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Cardiovascular side-effects and insulin secretion after intravenous administration of radiolabeled Exendin-4 in pigs
Swedish Univ Agr Sci, Fac Vet Med & Anim Sci, Dept Clin Sci, POB 7054, S-75007 Uppsala, Sweden..
Swedish Univ Agr Sci, Fac Vet Med & Anim Sci, Dept Clin Sci, POB 7054, S-75007 Uppsala, Sweden..
Swedish Univ Agr Sci, Fac Vet Med & Anim Sci, Dept Clin Sci, POB 7054, S-75007 Uppsala, Sweden..
Swedish Univ Agr Sci, Fac Vet Med & Anim Sci, Dept Clin Sci, POB 7054, S-75007 Uppsala, Sweden..
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2016 (Engelska)Ingår i: Nuclear Medicine and Biology, ISSN 0969-8051, E-ISSN 1872-9614, Vol. 43, nr 7, s. 397-402Artikel i tidskrift (Refereegranskat) Published
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Abstract [en]

Introduction: Radiolabeled Exendin-4, a synthetic glucagon-like peptide-1 (GLP-1) analog, is used as a tracer for diagnostic purposes of beta-cells and in experimental animal research. Exendin-4 can be radiolabeled with Ga-68, I-111 n or (99)mTc and used for positron emission tomography (PET) and single-photon emission computed tomography (SPECT) imaging to diagnose insulinomas, visualization of pancreatic beta-cell mass and transplanted Islets of Langerhans. In humans, Exendin-4 is widely used as a therapeutic agent for treatment of type 2 diabetes (T2D). The compound, which is administered subcutaneously (SC) may cause nausea, vomiting and a minor increase in the heart rate (HR). However, possible side-effects on cardiovascular functions after intravenous (IV) administration have not been reported. This study describes the Exendin-4 dose at which cardiovascular side-effects occur in pigs and cynomolgus monkeys. The IV effect of the tracer on insulin secretion is also investigated in pigs. Methods: Seven clinically healthy littermate pigs (40 days old) were used; three of them were made diabetic by streptozotocin (STZ). All pigs underwent PET imaging under general anesthesia to examine the glucagon-like peptide-1 receptor (GLP-1R) in beta-cells with radiolabeled Exendin-4. A baseline tracer dose IV [Ga-68]Exendin-4 (0.025 +/- 0.010 mu g/kg) followed by a competition dose IV [Ga-68]Exendin-4 (3.98 +/- 133 mu g/kg) 60 min later were administered. Blood samples were taken and analyzed for insulin secretion by using ELISA. Cardiovascular and respiratory variables were monitored throughout the experiment. Results: Immediately after administration of the high dose [Ga-68]Exendin-4 the HR rose from 122 14 to 227 +/- 40 bpm (p < 0.01) and from 100 +/- 5 to 181 +/- 13 bpm (p < 0.01) in healthy non -diabetic and diabetes-induced pigs, respectively. The tachycardia was observed for >2 h and one healthy non-diabetic pig suffered cardiac arrest 3 h after the IV [Ga-68]Exendin-4. Arrhythmia was detected by listening to the heart with a stethoscope up to 4 days after the [Ga-68]Exendin-4 injection. In all animals, no effect on the cardiovascular system was registered after the low dose of IV [Ga-68]Exendin-4. Insulin secretion increased (p < 0.05) when IV [Ga-68]Exendin-4 was given in dosages >= 0.14 mu g/kg. Conclusions: Intravenous administration of mu g/kg [Ga-68]Exendin-4 resulted in severe tachycardia and arrhythmias in healthy non -diabetic and diabetes-induced pigs, and the insulin secretion was stimulated in healthy non diabetic animals when >= 0.14 mu g/kg [Ga-68]Exendin-4 was given.

Ort, förlag, år, upplaga, sidor
2016. Vol. 43, nr 7, s. 397-402
Nyckelord [en]
Exenatide, Adverse-effects, Tachycardia, Arrhythmias, Swine, Imaging, PET, Monkeys
Nationell ämneskategori
Radiologi och bildbehandling
Identifikatorer
URN: urn:nbn:se:uu:diva-299855DOI: 10.1016/j.nucmedbio.2016.04.002ISI: 000378760500002PubMedID: 27179248OAI: oai:DiVA.org:uu-299855DiVA, id: diva2:950270
Forskningsfinansiär
Vetenskapsrådet, VR K2015-54X-12219-4BarndiabetesfondenDiabetesförbundetTillgänglig från: 2016-07-29 Skapad: 2016-07-28 Senast uppdaterad: 2017-11-28Bibliografiskt granskad

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Korsgren, OlleEriksson, Olof

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