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Approaches for Imaging Islets: Recent Advances and Future Prospects

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Book cover The Islets of Langerhans

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 654))

Abstract

The establishment of improved technologies for imaging of the pancreas is a key element in addressing several aspects of diabetes pathogenesis. In this respect, the development of a protocol that allows for non-invasive scoring of human islets, or islet β-cells, is of particular importance. The development of such a technology would have profound impact on both clinical and experimental medicine, ranging from early diagnosis of diabetes to the evaluation of therapeutic regimes. Another important task is the development of modalities for high-resolution imaging of experimental animal models for diabetes. Rodent models for diabetes research have for decades been instrumental to the diabetes research community. The ability to image, and to accurately quantify, key players of diabetogenic processes with molecular specificity will be of great importance for elucidating mechanistic aspects of the disease. This chapter aims to overview current progress within these research areas.

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Abbreviations

BCM:

β-cell mass

BLI:

Bioluminescence imaging

BLT:

Bioluminescence tomography

CLSM:

Confocal laser scanning microscopy

CT:

Computed tomography

LSM:

Laser scanning microscopy

MBT:

Multispectral bioluminescence tomography

MPLSM:

Multiphoton laser scanning microscopy

MRI:

Magnetic resonance imaging

NMRI:

Nuclear magnetic resonance imaging

OCT:

Optical coherence tomography

OPT:

Optical projection tomography

PET:

Positron emission tomography

SPECT:

Single photon emission computed tomography

SPIM:

Selective plane illumination microscopy

SPIO:

Superparamagnetic iron oxide

T1D:

Type 1 diabetes

T2D:

Type 2 diabetes

TPLSM:

Two photon laser scanning microscopy

References

  1. Meier JJ, Bhushan A, Butler PC, The potential for stem cell therapy in diabetes. Pediatric Research 2006;59:65R–73R.

    Article  PubMed  Google Scholar 

  2. Alanentalo T, Asayesh A, Morrison H, Loren CE, Holmberg D, Sharpe J, Ahlgren U. Tomographic molecular imaging and 3D quantification within adult mouse organs. Nature Methods 2007;4:31–3.

    Article  PubMed  CAS  Google Scholar 

  3. Brelje TC, Scharp DW. Sorenson RL. Three-dimensional imaging of intact isolated islets of Langerhans with confocal microscopy. Diabetes 1989;38:808–14.

    Article  PubMed  CAS  Google Scholar 

  4. Brissova M, Fowler MJ, Nicholson WE, Chu A, Hirshberg B, Harlan DM, Powers AC. Assessment of human pancreatic islet architecture and composition by laser scanning confocal microscopy. Journal of Histochemistry & Cytochemistry 2005;53: 1087–97.

    Article  CAS  Google Scholar 

  5. Martinic MM, von Herrath MG. Real-time imaging of the pancreas during development of diabetes. Immunol Rev 2008;221:200–13.

    Article  PubMed  CAS  Google Scholar 

  6. Nyman LR, Wells KS, Head WS, McCaughey M, Ford E, Brissova M, Piston DW, Powers AC. Real-time, multidimensional in vivo imaging used to investigate blood flow in mouse pancreatic islets. J Clin Invest 2008;118;3790–7.

    Article  PubMed  Google Scholar 

  7. Speier S, Nyqvist D, Cabrera O, Yu J, Molano RD, Pileggi A, Moede T, Kohler M, Wilbertz J, Leibiger B. et al. Noninvasive in vivo imaging of pancreatic islet cell biology. Nat Med 2008a;14:574–8.

    Article  PubMed  CAS  Google Scholar 

  8. Speier S, Nyqvist D, Kohler M, Caicedo A, Leibiger IB, Berggren PO. Noninvasive high-resolution in vivo imaging of cell biology in the anterior chamber of the mouse eye. Nat Protoc 2008b;3:1278–86.

    Article  PubMed  CAS  Google Scholar 

  9. Sharpe J, Ahlgren U, Perry P, Hill B, Ross A, Hecksher-Sorensen J, Baldock R, Davidson D. Optical Projection Tomography as a Tool for 3D Microscopy and Gene Expression Studies. Science 2002;296:541–5.

