PMID- 27679422
OWN - NLM
STAT- MEDLINE
DCOM- 20180105
LR  - 20221207
IS  - 1365-2125 (Electronic)
IS  - 0306-5251 (Print)
IS  - 0306-5251 (Linking)
VI  - 83
IP  - 3
DP  - 2017 Mar
TI  - The variability in beta-cell function in placebo-treated subjects with type 2 
      diabetes: application of the weight-HbA1c-insulin-glucose (WHIG) model.
PG  - 487-497
LID - 10.1111/bcp.13144 [doi]
AB  - AIM: The weight-glycosylated haemoglobin (HbA1C)-insulin-glucose (WHIG) model 
      describes the effects of changes in weight on insulin sensitivity (IS) in newly 
      diagnosed, obese subjects receiving placebo treatment. This model was applied to 
      a wider population of placebo-treated subjects, to investigate factors 
      influencing the variability in IS and beta-cell function. METHODS: The WHIG model 
      was applied to the WHIG dataset (Study 1) and two other placebo datasets (Studies 
      2 and 3). Studies 2 and 3 consisted of nonobese subjects and subjects with 
      advanced type 2 diabetes mellitus (T2DM). Body weight, fasting serum insulin 
      (FSI), fasting plasma glucose (FPG) and HbA1c were used for nonlinear 
      mixed-effects modelling (using NONMEM v7.2 software). Sources of interstudy 
      variability (ISV) and potential covariates (age, gender, diabetes duration, 
      ethnicity, compliance) were investigated. RESULTS: An ISV for baseline parameters 
      (body weight and beta-cell function) was required. The baseline beta-cell function was 
      significantly lower in subjects with advanced T2DM (median difference: Study 2: 
      15.6%, P < 0.001; Study 3: 22.7%, P < 0.001) than in subjects with newly 
      diagnosed T2DM (Study 1). A reduction in the estimated insulin secretory response 
      in subjects with advanced T2DM was observed but diabetes duration was not a 
      significant covariate. CONCLUSION: The WHIG model can be used to describe the 
      changes in weight, IS and beta-cell function in the diabetic population. IS remained 
      relatively stable between subjects but a large ISV in beta-cell function was 
      observed. There was a trend towards decreasing beta-cell responsiveness with 
      diabetes duration, and further studies, incorporating subjects with a longer 
      history of diabetes, are required.
CI  - (c) 2016 The British Pharmacological Society.
FAU - Duong, Janna K
AU  - Duong JK
AD  - Department of Medical Informatics, Erasmus Medical Centre, Rotterdam, the 
      Netherlands.
AD  - Leiden Academic Centre for Drug Research (LACDR), Division of Pharmacology, 
      Leiden University, Leiden, the Netherlands.
AD  - Faculty of Pharmacy, The University of Sydney, Sydney, NSW, Australia.
FAU - de Winter, Willem
AU  - de Winter W
AD  - Janssen Prevention Center, Leiden, the Netherlands.
FAU - Choy, Steve
AU  - Choy S
AD  - Department of Pharmaceutical Biosciences, Pharmacometrics Research Group, Uppsala 
      University, Uppsala, Sweden.
FAU - Plock, Nele
AU  - Plock N
AD  - Global Pharmacometrics, Takeda Pharmaceuticals International, Zurich and 
      Deerfield, Switzerland and USA.
FAU - Naik, Himanshu
AU  - Naik H
AD  - Global Pharmacometrics, Takeda Pharmaceuticals International, Zurich and 
      Deerfield, Switzerland and USA.
AD  - Quantitative Pharmacology, Biogen, Cambridge, MA, USA.
FAU - Krauwinkel, Walter
AU  - Krauwinkel W
AD  - Global Clinical Pharmacology and Exploratory Development, Astellas Pharma Europe 
      BV, Leiden, the Netherlands.
FAU - Visser, Sandra A G
AU  - Visser SA
AD  - Early Stage Quantitative Pharmacology & Pharmacometrics, Merck, Upper Gwynedd, 
      PA, USA.
FAU - Verhamme, Katia M
AU  - Verhamme KM
AD  - Department of Medical Informatics, Erasmus Medical Centre, Rotterdam, the 
      Netherlands.
FAU - Sturkenboom, Miriam C
AU  - Sturkenboom MC
AD  - Department of Medical Informatics, Erasmus Medical Centre, Rotterdam, the 
      Netherlands.
FAU - Stricker, B H
AU  - Stricker BH
AD  - Department of Epidemiology, Erasmus Medical Centre, Rotterdam, the Netherlands.
FAU - Danhof, Meindert
AU  - Danhof M
AD  - Leiden Academic Centre for Drug Research (LACDR), Division of Pharmacology, 
      Leiden University, Leiden, the Netherlands.
LA  - eng
PT  - Journal Article
PT  - Multicenter Study
PT  - Research Support, Non-U.S. Gov't
DEP - 20161117
PL  - England
TA  - Br J Clin Pharmacol
JT  - British journal of clinical pharmacology
JID - 7503323
RN  - 0 (Blood Glucose)
RN  - 0 (Glycated Hemoglobin A)
RN  - 0 (Insulin)
SB  - IM
MH  - *Blood Glucose
MH  - Body Weight/*physiology
MH  - Diabetes Mellitus, Type 2/blood/*physiopathology
MH  - Disease Progression
MH  - Fasting
MH  - Female
MH  - *Glycated Hemoglobin
MH  - Humans
MH  - Insulin/*blood
MH  - Insulin Resistance/*physiology
MH  - Insulin-Secreting Cells/*physiology
MH  - Male
MH  - Middle Aged
MH  - Models, Biological
MH  - Obesity/blood/physiopathology
MH  - Randomized Controlled Trials as Topic/statistics & numerical data
PMC - PMC5306484
OTO - NOTNLM
OT  - beta-cell function
OT  - disease progression
OT  - placebo treatment
OT  - semi-mechanistic modelling
OT  - type 2 diabetes mellitus
EDAT- 2016/09/30 06:00
MHDA- 2018/01/06 06:00
PMCR- 2018/03/01
CRDT- 2016/09/29 06:00
PHST- 2016/05/24 00:00 [received]
PHST- 2016/09/15 00:00 [revised]
PHST- 2016/09/25 00:00 [accepted]
PHST- 2016/09/30 06:00 [pubmed]
PHST- 2018/01/06 06:00 [medline]
PHST- 2016/09/29 06:00 [entrez]
PHST- 2018/03/01 00:00 [pmc-release]
AID - BCP13144 [pii]
AID - 10.1111/bcp.13144 [doi]
PST - ppublish
SO  - Br J Clin Pharmacol. 2017 Mar;83(3):487-497. doi: 10.1111/bcp.13144. Epub 2016 
      Nov 17.