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

被引:10
作者
Choy, Steve [1 ]
de Winter, Willem [2 ]
Karlsson, Mats O. [1 ]
Kjellsson, Maria C. [1 ]
机构
[1] Uppsala Univ, Dept Pharmaceut Biosci, POB 591, S-75124 Uppsala, Sweden
[2] Janssen Res & Dev, Janssen Prevent Ctr, Leiden, Netherlands
关键词
disease progression; semi-mechanistic model; type; 2; diabetes; weight; ZDSD rats; VISCERAL ADIPOSE-TISSUE; WEIGHT-LOSS; INSULIN; MELLITUS; GLUCOSE; EXCRETION; ADULTS;
D O I
10.1208/s12248-016-9931-0
中图分类号
R9 [药学];
学科分类号
100702 [药剂学];
摘要
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.
引用
收藏
页码:1203 / 1212
页数:10
相关论文
共 29 条
[1]
Insulin withdrawal-induced cell death in adult hippocampal neural stem cells as a model of autophagic cell death [J].
Baek, Seung-Hoon ;
Kim, Eun-Kyoung ;
Goudreau, John L. ;
Lookingland, Keith J. ;
Kim, Seong Who ;
Yu, Seong-Woon .
AUTOPHAGY, 2009, 5 (02) :277-279
[2]
Beal SS, 1989, NONMEM User's Guides
[3]
Quantifying the duration of pre-diabetes [J].
Bertram, Melanie Y. ;
Vos, Theo .
AUSTRALIAN AND NEW ZEALAND JOURNAL OF PUBLIC HEALTH, 2010, 34 (03) :311-314
[4]
Brody S., 1945, Bioenergetics and growth with special reference to the efficiency complex in domestic animals, P37
[5]
A rat-human scale-up procedure for the endocrine system [J].
Campetelli, German ;
Lombarte, Mercedes ;
Biset, Hernan ;
Rigalli, Alfredo ;
Basualdo, Marta S. .
COMPUTERS & CHEMICAL ENGINEERING, 2014, 71 :512-520
[6]
Protein metabolism in insulin-dependent diabetes mellitus [J].
Charlton, M ;
Nair, KS .
JOURNAL OF NUTRITION, 1998, 128 (02) :323S-327S
[7]
Weight-HbA1c-Insulin-Glucose Model for Describing Disease Progression of Type 2 Diabetes [J].
Choy, S. ;
Kjellsson, M. C. ;
Karlsson, M. O. ;
de Winter, W. .
CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY, 2016, 5 (01) :11-19
[8]
A mechanism-based disease progression model for comparison of long-term effects of pioglitazone, metformin and gliclazide on disease processes underlying type 2 diabetes mellitus [J].
de Winter, Willem ;
DeJongh, Joost ;
Post, Teun ;
Ploeger, Bart ;
Urquhart, Richard ;
Moules, Ian ;
Eckland, David ;
Danhof, Meindert .
JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS, 2006, 33 (03) :313-343
[9]
Dosne AG, POPULATION APPROACH
[10]
Eaton DM, 2013, FASEB J, V27