    Article  PubMed  CAS  Google Scholar 

  10. Asayesh A, Sharpe J, Watson RP, Hecksher-Sorensen J, Hastie ND, Hill RE, Ahlgren U. Spleen versus pancreas: strict control of organ interrelationship revealed by analyses of Bapx1-/- mice. Genes Dev 2006;20:2208–13.

    Article  PubMed  CAS  Google Scholar 

  11. Hecksher-Sorensen J, Watson RP, Lettice LA, Serup P, Eley L, De Angelis C, Ahlgren U, Hill RE. The splanchnic mesodermal plate directs spleen and pancreatic laterality, and is regulated by Bapx1/Nkx3.2. Development 2004;131: 4665–75.

    Article  PubMed  CAS  Google Scholar 

  12. Alanentalo T, Loren CE, Larefalk Å, Sharpe J, Holmberg D, Ahlgren U. High-resolution three-dimensional imaging of islet-infiltrate interactions based on optical projection tomography assessments of the intact adult mouse pancreas. J Biom Opt 2008;13:054070:1–4.

    Google Scholar 

  13. Park S-Y, Bell GI. Noninvasive monitoring of changes in Pancreatic Beta-cell Mass by Bioluminescent Imaging in MIP-luc Mice. Horm Meta Res 2009;41:1–4.

    Article  Google Scholar 

  14. Park S-Y, Wang X, Chen Z, Powers AC, Magnuson MA, Head WS, Piston DW, Bell GI. Optical imaging of pancreatic beta cells in living mice expressing a mouse insulin I promoter-firefly luciferase transgene. Genesis: the Journal of Genetics & Development 2005;43:80–6.

    CAS  Google Scholar 

  15. Smith SJ, Zhang H, Clermont AO, Powers AC, Kaufman DB, Purchio AF, West DB. In vivo monitoring of pancreatic beta-cells in a transgenic mouse model. Molecular Imaging: Official Journal of the Society for Molecular Imaging 2006;5:65–75.

    Google Scholar 

  16. Chen X, Zhang X, Larson CS, Baker MS, Kaufman DB. In vivo bioluminescence imaging of transplanted islets and early detection of graft rejection. Transplantation 2006;81:1421–7.

    Article  PubMed  Google Scholar 

  17. Fowler M, Virostko J, Chen Z, Poffenberger G, Radhika A, Brissova M, Shiota M, Nicholson WE, Shi Y, Hirshberg B. et al. Assessment of pancreatic islet mass after islet transplantation using in vivo bioluminescence imaging. Transplantation 2005;79:768–76.

    Article  PubMed  Google Scholar 

  18. Lu Y, Dang H, Middleton B, Zhang Z, Washburn L, Campbell-Thompson M, Atkinson MA, Gambhir SS, Tian J, Kaufman DL. Bioluminescent monitoring of islet graft survival after transplantation. Molecular Therapy: the Journal of the American Society of Gene Therapy 2004;9:428–35.

    CAS  Google Scholar 

  19. Chan KM, Raikwar SP, Zavazava N. Strategies for differentiating embryonic stem cells (ESC) into insulin-producing cells and development of non-invasive imaging techniques using bioluminescence. Immunologic Research 2007;39:261–70.

    Article  PubMed  CAS  Google Scholar 

  20. Virostko J, Chen Z, Fowler M, Poffenberger G, Powers AC, Jansen ED. Factors influencing quantification of in vivo bioluminescence imaging: application to assessment of pancreatic islet transplants. Molecular Imaging: Official Journal of the Society for Molecular Imaging 2004;3: 333–42.

    Google Scholar 

  21. Wang G, Cong W, Shen H, Qian X, Henry M, Wang Y. Overview of bioluminescence tomography – a new molecular imaging modality. Front Biosci 2008;13: 1281–93.

    Article  PubMed  CAS  Google Scholar 

  22. Jirak D, Kriz J, Herynek V, Andersson B, Girman P, Burian M, Saudek F, Hajek M. MRI of transplanted pancreatic islets. Magn Reson Med 2004;52:1228–33.

