title: Modeling the Disease Progression from Healthy to Overt Diabetes in ZDSD Rats.
abstract: Studying the critical transitional phase between healthy to overtly diabetic in type 2 diabetes mellitus (T2DM) is of interest, but acquiring such clinical data is impractical due to ethical concerns and would require a long study duration. A population model using Zucker diabetic Sprague-Dawley (ZDSD) rats was developed to describe this transition through altering insulin sensitivity (IS, %) as a result of accumulating excess body weight and β-cell function (BCF, %) to affect glucose-insulin homeostasis. Body weight, fasting plasma glucose (FPG), and fasting serum insulin (FSI) were collected biweekly over 24 weeks from ZDSD rats (n = 23) starting at age 7 weeks. A semi-mechanistic model previously developed with clinical data was adapted to rat data with BCF and IS estimated relative to humans. Non-linear mixed-effect model estimation was performed using NONMEM. Baseline IS and BCF were 41% compared to healthy humans. BCF was described with a non-linear rise which peaked at 14 weeks before gradually declining to a negligible level. A component for excess growth reflecting obesity was used to affect IS, and a glucose-dependent renal effect exerted a two- to sixfold increase on the elimination of glucose. A glucose-dependent weight loss effect towards the end of experiment was implemented. A semi-mechanistic model to describe the dynamics of glucose and insulin was successfully developed for a rat population, transitioning from healthy to advanced diabetes. It is also shown that weight loss can be modeled to mimic the glucotoxicity phenomenon seen in advanced hyperglycemia.
authors.affiliation: Department of Pharmaceutical Biosciences, Uppsala University, PO Box 591, 751 24, Uppsala, Sweden. steve.choy@farmbio.uu.se.
authors.forename: Steve
authors.initials: S
authors.lastname: Choy
authors.affiliation: Janssen Prevention Center, Janssen Research and Development, Leiden, The Netherlands.
authors.forename: Willem
authors.initials: W
authors.lastname: de Winter
authors.affiliation: Department of Pharmaceutical Biosciences, Uppsala University, PO Box 591, 751 24, Uppsala, Sweden.
authors.forename: Mats O
authors.initials: MO
authors.lastname: Karlsson
authors.affiliation: Department of Pharmaceutical Biosciences, Uppsala University, PO Box 591, 751 24, Uppsala, Sweden.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Kjellsson
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000473:pathology*; D004195:Disease Models, Animal; D018450:Disease Progression; D007328:Insulin / Q000097:blood; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker
chemical_list: D001786:Blood Glucose; D007328:Insulin
keywords: ZDSD rats; disease progression; semi-mechanistic model; type 2 diabetes; weight