PMID- 27245226
OWN - NLM
STAT- MEDLINE
DCOM- 20170120
LR  - 20190815
IS  - 1550-7416 (Electronic)
IS  - 1550-7416 (Linking)
VI  - 18
IP  - 5
DP  - 2016 Sep
TI  - Modeling the Disease Progression from Healthy to Overt Diabetes in ZDSD Rats.
PG  - 1203-1212
LID - 10.1208/s12248-016-9931-0 [doi]
AB  - 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.
FAU - Choy, Steve
AU  - Choy S
AD  - Department of Pharmaceutical Biosciences, Uppsala University, PO Box 591, 751 24, 
      Uppsala, Sweden. steve.choy@farmbio.uu.se.
FAU - de Winter, Willem
AU  - de Winter W
AD  - Janssen Prevention Center, Janssen Research and Development, Leiden, The 
      Netherlands.
FAU - Karlsson, Mats O
AU  - Karlsson MO
AD  - Department of Pharmaceutical Biosciences, Uppsala University, PO Box 591, 751 24, 
      Uppsala, Sweden.
FAU - Kjellsson, Maria C
AU  - Kjellsson MC
AD  - Department of Pharmaceutical Biosciences, Uppsala University, PO Box 591, 751 24, 
      Uppsala, Sweden.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20160531
PL  - United States
TA  - AAPS J
JT  - The AAPS journal
JID - 101223209
RN  - 0 (Blood Glucose)
RN  - 0 (Insulin)
SB  - IM
MH  - Animals
MH  - Blood Glucose/metabolism
MH  - Diabetes Mellitus, Type 2/*blood/*pathology
MH  - *Disease Models, Animal
MH  - *Disease Progression
MH  - Insulin/blood
MH  - Male
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Rats, Zucker
OTO - NOTNLM
OT  - ZDSD rats
OT  - disease progression
OT  - semi-mechanistic model
OT  - type 2 diabetes
OT  - weight
EDAT- 2016/06/02 06:00
MHDA- 2017/01/21 06:00
CRDT- 2016/06/02 06:00
PHST- 2016/01/21 00:00 [received]
PHST- 2016/05/06 00:00 [accepted]
PHST- 2016/06/02 06:00 [entrez]
PHST- 2016/06/02 06:00 [pubmed]
PHST- 2017/01/21 06:00 [medline]
AID - 10.1208/s12248-016-9931-0 [pii]
AID - 10.1208/s12248-016-9931-0 [doi]
PST - ppublish
SO  - AAPS J. 2016 Sep;18(5):1203-1212. doi: 10.1208/s12248-016-9931-0. Epub 2016 May 
      31.