Top

European Journal of Nuclear Medicine and Molecular Imaging

Published in:

01-09-2014 | Original Article

Positron emission tomography imaging of the glucagon-like peptide-1 receptor in healthy and streptozotocin-induced diabetic pigs

Authors: Lovisa Nalin, Ram K. Selvaraju, Irina Velikyan, Marie Berglund, Susanne Andréasson, Anna Wikstrand, Anneli Rydén, Mark Lubberink, Fouad Kandeel, Görel Nyman, Olle Korsgren, Olof Eriksson, Marianne Jensen-Waern

Published in: European Journal of Nuclear Medicine and Molecular Imaging | Issue 9/2014

Abstract

Purpose

The glucagon-like peptide-1 receptor (GLP-1R) has been proposed as a target for molecular imaging of beta cells. The feasibility of non-invasive imaging and quantification of GLP-1R in pancreas using the positron emission tomography (PET) tracer [⁶⁸Ga]Ga-DO3A-VS-Cys⁴⁰-Exendin-4 in non-diabetic and streptozotocin (STZ)–induced diabetic pigs treated with insulin was investigated.

Methods

Non-diabetic (n = 4) and STZ-induced diabetic pigs (n = 3) from the same litter were examined. Development of diabetes was confirmed by blood glucose values, clinical examinations and insulin staining of pancreatic sections post mortem. Tissue perfusion in the pancreas and kidneys was evaluated by [¹⁵O]water PET/computed tomography (CT) scans. The in vivo receptor specificity of [⁶⁸Ga]Ga-DO3A-VS-Cys⁴⁰-Exendin-4 was assessed by administration of either tracer alone or by competition with 3–6.5 μg/kg of Exendin-4. Volume of distribution and occupancy in the pancreas were quantified with a single tissue compartment model.

Results

[¹⁵O]water PET/CT examinations showed reduced perfusion in the pancreas and kidneys in diabetic pigs. [⁶⁸Ga]Ga-DO3A-VS-Cys⁴⁰-Exendin-4 uptake in the pancreas of both non-diabetic and diabetic pigs was almost completely abolished by co-injection of unlabeled Exendin-4 peptide. [⁶⁸Ga]Ga-DO3A-VS-Cys⁴⁰-Exendin-4 uptake did not differ between non-diabetic and diabetic pigs. In all animals, administration of the tracer resulted in an immediate increase in the heart rate (HR).

Conclusion

Pancreatic uptake of [⁶⁸Ga]Ga-DO3A-VS-Cys⁴⁰-Exendin-4 was not reduced by destruction of beta cells in STZ-induced diabetic pigs.

Whiting DR, Guariguata L, Weil C, Shaw J. IDF diabetes atlas: global estimates of the prevalence of diabetes for 2011 and 2030. Diabetes Res Clin Pract. 2011;94:311–21.PubMedCrossRef

King H, Aubert RE, Herman WH. Global burden of diabetes, 1995–2025: prevalence, numerical estimates, and projections. Diabetes Care. 1998;21:1414–31.PubMedCrossRef

Amos AF, McCarty DJ, Zimmet P. The rising global burden of diabetes and its complications: estimates and projections to the year 2010. Diabet Med. 1997;14 Suppl 5:S1–85.PubMed

King H, Rewers M. Global estimates for prevalence of diabetes mellitus and impaired glucose tolerance in adults. WHO Ad Hoc Diabetes Reporting Group. Diabetes Care. 1993;16:157–77.PubMedCrossRef

Souza F, Freeby M, Hultman K, Simpson N, Herron A, Witkowsky P, et al. Current progress in non-invasive imaging of beta cell mass of the endocrine pancreas. Curr Med Chem. 2006;13:2761–73.PubMedCrossRef

Tornehave D, Kristensen P, Romer J, Knudsen LB, Heller RS. Expression of the GLP-1 receptor in mouse, rat, and human pancreas. J Histochem Cytochem. 2008;56:841–51.PubMedCentralPubMedCrossRef

Leech CA, Dzhura I, Chepurny OG, Kang G, Schwede F, Genieser HG, et al. Molecular physiology of glucagon-like peptide-1 insulin secretagogue action in pancreatic beta cells. Prog Biophys Mol Biol. 2011;107:236–47.PubMedCentralPubMedCrossRef

Meloni AR, DeYoung MB, Lowe C, Parkes DG. GLP-1 receptor activated insulin secretion from pancreatic beta-cells: mechanism and glucose dependence. Diabetes Obes Metab. 2013;15:15–27.PubMedCentralPubMedCrossRef

Vilsboll T, Agerso H, Krarup T, Holst JJ. Similar elimination rates of glucagon-like peptide-1 in obese type 2 diabetic patients and healthy subjects. J Clin Endocrinol Metab. 2003;88:220–4.PubMedCrossRef

10.

