Analysis of transition from pre-diabetes to diabetes in two animal models and evaluation of anti-diabetic effects of salsalate
Type 2 diabetes, once called non-insulin-dependent diabetes, is the most common form of diabetes worldwide. It is characterized by insulin resistance and progressive beta cell failure. This thesis aims at investigating the effects of the anti-inflammatory drug salsalate on type 2 diabetes in animal models and evaluating variations of type 2 diabetes disease progression in two diabetic animal models: non-obese Goto-Kakizaki (GK) rats and obese Zucker Diabetic Fatty (ZDF) rats. Salsalate is a non-steroidal anti-inflammatory drug, which is used to reduce pain and inflammation caused by conditions such as rheumatoid arthritis, osteoarthritis, and related rheumatic conditions. Recently, growing evidence has linked inflammation with type 2 diabetes. Therefore, in this thesis, we investigated the anti-diabetic effects and action mechanisms of salsalate on GK rats. The GK rat is a polygenetic spontaneous non-obese animal model for studies of type 2 diabetes. Both GK rats and non-diabetic control Wistar Kyoto (WKY) rats were treated with salsalate from the age of 4 weeks up until sacrifice at age 21 weeks. GK and WKY rats without salsalate treatment were included as the control groups. Physiological biomarkers and selective gene expression were measured during the time of salsalate treatment as well as at sacrifice. Results showed that salsalate ameliorated the hyperglycemia in GK rats and largely prevented type 2 diabetes disease progression by increasing the plasma adiponectin concentrations and suppressing certain inflammation related gene (interferon-induced protein with tetratricopeptide repeats 1, Ifit1; interferon inducible GTPase 1, Iigp1) expressions in adipose tissue. However, we have also noted differences in disease progression in two series of GK animals from Taconic USA. Development of hyperglycemia was more rapid in GKs derived in 2006 (Series 1) than those re-derived in 2010 (Series 2). A comparison between GK animals indicates that, although the hyperglycemic driving force was greater in Series 1 GKs, the sensitivity of beta cells to failure was higher in Series 2. A second animal model used in type 2 diabetes research is the leptin deficient ZDF rat. This model differs from the non-obese GK rat since it is hyperphagic and obese. We also documented that variations in disease manifestations occur in ZDF rats. In this case, not all ZDFs developed hyperglycemia relative to Zucker lean rats (ZLR). The difference was very clear between ZDFs that became hyperglycemic and those that did not. The ZDFs that became hyperglycemic with age lost the ability to produce insulin while non-hyperglycemic animals remained chronically hyperinsulinemic. Our analysis of gene expression related to inflammation and the effects of anti-inflammatory therapy suggest that inflammation was greater in both GK populations than ZDFs regardless of the development of diabetes. This comparison suggests the existence of different driving forces and etiology in these two models. The existing differences in diabetic animal models reflect the variability of disease progression in human type 2 diabetes. In summary, this dissertation provides insights regarding the anti-diabetic effects and molecular mechanisms of salsalate. Furthermore, our efforts validated two diabetic animal models and provide additional information to better understand the disease progression of type 2 diabetes.
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