Modeling the Disease Progression from Healthy to Overt Diabetes in ZDSD Rats View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2016-09

AUTHORS

Steve Choy, Willem de Winter, Mats O Karlsson, Maria C Kjellsson

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. More... »

PAGES

1203-1212

Identifiers

URI

http://scigraph.springernature.com/pub.10.1208/s12248-016-9931-0

DOI

http://dx.doi.org/10.1208/s12248-016-9931-0

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1040081095

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/27245226


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