PMID- 30557325
OWN - NLM
STAT- MEDLINE
DCOM- 20190510
LR  - 20200309
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 13
IP  - 12
DP  - 2018
TI  - Exploring the insulin secretory properties of the PGD2-GPR44/DP2 axis in vitro 
      and in a randomized phase-1 trial of type 2 diabetes patients.
PG  - e0208998
LID - 10.1371/journal.pone.0208998 [doi]
LID - e0208998
AB  - AIMS/HYPOTHESIS: GPR44 (DP2, PTGDR2, CRTh2) is the receptor for the 
      pro-inflammatory mediator prostaglandin D2 (PGD2) and it is enriched in human 
      islets. In rodent islets, PGD2 is produced in response to glucose, suggesting 
      that the PGD2-GPR44/DP2 axis may play a role in human islet function during 
      hyperglycemia. Consequently, the aim of this work was to elucidate the 
      insulinotropic role of GPR44 antagonism in vitro in human beta-cells and in type 
      2 diabetes (T2DM) patients. METHODS: We determined the drive on PGD2 secretion by 
      glucose and IL-1beta, as well as, the impact on insulin secretion by 
      pharmacological GPR44/DP2 antagonism (AZD1981) in human islets and beta-cells in 
      vitro. To test if metabolic control would be improved by antagonizing a 
      hyperglycemia-driven increased PGD2 tone, we performed a proof-of-mechanism study 
      in 20 T2DM patients (average 54 years, HbA1c 9.4%, BMI 31.6 kg/m2). The 
      randomized, double-blind, placebo-controlled cross-over study consisted of two 
      three-day treatment periods (AZD1981 or placebo) separated by a three-day 
      wash-out period. Mixed meal tolerance test (MMTT) and intravenous graded glucose 
      infusion (GGI) was performed at start and end of each treatment period. 
      Assessment of AZD1981 pharmacokinetics, glucose, insulin, C-peptide, glucagon, 
      GLP-1, and PGD2 pathway biomarkers were performed. RESULTS: We found (1) that 
      PGD2 is produced in human islet in response to high glucose or IL-1beta, but 
      likely by stellate cells rather than endocrine cells; (2) that PGD2 suppresses 
      both glucose and GLP-1 induced insulin secretion in vitro; and (3) that the 
      GPR44/DP2 antagonist (AZD1981) in human beta-cells normalizes insulin secretion. 
      However, AZD1981 had no impact on neither glucose nor incretin dependent insulin 
      secretion in humans (GGI AUC C-peptide 1-2h and MMTT AUC Glucose 0-4h LS mean 
      ratios vs placebo of 0.94 (80% CI of 0.90-0.98, p = 0.12) and 0.99 (90% CI of 
      0.94-1.05, p = 0.45), despite reaching the expected antagonist exposure. 
      CONCLUSION/INTERPRETATION: Pharmacological inhibition of the PGD2-GPR44/DP2 axis 
      has no major impact on the modulation of acute insulin secretion in T2DM 
      patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT02367066.
FAU - Skrtic, Stanko
AU  - Skrtic S
AUID- ORCID: 0000-0002-1950-5418
AD  - Cardiovascular, Renal and Metabolism, IMED Biotech Unit, AstraZeneca Gothenburg, 
      Molndal, Sweden.
AD  - Department of Endocrinology, Sahlgrenska University Hospital and Institute of 
      Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
FAU - Tyrberg, Bjorn
AU  - Tyrberg B
AUID- ORCID: 0000-0003-0976-1220
AD  - Cardiovascular, Renal and Metabolism, IMED Biotech Unit, AstraZeneca Gothenburg, 
      Molndal, Sweden.
FAU - Broberg, Malin
AU  - Broberg M
AD  - Cardiovascular, Renal and Metabolism, IMED Biotech Unit, AstraZeneca Gothenburg, 
      Molndal, Sweden.
FAU - Ericsson, Hans
AU  - Ericsson H
AD  - Cardiovascular, Renal and Metabolism, IMED Biotech Unit, AstraZeneca Gothenburg, 
      Molndal, Sweden.
FAU - Schnecke, Volker
AU  - Schnecke V
AD  - Cardiovascular, Renal and Metabolism, IMED Biotech Unit, AstraZeneca Gothenburg, 
      Molndal, Sweden.
FAU - Kjaer, Magnus
AU  - Kjaer M
AD  - Cardiovascular, Renal and Metabolism, IMED Biotech Unit, AstraZeneca Gothenburg, 
      Molndal, Sweden.
FAU - Hompesch, Marcus
AU  - Hompesch M
AD  - ProSciento Inc, Chula Vista, CA, United States of America.
FAU - Andersson, Eva-Marie
AU  - Andersson EM
AD  - Cardiovascular, Renal and Metabolism, IMED Biotech Unit, AstraZeneca Gothenburg, 
      Molndal, Sweden.
