Abstract

Type 2 diabetes mellitus (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 evaluate the potential role of the anti-inflammatory agent salsalate. The GK rats were divided into control groups (n = 6) and salsalate treatment groups (n = 6), which were fed a salsalate-containing diet from 5 to 21 weeks of age. Blood glucose and salicylate concentrations were measured once a week. Glucose concentrations showed a biphasic increase in which the first phase started at approximately 5 weeks, resulting in an increase by 15 to 25 mg/dl and a second phase at 14 to 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 by using a population method in S-ADAPT. 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. In addition, 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.