Briones M, Bajaj M. Exenatide: a GLP-1 receptor agonist as novel therapy for Type 2 diabetes mellitus. Expert Opin Pharmacother. 2006;7:1055–64.PubMedCrossRef

11.

Selvaraju RK, Velikyan I, Johansson L, Wu Z, Todorov I, Shively J, et al. In vivo imaging of the glucagonlike peptide 1 receptor in the pancreas with 68Ga-labeled DO3A-exendin-4. J Nucl Med. 2013;54:1458–63.PubMedCrossRef

12.

Jensen-Waern M, Andersson M, Kruse R, Nilsson B, Larsson R, Korsgren O, et al. Effects of streptozotocin-induced diabetes in domestic pigs with focus on the amino acid metabolism. Lab Anim. 2009;43:249–54.PubMedCrossRef

13.

Manell E, Rydén A, Hedenqvist P, Jacobson M, Jensen-Waern M. Insulin treatment of streptozotocin-induced diabetes re-establishes the patterns in carbohydrate, fat and amino acid metabolism in growing pigs. Lab Anim. 2014.

14.

Swindle MM, Smith AC. Comparative anatomy and physiology of the pig. Scand J Lab Anim Sci. 1998;25:11–21.

15.

Yamaguchi T, Mullen Y, Watanabe Y, Nomura Y, Cass D, Brunicardi C. Isolation and Function of Islets from Young-Adult Pig Pancreas. Transplant Proc. 1992;24:1010–2.PubMed

16.

Ambrisko TD, Hikasa Y, Sato K. Influence of medetomidine on stress-related neurohormonal and metabolic effects caused by butorphanol, fentanyl, and ketamine administration in dogs. Am J Vet Res. 2005;66:406–12.PubMedCrossRef

17.

Pfeiffer N, Ebner J, von Thaden A-K, Schuster T, Erhardt W, Baumgartner C. Cardiovascular effects of alfaxalone on hemodynamic function in pigs. Open Access Anim Physiol. 2013;2013:15–26.CrossRef

18.

van der Veldt AA, Hendrikse NH, Harms HJ, Comans EF, Postmus PE, Smit EF, et al. Quantitative parametric perfusion images using 15O-labeled water and a clinical PET/CT scanner: test-retest variability in lung cancer. J Nucl Med. 2010;51:1684–90.PubMedCrossRef

19.

Fehmann HC, Habener JF. Functional receptors for the insulinotropic hormone glucagon-like peptide-I(7–37) on a somatostatin secreting cell line. FEBS Lett. 1991;279:335–40.PubMedCrossRef

20.

Fehmann HC, Janssen M, Göke B. Interaction of glucagon-like peptide-I (GLP-I) and galanin in insulin (beta TC-1)- and somatostatin (RIN T3)-secreting cells and evidence that both peptides have no receptors on glucagon (INR1G9)-secreting cells. Acta Diabetol. 1995;32:176–81.PubMedCrossRef

21.

Heller RS, Kieffer TJ, Habener JF. Insulinotropic glucagon-like peptide I receptor expression in glucagon-producing alpha-cells of the rat endocrine pancreas. Diabetes. 1997;46:785–91.PubMedCrossRef

22.

Wild D, Wicki A, Mansi R, Béhé M, Keil B, Bernhardt P, et al. Exendin-4-based radiopharmaceuticals for glucagonlike peptide-1 receptor PET/CT and SPECT/CT. J Nucl Med. 2010;51:1059–67.PubMedCrossRef

23.

Eich T, Eriksson O, Sundin A, Estrada S, Brandhorst D, Brandhorst H, et al. Positron emission tomography: a real-time tool to quantify early islet engraftment in a preclinical large animal model. Transplantation. 2007;84:893–8.PubMedCrossRef

24.

Hildebrandt IJ, Su H, Weber WA. Anesthesia and other considerations for in vivo imaging of small animals. ILAR J. 2008;49:17–26.PubMedCrossRef

25.

Momosaki S, Hatano K, Kawasumi Y, Kato T, Hosoi R, Kobayashi K, et al. Rat-PET study without anesthesia: anesthetics modify the dopamine D1 receptor binding in rat brain. Synapse. 2004;54:207–13.PubMedCrossRef

26.

Nicholas TE, Jones ME, Johnson DW, Phillipou G. Metabolism of the steroid anaesthetic alphaxalone by the isolated perfused rat lung. J Steroid Biochem. 1981;14:45–51.PubMedCrossRef

27.