FAU - Ryberg, Erik
AU  - Ryberg E
AD  - Cardiovascular, Renal and Metabolism, IMED Biotech Unit, AstraZeneca Gothenburg, 
      Molndal, Sweden.
FAU - Aivazidis, Alexander
AU  - Aivazidis A
AD  - Cardiovascular, Renal and Metabolism, IMED Biotech Unit, AstraZeneca Gothenburg, 
      Molndal, Sweden.
FAU - Wennberg Huldt, Charlotte
AU  - Wennberg Huldt C
AD  - Cardiovascular, Renal and Metabolism, IMED Biotech Unit, AstraZeneca Gothenburg, 
      Molndal, Sweden.
FAU - Lofgren, Lars
AU  - Lofgren L
AD  - Cardiovascular, Renal and Metabolism, IMED Biotech Unit, AstraZeneca Gothenburg, 
      Molndal, Sweden.
FAU - Morrow, Linda
AU  - Morrow L
AD  - ProSciento Inc, Chula Vista, CA, United States of America.
FAU - Parkinson, Joanna
AU  - Parkinson J
AD  - Cardiovascular, Renal and Metabolism, IMED Biotech Unit, AstraZeneca Gothenburg, 
      Molndal, Sweden.
FAU - Ryden-Bergsten, Tina
AU  - Ryden-Bergsten T
AD  - Cardiovascular, Renal and Metabolism, IMED Biotech Unit, AstraZeneca Gothenburg, 
      Molndal, Sweden.
FAU - Watkins, Elaine
AU  - Watkins E
AUID- ORCID: 0000-0002-6901-6567
AD  - ProSciento Inc, Chula Vista, CA, United States of America.
FAU - Sorhede Winzell, Maria
AU  - Sorhede Winzell M
AUID- ORCID: 0000-0003-3125-4858
AD  - Cardiovascular, Renal and Metabolism, IMED Biotech Unit, AstraZeneca Gothenburg, 
      Molndal, Sweden.
LA  - eng
SI  - ClinicalTrials.gov/NCT02367066
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20181217
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Acetates)
RN  - 0 (Blood Glucose)
RN  - 0 (C-Peptide)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Indoles)
RN  - 0 (Insulin)
RN  - 0 (Receptors, Immunologic)
RN  - 0 (Receptors, Prostaglandin)
RN  - 0 (TFDP2 protein, human)
RN  - 0 (Transcription Factors)
RN  - 2AD53WQ2CX (AZD1981)
RN  - RXY07S6CZ2 (Prostaglandin D2)
RN  - XZF106QU24 (prostaglandin D2 receptor)
SB  - IM
MH  - Acetates/pharmacology/therapeutic use
MH  - Blood Glucose/metabolism
MH  - C-Peptide/blood
MH  - Cell Line
MH  - DNA-Binding Proteins/antagonists & inhibitors/*metabolism
MH  - Diabetes Mellitus, Type 2/drug therapy/*metabolism
MH  - Female
MH  - Gene Expression Regulation/drug effects
MH  - Humans
MH  - Indoles/pharmacology/therapeutic use
MH  - Insulin/*metabolism
MH  - Islets of Langerhans/drug effects/metabolism
MH  - Male
MH  - Middle Aged
MH  - Prostaglandin D2/antagonists & inhibitors/*metabolism
MH  - Receptors, Immunologic/antagonists & inhibitors/*metabolism
MH  - Receptors, Prostaglandin/antagonists & inhibitors/*metabolism
MH  - Transcription Factors/antagonists & inhibitors/*metabolism
PMC - PMC6296667
COIS- All authors apart from MH, LM and EW are employees or shareholders of AstraZeneca 
      AB. MH, LM, and EW received funding as a contract research organization by 
      AstraZeneca for the clinical study. EW is affiliated with ProSciento Inc. There 
      are no patents, products in development, or marketed products to declare. This 
      does not alter our adherence to all the PLOS ONE policies on sharing data and 
      materials.
EDAT- 2018/12/18 06:00
MHDA- 2019/05/11 06:00
PMCR- 2018/12/17
CRDT- 2018/12/18 06:00
PHST- 2018/04/09 00:00 [received]
PHST- 2018/10/08 00:00 [accepted]
PHST- 2018/12/18 06:00 [entrez]
PHST- 2018/12/18 06:00 [pubmed]
PHST- 2019/05/11 06:00 [medline]
PHST- 2018/12/17 00:00 [pmc-release]
AID - PONE-D-18-04138 [pii]
AID - 10.1371/journal.pone.0208998 [doi]
PST - epublish
SO  - PLoS One. 2018 Dec 17;13(12):e0208998. doi: 10.1371/journal.pone.0208998. 
      eCollection 2018.