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Exploring the insul...
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Skrtic, Stanko,1970Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för invärtesmedicin och klinisk nutrition,Institute of Medicine, Department of Internal Medicine and Clinical Nutrition
(author)
Exploring the insulin secretory properties of the PGD(2)-GPR44/DP2 axis in vitro and in a randomized phase-1 trial of type 2 diabetes patients
- Article/chapterEnglish2018
Publisher, publication year, extent ...
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2018-12-17
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Public Library of Science (PLoS),2018
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LIBRIS-ID:oai:gup.ub.gu.se/276602
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https://gup.ub.gu.se/publication/276602URI
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https://doi.org/10.1371/journal.pone.0208998DOI
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Aims/Hypothesis GPR44 (DP2, PTGDR2, CRTh2) is the receptor for the pro-inflammatory mediator prosta-glandin D-2 (PGD(2)) and it is enriched in human islets. In rodent islets, PGD(2) is produced in response to glucose, suggesting that the PGD(2)-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. We determined the drive on PGD(2) secretion by glucose and IL-1 beta, 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 PGD(2) tone, we performed a proof-of-mechanism study in 20 T2DM patients (average 54 years, HbA1c 9.4%, BMI 31.6 kg/m(2)). 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 PGD(2) pathway biomarkers were performed. We found (1) that PGD(2) is produced in human islet in response to high glucose or IL-1 beta, but likely by stellate cells rather than endocrine cells; (2) that PGD(2) 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. Pharmacological inhibition of the PGD(2)-GPR44/DP2 axis has no major impact on the modulation of acute insulin secretion in T2DM patients.
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Tyrberg, B.
(author)
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Broberg, M.
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Ericsson, H.
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Schnecke, V.
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Kjaer, M.
(author)
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Hompesch, M.
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Andersson, E. M.
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Ryberg, E.
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Aivazidis, A.
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Huldt, C. W.
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Lofgren, L.
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Morrow, L.
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Parkinson, J.
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Ryden-Bergsten, T.
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Watkins, E.
(author)
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Winzell, M. S.
(author)
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Göteborgs universitetInstitutionen för medicin, avdelningen för invärtesmedicin och klinisk nutrition
(creator_code:org_t)
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In:PLoS ONE: Public Library of Science (PLoS)13:121932-6203
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Skrtic, Stanko, ...
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Tyrberg, B.
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Broberg, M.
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Ericsson, H.
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Schnecke, V.
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Kjaer, M.
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Hompesch, M.
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Andersson, E. M.
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Ryberg, E.
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Aivazidis, A.
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Huldt, C. W.
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Lofgren, L.
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Morrow, L.
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Parkinson, J.
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Ryden-Bergsten, ...
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Watkins, E.
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Winzell, M. S.
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