences susceptibility to diabetes [3,13,19]. Chung et al studied two rat models of diabetic and non-diabetic strains having the Lepr fa mutation [3] and determined three QTLs for the variability in the susceptibility to obese diabetes [3]. Of these QTLs, interestingly, the locus regulating adiposity and the number of pancreatic islets was mapped on chromosome 1, positionally overlapping a highly significant QTL, Gisdt1, for glucose intolerance in the SDT rat [11].…”

“…The decreased sensitivity to insulin leads to an increased requirement for insulin, and is often associated with obesity in which metabolic disturbances are marked in insulin-target organs, such as the liver, muscle and adipose tissues [1,14]. It is well known that the β-cell response to increased insulin requirements is strongly determined by animals' genetic backgrounds [3,19,21].…”

Confirmation and Characterization of Murine Body Weight QTLs, <i>Bwq1</i> and <i>Bwq2</i>, Identified in C57BL/6J &times; KK-<i>A</i>^y/<i>a</i> F₂-<i>A</i>^y/<i>a</i> Mice

“…Thus, the variability of mutant phenotypes [8,10]. Indeed, Chung et al [7] have identified three modifier loci for diabetes and obesity traits caused by Lepr fa on Chrs 1, 12, and 16 in rats. Thus, it may be straightforward to consider that there will be several modifier loci for traits induced by the A y allele, and as a result, we have identified a modifier locus, Bwq2, on Chr 6.…”