Comparison of Two New Mouse Models of Polygenic Type 2 Diabetes at the Jackson Laboratory, NONcNZO10Lt/J and TALLYHO/JngJ

This review compares two novel polygenic mouse models of type 2 diabetes (T2D), TALLYHO/JngJ and NONcNZO10/LtJ, and contrasts both with the well-known C57BLKS/J-Leprdb (db/db) monogenic diabesity model. We posit that the new polygenic models are more representative of the “garden variety” obesity underlying human T2D in terms of their polygenetic rather than monogenic etiology. Moreover, the clinical phenotypes in these new models are less extreme, for example, more moderated development of obesity coupled with less extreme endocrine disturbances. The more progressive development of obesity produces a maturity-onset development of hyperglycemia in contrast to the juvenile-onset diabetes observed in the morbidly obese db/db model. Unlike the leptin receptor-deficient db/db models with central leptin resistance, the new models develop a progressive peripheral leptin resistance and are able to maintain reproductive function. Although the T2D pathophysiology in both TALLYHO/JngJ and NONcNZO10/LtJ is remarkably similar, their genetic etiologies are clearly different, underscoring the genetic heterogeneity underlying T2D in humans. 1. Introduction The purpose of this review is to introduce two new polygenic mouse models of type 2 diabetes (T2D) and to contrast them with the most commonly studied monogenic model, the leptin receptor-deficient C57BLKS/J- ？？(hereafter abbreviated as db/db) mouse. On the basis of their polygenic etiologies, the absence of juvenile-onset morbid obesity, their more protracted maturity-onset development of hyperglycemia, and the absence of severe endocrine/neuroendocrine disturbances, the two polygenic models more closely reflect the phenotypes associated with the “garden variety” obesity and obesity-induced diabetes (diabesity) in humans. The genetic origins of each model will be described separately, and then their diabesity phenotypes will be compared. 2. The C57BLKS/J-db/db Mouse (JAX Stock 642) Great interest accompanied the publication of the “diabetes” mouse in 1966 [1]. A recessive mutation occurring spontaneously in the C57BLKS/J (BKS) strain produces early onset diabesity with initial moderate hyperinsulinemia followed by insulinopenia as the pancreatic islets undergo atropy due to beta-cell degeneration [1]. The mutation was identified in 1996 [2, 3] as the receptor for leptin, the adipokine hormone missing in the ob/ob (now designated ) mouse [4]. Leptin sensing in hypothalamic nuclei is essential for normal regulation of satiety as well as multiple metabolic and neuroendocrine/reproduction pathways. Hence, the extreme