Modeling the Disease Progression from Healthy to Overt Diabetes in ZDSD Rats
2016 (English)In: AAPS Journal, ISSN 1550-7416, E-ISSN 1550-7416, Vol. 18, no 5, 1203-1212 p.Article in journal (Refereed) Published
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 beta-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.
Place, publisher, year, edition, pages
2016. Vol. 18, no 5, 1203-1212 p.
disease progression, semi-mechanistic model, type 2 diabetes, weight, ZDSD rats
Pharmacology and Toxicology
IdentifiersURN: urn:nbn:se:uu:diva-304157DOI: 10.1208/s12248-016-9931-0ISI: 000382094200014PubMedID: 27245226OAI: oai:DiVA.org:uu-304157DiVA: diva2:1014918