Differential Levels of Diabetogenic Stress in Two New Mouse Models of Obesity and Type 2 Diabetes

Abstract

The genetic basis for the more common forms of human obesity predisposing to insulin resistance and development of type 2 diabetes is multigenic rather than monogenic in origin. New mouse "diabesity" models have been created by combining independent diabetes riskconferring quantitative trait loci from two unrelated parental strains: New Zealand Obese (NZO/HlLt) and Nonobese Nondiabetic (NON/Lt). F1 hybrid males, heterozygous at all polymorphic autosomal loci distinguishing the two parental strains, are driven to obesityinduced diabetes (diabesity) at high frequencies. This review focuses on two new recombinant congenic strains (RCSs) developed by introgressing multiple NZO/HlLt chromosomal segments into the nominally diabesity-resistant NON/Lt strain background. Both RCSs gain more weight than NON animals. Although exhibiting comparable weight gain and adiposity, only one of the two RCSs develops diabetes. Hence, these two RCSs will be instructive in elucidating genetic and pathophysiological differences underlying uncomplicated obesity syndromes versus diabetogenic obesity (diabesity) syndromes. Unlike mice with null mutations in a single gene producing morbid obesity, the new models develop a more moderate obesity produced by the interaction of numerous genes with relatively small effects. These RCSs are differentially sensitive to adverse side effects of thiazolidinediones and thus should be particularly useful for pharmacogenetic analyses. Diabetes 53 (Suppl. 1):S4 -S11, 2004 G enetic architecture is a term used to describe the full range of genetic effects on a phenotype. This architecture is not a fixed entity but changes according to age-and sex-mediated shifts in gene expression, as well as changes in the physical environment. Most common forms of type 2 diabetes entail a complex interaction between multiple genes and the nutritional environment. Obesity represents a major phenotypic risk factor for type 2 diabetes susceptibility. Subphenotypic components of human obesity, such as body weight (BW) and percent fat, are continuously varying traits reflecting contributions from numerous quantitative trait loci (QTL) (1). Geneticists are currently grappling with the molecular genetic basis for variation in a complex phenotypic trait such as obesity that confers type 2 diabetes susceptibility (2). This effort requires development of new computational frameworks to enhance power to detect gene-gene interactions in genome-wide screens (3). However, understanding how these genomic interactions translate into dysregulated metabolic pathways (physiogenomics) is still difficult in humans. Currently, mutant stocks with defects in the leptin receptor or leptin genes (Lepr db and Lep ob mice) represent the most intensively studied mouse models of obesity-associated type 2 diabetes ("diabesity"). Although these mutant stocks are very useful, the genetic basis for their morbid obesity, as well as the pathophysiological basis for their insulin resistance, is not reflective of what is sometimes referred to as "garden-vari...

Laboratory animals as surrogate models of human obesity

“…Both subcutaneous and visceral fat is accumulated. Furthermore, the mouse develops type 2 diabetes, although at varying frequencies depending on substrain and gender [81,82] . The NZO mice have been crossed with the nonobese nondiabetic (NON) mouse, which has impaired glucose tolerance and impaired β-cell insulin secretion capacity but still do not develop overt diabetes.…”

Mouse models of diabetic neuropathy

“…NONcNZO/LtJ mice develop hyperglycemia in the absence of obesity, with 56% of male mice exhibiting diabetes at 24 weeks of age (Reifsnyder et al 2000). Further backcrossing of NONcNZO/LtJ mice with NON/ShiLtJ mice selected for multiple combinations of polygenic diabetes loci has resulted in various recombinant congenic strains, including NONcNZO10/LtJ mice that exhibit obesity, hyperinsulinemia, and IGT in 90-100% of male mice at 24 weeks of age (Leiter and Reifsnyder 2004). Finally, TALLYHO mice are useful to study diabetes onset and progression because they develop hyperinsulinemia around 6 weeks of age and hyperglycemia by 12 to 14 weeks of age in the presence of only modest obesity.…”

Adenovirus-Mediated Overexpression of O -GlcNAcase Improves Contractile Function in the Diabetic Heart

“…The cellular O-GlcNAcylation in these hearts was compared with that of the noninsulin-treated diabetic hearts. In addition, several 20-week-old male polygenic diabetic NONcNZO10/LtJ mice (The Jackson Laboratory, Bar Harbor, Me) 23,24 were used as a type II diabetic model to investigate the excess O-GlcNAcyaltion level in the diabetic heart independent of STZ administration. These mice developed hyperglycemia at 12 to 16 weeks.…”