PMID- 20484615
OWN - NLM
STAT- MEDLINE
DCOM- 20101108
LR  - 20141120
IS  - 1552-4604 (Electronic)
IS  - 0091-2700 (Linking)
VI  - 50
IP  - 8
DP  - 2010 Aug
TI  - A model for glucose, insulin, and beta-cell dynamics in subjects with insulin 
      resistance and patients with type 2 diabetes.
PG  - 861-72
LID - 10.1177/0091270009349711 [doi]
AB  - Type 2 diabetes mellitus (T2DM) is a progressive, metabolic disorder 
      characterized by reduced insulin sensitivity and loss of beta-cell mass (BCM), 
      resulting in hyperglycemia. Population pharmacokinetic-pharmacodynamic (PKPD) 
      modeling is a valuable method to gain insight into disease and drug action. A 
      semi-mechanistic PKPD model incorporating fasting plasma glucose (FPG), fasting 
      insulin, insulin sensitivity, and BCM in patients at various disease stages was 
      developed. Data from 3 clinical trials (phase II/III) with a peroxisome 
      proliferator-activated receptor agonist, tesaglitazar, were used to develop the 
      model. In this, a modeling framework proposed by Topp et al was expanded to 
      incorporate the effects of treatment and impact of disease, as well as 
      variability between subjects. The model accurately described FPG and fasting 
      insulin data over time. The model included a strong relation between insulin 
      clearance and insulin sensitivity, predicted 40% to 60% lower BCM in T2DM 
      patients, and realistic improvements of BCM and insulin sensitivity with 
      treatment. The treatment response on insulin sensitivity occurs within the first 
      weeks, whereas the positive effects on BCM arise over several months. The 
      semi-mechanistic PKPD model well described the heterogeneous populations, ranging 
      from nondiabetic, insulin-resistant subjects to long-term treated T2DM patients. 
      This model also allows incorporation of clinical-experimental studies and actual 
      observations of BCM.
FAU - Ribbing, Jakob
AU  - Ribbing J
AD  - Pharmacometrics, Clinical Pharmacology, Sandwich Laboratories, IPC 096, Pfizer 
      Ltd, Sandwich, Kent, CT13 9NJ, United Kingdom. Jakob.Ribbing@pfizer.com
FAU - Hamren, Bengt
AU  - Hamren B
FAU - Svensson, Maria K
AU  - Svensson MK
FAU - Karlsson, Mats O
AU  - Karlsson MO
LA  - eng
PT  - Journal Article
DEP - 20100519
PL  - England
TA  - J Clin Pharmacol
JT  - Journal of clinical pharmacology
JID - 0366372
RN  - 0 (Alkanesulfonates)
RN  - 0 (Blood Glucose)
RN  - 0 (Hypoglycemic Agents)
RN  - 0 (Insulin)
RN  - 0 (Peroxisome Proliferator-Activated Receptors)
RN  - 0 (Phenylpropionates)
RN  - 6734037O3L (tesaglitazar)
SB  - IM
MH  - Alkanesulfonates/pharmacology
MH  - Blood Glucose/*metabolism
MH  - Clinical Trials, Phase II as Topic
MH  - Clinical Trials, Phase III as Topic
MH  - Diabetes Mellitus, Type 2/*physiopathology
MH  - Fasting/blood
MH  - Humans
MH  - Hypoglycemic Agents/pharmacology
MH  - Insulin/*metabolism
MH  - Insulin Resistance/*physiology
MH  - Insulin-Secreting Cells/drug effects/*metabolism
MH  - *Models, Biological
MH  - Peroxisome Proliferator-Activated Receptors/agonists
MH  - Phenylpropionates/pharmacology
MH  - Predictive Value of Tests
MH  - Time Factors
EDAT- 2010/05/21 06:00
MHDA- 2010/11/09 06:00
CRDT- 2010/05/21 06:00
PHST- 2010/05/21 06:00 [entrez]
PHST- 2010/05/21 06:00 [pubmed]
PHST- 2010/11/09 06:00 [medline]
AID - 0091270009349711 [pii]
AID - 10.1177/0091270009349711 [doi]
PST - ppublish
SO  - J Clin Pharmacol. 2010 Aug;50(8):861-72. doi: 10.1177/0091270009349711. Epub 2010 
      May 19.