    Article  PubMed  Google Scholar 

  23. Kriz J, Jirak D, Girman P, Berkova Z, Zacharovova K, Honsova E, Lodererova A, Hajek M, Saudek F. Magnetic resonance imaging of pancreatic islets in tolerance and rejection. Transplantation 2005;80:1596–603.

    Article  PubMed  Google Scholar 

  24. Evgenov NV, Medarova Z, Dai G, Bonner-Weir S, Moore A. In vivo imaging of islet transplantation. Nat Med 2006;12:144–8.

    Article  PubMed  CAS  Google Scholar 

  25. Toso C, Vallee JP, Morel P, Ris F, Demuylder-Mischler S, Lepetit-Coiffe M, Marangon N, Saudek F, James Shapiro AM, Bosco D. et al. Clinical magnetic resonance imaging of pancreatic islet grafts after iron nanoparticle labeling. Am J Transplant 2008;8:701–6.

    Article  PubMed  CAS  Google Scholar 

  26. Crich SG, Biancone L, Cantaluppi V, Duo D, Esposito G, Russo S, Camussi G, Aime S. Improved route for the visualization of stem cells labeled with a Gd-/Eu-chelate as dual (MRI and fluorescence) agent. Magn Reson Med 2004;51:938–44.

    Article  PubMed  CAS  Google Scholar 

  27. Biancone L, Crich SG, Cantaluppi V, Romanazzi GM, Russo S, Scalabrino E, Esposito G, Figliolini F, Beltramo S, Perin PC. et al. Magnetic resonance imaging of gadolinium-labeled pancreatic islets for experimental transplantation. NMR Biomed 2007;20:40–8.

    Article  PubMed  Google Scholar 

  28. Zheng Q, Dai H, Merritt ME, Malloy C, Pan CY, Li WH. A new class of macrocyclic lanthanide complexes for cell labeling and magnetic resonance imaging applications. J Am Chem Soc 2005;127:16178–88.

    Article  PubMed  CAS  Google Scholar 

  29. Ahrens ET, Flores R, Xu H, Morel PA. In vivo imaging platform for tracking immunotherapeutic cells. Nat Biotechnol 2005;23:983–7.

    Article  PubMed  CAS  Google Scholar 

  30. Srinivas M, Morel PA, Ernst LA, Laidlaw DH, Ahrens ET. Fluorine-19 MRI for visualization and quantification of cell migration in a diabetes model. Magn Reson Med 2007;58:725–34.

    Article  PubMed  CAS  Google Scholar 

  31. Antkowiak PF, Tersey SA, Carter JD, Vandsburger MH, Nadler JL, Epstein FH, Mirmira RG. Noninvasive assessment of pancreatic beta-cell function in vivo with manganese-enhanced magnetic resonance imaging. Am J Physiol Endocrinol Metab 2009;296, E573–8.

    Article  PubMed  CAS  Google Scholar 

  32. Gotthardt M, Boermann OC, Behr TM, Behe MP, Oyen WJ. Development and clinical application of peptide-based radiopharmaceuticals. Curr Pharm Des 2004;10: 2951–63

    Article  PubMed  CAS  Google Scholar 

  33. Moore A, Bonner-Weir S, Weissleder R. Noninvasive in vivo measurement of beta-cell mass in mouse model of diabetes. Diabetes 2001;50:2231–6.

    Article  PubMed  CAS  Google Scholar 

  34. Paty BW, Bonner-Weir S, Laughlin MR, McEwan AJ, Shapiro AM. Toward development of imaging modalities for islets after transplantation: insights from the National Institutes of Health Workshop on Beta Cell Imaging. Transplantation 2004;77:1133–7.

    Article  PubMed  Google Scholar 

  35. Schmitz A, Shiue CY, Feng Q, Shiue GG, Deng S, Pourdehnad MT, Schirrmacher R, Vatamaniuk M, Doliba N, Matschinsky F. et al. Synthesis and evaluation of fluorine-18 labeled glyburide analogs as beta-cell imaging agents. Nucl Med Biol 2004;31:483–91.

