title: Modeling diabetes disease progression and salsalate intervention in Goto-Kakizaki rats.
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.
authors: Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York, Buffalo, NY 14260, USA.
authors: Yanguang
authors: Y
authors: Cao
authors: Debra C
authors: DC
authors: Dubois
authors: Hao
authors: H
authors: Sun
authors: Richard R
authors: RR
authors: Almon
authors: William J
authors: WJ
authors: Jusko
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001786:Blood Glucose / Q000032:analysis; D001835:Body Weight; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D018450:Disease Progression; D008297:Male; D008954:Models, Biological; D011897:Random Allocation; D051381:Rats; D011921:Rats, Inbred WKY; D012459:Salicylates / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D012980:Sodium Salicylate / Q000097:blood / Q000493:pharmacokinetics; D012984:Software
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D001786:Blood Glucose; D012459:Salicylates; C014182:salicylsalicylic acid; D012980:Sodium Salicylate