Liu IM, Chang CK, Juang SW, Kou DH, Tong YC, Cheng KC, et al. Role of hyperglycaemia in the pathogenesis of hypotension observed in type-1 diabetic rats. Int J Exp Pathol. 2008;89:292–300.PubMedCentralPubMedCrossRef

28.

Oliver JA, Clark L, Corletto F, Gould DJ. A comparison of anesthetic complications between diabetic and nondiabetic dogs undergoing phacoemulsification cataract surgery: a retrospective study. Vet Ophthalmol. 2010;13:244–50.PubMedCrossRef

29.

Oelze M, Knorr M, Schuhmacher S, Heeren T, Otto C, Schulz E, et al. Vascular dysfunction in streptozotocin-induced experimental diabetes strictly depends on insulin deficiency. J Vasc Res. 2011;48:275–84.PubMedCrossRef

30.

Barragan JM, Rodriguez RE, Blazquez E. Changes in arterial blood pressure and heart rate induced by glucagon-like peptide-1-(7–36) amide in rats. Am J Physiol. 1994;266:E459–66.PubMed

31.

Barragan JM, Rodriguez RE, Eng J, Blazquez E. Interactions of exendin-(9–39) with the effects of glucagon-like peptide-1-(7–36) amide and of exendin-4 on arterial blood pressure and heart rate in rats. Regul Pept. 1996;67:63–8.PubMedCrossRef

32.

Isbil-Buyukcoskun N, Gulec G. Effects of intracerebroventricularly injected glucagon-like peptide-1 on cardiovascular parameters; role of central cholinergic system and vasopressin. Regul Pept. 2004;118:33–8.PubMedCrossRef

33.

Yamamoto H, Lee CE, Marcus JN, Williams TD, Overton JM, Lopez ME, et al. Glucagon-like peptide-1 receptor stimulation increases blood pressure and heart rate and activates autonomic regulatory neurons. J Clin Invest. 2002;110:43–52.PubMedCentralPubMedCrossRef

34.

Edwards CM, Edwards AV, Bloom SR. Cardiovascular and pancreatic endocrine responses to glucagon-like peptide-1(7–36) amide in the conscious calf. Exp Physiol. 1997;82:709–16.PubMed

35.

Robinson LE, Holt TA, Rees K, Randeva HS, O’Hare JP. Effects of exenatide and liraglutide on heart rate, blood pressure and body weight: systematic review and meta-analysis. BMJ Open. 2013;3

36.

Gros R, You X, Baggio LL, Kabir MG, Sadi AM, Mungrue IN, et al. Cardiac function in mice lacking the glucagon-like peptide-1 receptor. Endocrinology. 2003;144:2242–52.PubMedCrossRef

37.

Orskov C, Poulsen SS, Moller M, Holst JJ. Glucagon-like peptide I receptors in the subfornical organ and the area postrema are accessible to circulating glucagon-like peptide I. Diabetes. 1996;45:832–5.PubMedCrossRef

Title: Positron emission tomography imaging of the glucagon-like peptide-1 receptor in healthy and streptozotocin-induced diabetic pigs
Authors: Lovisa Nalin
Ram K. Selvaraju
Irina Velikyan
Marie Berglund
Susanne Andréasson
Anna Wikstrand
Anneli Rydén
Mark Lubberink
Fouad Kandeel
Görel Nyman
Olle Korsgren
Olof Eriksson
Marianne Jensen-Waern
Publication date: 01-09-2014
Publisher: Springer Berlin Heidelberg
Published in: European Journal of Nuclear Medicine and Molecular Imaging / Issue 9/2014
Print ISSN: 1619-7070
Electronic ISSN: 1619-7089
DOI: https://doi.org/10.1007/s00259-014-2745-3

ACC 2024 Congress

Springer Medicine

Positron emission tomography imaging of the glucagon-like peptide-1 receptor in healthy and streptozotocin-induced diabetic pigs

Abstract

Purpose

Methods

Results

Conclusion

ACC 2024 Congress

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 9/2014

Examining recombinant human TSH primed 131I therapy protocol in patients with metastatic differentiated thyroid carcinoma: comparison with the traditional thyroid hormone withdrawal protocol

The value of 18F-FDG PET/CT in the management of malignant peripheral nerve sheath tumors

Relationship between quantitative cardiac neuronal imaging with 123I-meta-iodobenzylguanidine and hospitalization in patients with heart failure

Parametric imaging of 18F-fluoro-3-deoxy-3-l-fluorothymidine PET data to investigate tumour heterogeneity

Regional heterogeneity in cardiac sympathetic innervation in acute myocardial infarction: relationship with myocardial oedema on magnetic resonance

Preoperative PET/CT standardized FDG uptake values of pelvic lymph nodes as a significant prognostic factor in patients with endometrial cancer