PMID- 23904152
OWN - NLM
STAT- MEDLINE
DCOM- 20140508
LR  - 20211021
IS  - 1550-7416 (Electronic)
IS  - 1550-7416 (Linking)
VI  - 15
IP  - 4
DP  - 2013 Oct
TI  - Population pharmacodynamic modeling of hyperglycemic clamp and meal tolerance 
      tests in patients with type 2 diabetes mellitus.
PG  - 1051-63
LID - 10.1208/s12248-013-9512-4 [doi]
AB  - In this study, glucose and insulin concentration-time profiles in subjects with 
      type 2 diabetes mellitus (T2DM) under meal tolerance test (MTT) and hyperglycemic 
      clamp (HGC) conditions were co-modeled simultaneously. Blood glucose and insulin 
      concentrations were obtained from 20 subjects enrolled in a double-blind, 
      placebo-controlled, randomized, two-way crossover study. Patients were treated 
      with palosuran or placebo twice daily for 4 weeks and then switched to the 
      alternative treatment after a 4-week washout period. The MTT and HGC tests were 
      performed 1 h after drug administration on days 28 and 29 of each treatment 
      period. Population data analysis was performed using NONMEM. The HGC model 
      incorporates insulin-dependent glucose clearance and glucose-induced insulin 
      secretion. This model was extended for the MTT, in which glucose absorption was 
      described using a transit compartment with a mean transit time of 62.5 min. The 
      incretin effect (insulin secretion triggered by oral glucose intake) was also 
      included, but palosuran did not influence insulin secretion or sensitivity. 
      Glucose clearance was 0.164 L/min with intersubject and interoccasion variability 
      of 9.57% and 31.8%. Insulin-dependent glucose clearance for the HGC was about 
      3-fold greater than for the MTT (0.0111 vs. 0.00425 L/min/[mU/L]). The maximal 
      incretin effect was estimated to enhance insulin secretion 2-fold. The lack of 
      palosuran effect coupled with a population-based analysis provided quantitative 
      insights into the variability of glucose and insulin regulation in patients with 
      T2DM following multiple glucose tolerance tests. Application of these models may 
      also prove useful in antihyperglycemic drug development and assessing 
      glucose-insulin homeostasis.
FAU - Hong, Ying
AU  - Hong Y
AD  - Department of Pharmaceutical Sciences, University at Buffalo, SUNY, 431 Kapoor 
      Hall, Buffalo, New York, 14214, USA.
FAU - Dingemanse, Jasper
AU  - Dingemanse J
FAU - Sidharta, Patricia
AU  - Sidharta P
FAU - Mager, Donald E
AU  - Mager DE
LA  - eng
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20130801
PL  - United States
TA  - AAPS J
JT  - The AAPS journal
JID - 101223209
RN  - 0 (Blood Glucose)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Blood Glucose/*metabolism
MH  - Cross-Over Studies
MH  - Diabetes Mellitus, Type 2/*blood/diagnosis
MH  - Double-Blind Method
MH  - Fasting/*blood
MH  - Female
MH  - Glucose Clamp Technique/*methods
MH  - Humans
MH  - Hyperglycemia/*blood/diagnosis
MH  - Male
MH  - Middle Aged
MH  - *Models, Biological
PMC - PMC3787242
EDAT- 2013/08/02 06:00
MHDA- 2014/05/09 06:00
PMCR- 2014/08/01
CRDT- 2013/08/02 06:00
PHST- 2013/04/02 00:00 [received]
PHST- 2013/07/08 00:00 [accepted]
PHST- 2013/08/02 06:00 [entrez]
PHST- 2013/08/02 06:00 [pubmed]
PHST- 2014/05/09 06:00 [medline]
PHST- 2014/08/01 00:00 [pmc-release]
AID - 9512 [pii]
AID - 10.1208/s12248-013-9512-4 [doi]
PST - ppublish
SO  - AAPS J. 2013 Oct;15(4):1051-63. doi: 10.1208/s12248-013-9512-4. Epub 2013 Aug 1.