TY - JOUR T1 - Modeling Diabetes Disease Progression and Salsalate Intervention in Goto-Kakizaki Rats JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.111.185686 SP - jpet.111.185686 AU - Yanguang Cao AU - Debra C. DuBois AU - Hao Sun AU - Richard R. Almon AU - William J. Jusko Y1 - 2011/01/01 UR - http://jpet.aspetjournals.org/content/early/2011/09/08/jpet.111.185686.abstract N2 - Type 2 diabetes (T2DM) arises owing to insulin resistance and β-cell dysfunction. Chronic inflammation is widely identified as a cause of T2DM. The Goto-Kakizaki (GK) rat is a spontaneous rodent model for T2DM with chronic inflammation. The purpose of this study was to characterize diabetes progression in GK rats and to evaluate the potential role of the anti-inflammatory agent salsalate. The GK rats were divided into control (n=6) and salsalate treatment groups (n=6) which were fed a salsalate-containing diet from 5 to 21 weeks age. Blood glucose and concentrations of salicylate were measured once a week. Glucose concentrations showed a biphasic increase in which the first phase started around 5 weeks resulting in an increase by 15-25 mg/dL and a second phase at 14-15 weeks with an upsurge of more than 100 mg/dL. A mechanism-based model was proposed to describe the natural diabetes progression and salsalate pharmacodynamics using a population method in S-ADAPT (V1.56, beta). Two transduction cascades were applied to mimic the two T2DM components: insulin resistance and β-cell dysfunction. Salsalate suppressed both disease factors by a fraction of 0.622 on insulin resistance and 0.134 on β-cell dysfunction. The substantial alleviation of diabetes by salsalate supports the hypothesis that chronic inflammation is a pathogenic factor of diabetes in GK rats. Additionally, body weight and food intake were measured and further modeled by a mechanism-based growth model. Modeling results suggest that salsalate reduces weight gain by enhancing metabolic rate and energy expenditure in both GK and Wister-Kyoto rats. ER -