Cardiovascular side-effects and insulin secretion after intravenous administration of radiolabeled Exendin-4 in pigs

Rydén, Anneli; Nyman, Görel; Nalin, Lovisa; Andréasson, Susanne; Korsgren, Olle; Eriksson, Olof; Jensen-Waern, Marianne

doi:10.1016/j.nucmedbio.2016.04.002

Cited by 11 publications

(8 citation statements)

References 27 publications

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“…10 Furthermore, when administering high doses of exendin-4 intravenously to pigs, severe tachycardia >200 bpm develops. 35 Although exendin-4 increases heart rate in other species such as non-human primates, the tachycardia is not as severe. 35 Pigs might not be as well adapted to high plasma concentrations of GLP-1 as other species.…”

Section: Discussionmentioning

confidence: 99%

“…35 Although exendin-4 increases heart rate in other species such as non-human primates, the tachycardia is not as severe. 35 Pigs might not be as well adapted to high plasma concentrations of GLP-1 as other species. While pigs and humans share many physiological characteristics, 12 and there are several advantages of using animal models in situations where experiments cannot be carried out in humans, differences in GLP-1 regulation and secretion must be kept in mind when using pigs as animal models.…”

Section: Discussionmentioning

confidence: 99%

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Exploring the GLP-1–GLP-1R axis in porcine pancreas and gastrointestinal tract in vivo by ex vivo autoradiography

Manell

Puuvuori

Svensson

et al. 2021

BMJ Open Diab Res Care

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IntroductionGlucagon-like peptide-1 (GLP-1) increases insulin secretion from pancreatic beta-cells and GLP-1 receptor (GLP-1R) agonists are widely used as treatment for type 2 diabetes mellitus. Studying occupancy of the GLP-1R in various tissues is challenging due to lack of quantitative, repeatable assessments of GLP-1R density. The present study aimed to describe the quantitative distribution of GLP-1Rs and occupancy by endogenous GLP-1 during oral glucose tolerance test (OGTT) in pigs, a species that is used in biomedical research to model humans.Research design and methodsGLP-1R distribution and occupancy were measured in pancreas and gastrointestinal tract by ex vivo autoradiography using the GLP-1R-specific radioligand 177Lu-exendin-4 in two groups of pigs, control or bottle-fed an oral glucose load. Positron emission tomography (PET) data from pigs injected with 68Ga-exendin-4 in a previous study were used to retrieve data on biodistribution of GLP-1R in the gastrointestinal tract.ResultsHigh homogenous uptake of 177Lu-exendin-4 was found in pancreas, and even higher uptake in areas of duodenum. Low uptake of 177Lu-exendin-4 was found in stomach, jejunum, ileum and colon. During OGTT, there was no increase in plasma GLP-1 concentrations and occupancy of GLP-1Rs was low. The ex vivo autoradiography results were highly consistent with to the biodistribution of 68Ga-exendin-4 in pigs scanned by PET.ConclusionWe identified areas with similarities as well as important differences regarding GLP-1R distribution and occupancy in pigs compared with humans. First, there was strong ligand binding in the exocrine pancreas in islets. Second, GLP-1 secretion during OGTT is minimal and GLP-1 might not be an important incretin in pigs under physiological conditions. These findings offer new insights on the relevance of porcine diabetes models.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Exploring the GLP-1–GLP-1R axis in porcine pancreas and gastrointestinal tract in vivo by ex vivo autoradiography

Manell

Puuvuori

Svensson

et al. 2021

BMJ Open Diab Res Care

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“…Thus, the pancreatic distribution of GLP-1R seems to differ radically in pigs compared to rats, with more expression in the exocrine pancreas. Interestingly, the pigs experienced dose dependently increased heart rate after administration of [ 68 Ga]Ga-DO3A-VS-Cys 40 -exendin-4 96, 97 to a degree which usually not seen in other species. Strong pancreatic binding of [ 68 Ga]Ga-DO3A-VS-Cys 40 -exendin-4 was also observed in cynomolgus monkeys (NHP).…”

Section: Imaging Agents: Chemistry and Pre-clinical Evaluationmentioning

confidence: 91%

Advances in GLP-1 receptor targeting radiolabeled agent development and prospective of theranostics

Velikyan

Eriksson

2020

Theranostics

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In the light of theranostics/radiotheranostics and prospective of personalized medicine in diabetes and oncology, this review presents prior and current advances in the development of radiolabeled imaging and radiotherapeutic exendin-based agents targeting glucagon-like peptide-1 receptor. The review covers chemistry, preclinical, and clinical evaluation. Such critical aspects as structure-activity-relationship, stability, physiological potency, kidney uptake, and dosimetry are discussed.

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“…Anaesthesia was induced in the pigs' home pens with tiletamine-zolazepam mixed with medetomidine intramuscularly (IM). 21 Pre-operatively, buprenorphine was given at a dose of 0.01 mg/kg BW IM and bensylpenicillinprokain (Penovet Õ vet. 300 mg/mL, Beohringer Ingelheim, Ingelheim, Germany) at 20 mg/kg BW IM.…”

Section: Anaesthesia and Catheterisationmentioning

confidence: 99%

Nursing and training of pigs used in renal transplantation studies

et al. 2019

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The pig is commonly used in renal transplantation studies since the porcine kidney resembles the human kidney. To meet the requirements of intense caretaking and examination without stress, a 2-week socialisation and training programme was developed. Conventional cross-breed pigs ( n = 36) with high health status were trained for 15 min/day in a four-step training programme before kidney transplantation. The systematic training resulted in calm animals, which allowed for ultrasound examination, blood sampling and urine sampling without restraint. When a 2-methacryloyloxyethyl phosphorylcholine polymer-coated jugular catheter introduced via the auricular vein was used for post-operative blood sampling, clotting was avoided. To assess renal function, urinary output was observed and creatinine and cystatin C were measured; the latter was not found to be useful in recently transplanted pigs. The results presented contribute to the 3Rs (refine, reduce, replace).

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Cardiovascular side-effects and insulin secretion after intravenous administration of radiolabeled Exendin-4 in pigs

Cited by 11 publications

References 27 publications

Exploring the GLP-1–GLP-1R axis in porcine pancreas and gastrointestinal tract in vivo by ex vivo autoradiography

Exploring the GLP-1–GLP-1R axis in porcine pancreas and gastrointestinal tract in vivo by ex vivo autoradiography

Advances in GLP-1 receptor targeting radiolabeled agent development and prospective of theranostics

Nursing and training of pigs used in renal transplantation studies

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