Steve Choy (1), Willem de Winter (2), Mats O Karlsson (1), Maria C Kjellsson (1)
(1) Department of Pharmaceutical Biosciences, Uppsala University, Sweden, (2) Clinical Pharmacology, Johnson & Johnson Pharmaceutical Research and Development, Beerse, Belgium
Objectives: Type 2 diabetes (T2DM) is a disease exhibiting a gradual worsening of hyperglycemia, on the timescale of years. Studying the critical transitional phase from healthy to diabetic is of interest, but acquiring such data in humans is not practical due to ethical reasons and the long study duration required.
ZDSD rats, a strain of rats bred specifically to spontaneously develop metabolic syndrome and type 2 diabetic symptoms [1] has been used in a population model to describe the changes in insulin sensitivity (IS), beta-cell function (BCF) throughout different phases of diabetes and their effects on glucose and insulin.
Methods: Body weight (WT), fasting plasma glucose (FPG), and fasting serum insulin (FSI) were collected every 2 weeks for 24 weeks from ZDSD rats (n=23) starting from age 7 weeks. During these 24 weeks the rats’ insulin sensitivity is decreased as indicated by hyperinsulinemia with normoglycemia. Eventually the rats become overtly diabetic with hypoinsulinemia and hyperglycemia. The weight of the rats increases due to natural growth and excess growth owing to the strain’s propensity for fat storage and obesity. As the rats become hyperglycemic the weight decreases slightly. A semi-mechanistic model previously developed with human data [2] was adapted to rat data. Baseline IS and BCF were estimated according to the human homeostatic assessment model (HOMA) [3]. Non-linear mixed-effect model estimation was performed with NONMEM 7.3 [4] with first-order interaction.
Results: Baseline estimated IS and BCF were 39% and 41% of normal humans, respectively. Egrowth was best described with a stimulatory effect with a maximum of 1.8, gradually decreasing to 1. BCF was described with a non-linear rise until it reached a mean peak around 14 weeks, before it declined to a negligible level, leading to hypoinsulinemia and hyperglycemia. The FPG-dependent urine effect exerted a 2 to 6-fold increase on the Kout of FPG
Conclusions: A semi-mechanistic model was successfully developed for a rat population to describe insulin and glucose profiles adequately, transitioning from healthy to an advanced stage of diabetes. It is also shown that weight loss can be modeled to mimic “starvation in the midst of plenty” which is a phenomenon related to hypoinsulinemia and hyperglycemia.
References:
[1] Davidson EP, Coppey LJ, Holmes A, Lupachyk S, Dake BL, Oltman CL, et al. Characterization of diabetic neuropathy in the Zucker diabetic Sprague-Dawley rat: A new animal model for type 2 diabetes. Journal of Diabetes Research 2014, 2014.
[2] Choy S, Kjellsson M, Karlsson MO, de Winter W. Weight-HbA1c-Insulin-Glucose (WHIG) Model for long term disease progression of Type 2 Diabetes. Population Approach Group of Australia & New Zealand. 2013. (Oral presentation).
[3] Levy JC, Matthews DR, Hermans MP. Correct homeostasis model assessment (HOMA) evaluation uses the computer program [3]. Diabetes Care 1998, 21(12): 2191-2192.
[4] Beal SL, Sheiner LB, Boeckmann AJ, Bauer RJ. NONMEM User’s Guides. Ellicott City, MD, USA: Icon Development Solutions; 1989-2014.
Reference: PAGE 24 () Abstr 3547 [www.page-meeting.org/?abstract=3547]
Poster: Drug/Disease modeling - Endocrine