Modelling the disease progression from healthy to overt diabetes in ZDSD rats
(English)In: AAPS Journal, ISSN 1550-7416, E-ISSN 1550-7416Article in journal (Other academic) Submitted
Introduction: 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 the long study duration required. ZDSD rats are a strain of rats bred specifically to spontaneously develop T2DM, and a population model using 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.
Methods and Materials: Body weight, fasting plasma glucose (FPG), and fasting serum insulin (FSI) were collected over 24 weeks from ZDSD rats (n=23) 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 7.3 with first-order interaction.
Results and Discussion: 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 FPG-dependent urine effect exerted a 2 to 6-fold increase on the elimination of FPG.
Conclusion: 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 “starvation in the midst of plenty” phenomenon seen in advanced hyperglycemia.
diabetes, disease progression, population model, rats, glucose, insulin, weight, insulin, glucose, Beta-cell function
Endocrinology and Diabetes
Research subject Pharmaceutical Science
IdentifiersURN: urn:nbn:se:uu:diva-272230OAI: oai:DiVA.org:uu-272230DiVA: diva2:893559