Experimental Animal Models

Currently there exist several experimental animal models for the study of diabetes (Mathews, 2002). The most currently used are from rodents. All these animal models mainly reproduce by genetic engineering single specific alterations found in type 2 diabetes. These models try to elucidate one particular pathological aspect of the disease. The most widely used are the leptin-deficient ob/ob_/~ mice, db/db+/+ mice, KATp-channel mutated, ApoE deficient mice with other deficiencies, several knock-out mice including for RAGE, for specific signaling molecules for IR, for PTP1B.

In this context new models constantly are being developed, such as a transgenic rat model for human islet amyloid polypetide (IAPP) for studying specifically the loss of beta-cell mass and whether this is occurring by apoptosis (Butler et al., 2004). These rats develop diabetes between 5 and 10 months of age. This model proved very useful to demonstrate certain aspects of the beta-cell toxicity in diabetes mellitus, mainly in the context of glucose toxicity. It is of note that the time of development is very early in life, and perhaps would not be relevant for the age-related effect on diabetes development. Another murine model has been developed to study the role of low birth weight in the development of type 2 diabetes via beta cell dysfunction (Jimenez-Chillaron et al., 2005). This mouse model was developed by undernutrition during pregnancy. These mice developed severe glucose intolerance after six months of age. This is a very useful model; however, the very early development of diabetes renders its application difficult in the context of aging. Nevertheless, this could be a model for some pathophysiological changes occurring as a life-long process in relation to the development of diabetes and perhaps frailty with age. The number of models in development is too many to be enumerated here.

There are only a few models that try to integrate the whole pathophysiological aspects of diabetes like the streptozocine-induced diabetic mice, Zucker fatty rats,

Goto-Kakizaki (GK) rats developed by selective breeding of nondiabetic Wistar rats, or the KK. The KK mouse strain shows inherently glucose-intolerance and insulinresistance (Ikeda, 1994). These mice become easily obese even by aging itself and show an overt diabetic state. Thus, these mice could be a good model for the study of obesity-related diabetes and also for age-related diabetes. This aspect needs further study.

Recently, the use of nonhuman primates also was advocated as being close to human physiology and pathophysiology (Bruns et al., 2004). Obviously their use is not easy and is very costly. Nevertheless, in some circumstances their use, such as the study of factors related to insulin sensitivity, proved to be very rewarding.

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