    Article  PubMed  CAS  Google Scholar 

  36. Sweet IR, Cook DL, Lernmark A, Greenbaum CJ, Wallen AR, Marcum ES, Stekhova SA, Krohn KA. Systematic screening of potential beta-cell imaging agents. Biochem Biophys Res Commun 2004;314:976–83.

    Article  PubMed  CAS  Google Scholar 

  37. Wangler B, Schneider S, Thews O, Schirrmacher E, Comagic S, Feilen P, Schwanstecher C, Schwanstecher M, Shiue CY, Alavi A. et al. Synthesis and evaluation of (S)-2-(2-[18F]fluoroethoxy)-4-([3-methyl-1-(2 -piperidin-1-yl-phenyl)-butyl-carbamoyl]-methyl)-benzoic acid ([18F]repaglinide): a promising radioligand for quantification of pancreatic beta-cell mass with positron emission tomography (PET). Nucl Med Biol 2004;31: 639–47.

    Article  PubMed  CAS  Google Scholar 

  38. Souza F, Freeby M, Hultman K, Simpson N, Herron A, Witkowsky P, Liu E, Maffei A, Harris PE. (2006a). Current progress in non-invasive imaging of beta cell mass of the endocrine pancreas. Curr Med Chem 13:2761–73.

    Article  PubMed  CAS  Google Scholar 

  39. Souza F, Simpson N, Raffo A, Saxena C, Maffei A, Hardy M, Kilbourn M, Goland R, Leibel R, Mann JJ. et al. (2006b). Longitudinal noninvasive PET-based beta cell mass estimates in a spontaneous diabetes rat model. J Clin Invest 116:1506–13.

    Article  PubMed  CAS  Google Scholar 

  40. Kung M, Lieberman B, Hou C, Ponde D, Goswami R, Skovronsky D, Deng S, Markmann JF, Kung HF. F-18(+)FP-DTBZ: an investigational PET ligand for measuring beta-cell mass in the pancreas. J Nucl Med 2007;48 Suppl 2:114P.

    Google Scholar 

  41. Freeby M, Simpson N, Saxena C, Dashnaw S, Hirsch J, Prince M, Parsey R, Mann JJ, Ichise M, Leibel R. et al. Non-invasive pancreatic beta-cell imaging using C-11 dihydrotetrabenazine and positron emission tomography. Diabetes 2007;56 Suppl 1, A84.

    Google Scholar 

  42. Liu EH, Herscovitch P, Barker C, Channing M, Geras-Raaka E, Pechhold K, Harris PE, Harlen DM, C-11-DTBZ PET scanning: its potential for measuring beta-cell mass in vivo. Diabetes 2007;56 Suppl 1, A83.

    Google Scholar 

  43. Gotthardt M, Baumeister P, Laverman P, Oyen W JG, Boerman OC, Behe MB-c iwrG-a. Beta-cell imaging with radiolabeled GLP-1 analogs. J Nucl Med 2007;48 Suppl 2:178.

    Google Scholar 

  44. Gotthardt M, Lalyko G, van Eerd-Vismale J, Keil B, Schurrat T, Hower M, Laverman P, Behr TM, Boerman OC, Goke B. et al. A new technique for in vivo imaging of specific GLP-1 binding sites: first results in small rodents. Regul Pept 2006;137:162–7.

    Article  PubMed  CAS  Google Scholar 

  45. Huang D, Swanson EA, Lin CP, Schuman JS, Stinson WG, Chang W, Hee MR, Flotte T, Gregory K, Puliafito CA. Optical coherence tomography. Science 1991;254: 1178–81.

    Article  PubMed  CAS  Google Scholar 

  46. Leitgeb RA, Villiger M, Bachmann AH, Steinmann L, Lasser T. Extended focus depth for Fourier domain optical coherence microscopy. Opt Lett 2006;31:2450–2.

    Article  PubMed  CAS  Google Scholar 

  47. Huisken J, Swoger J, Del Bene F, Wittbrodt J, Stelzer EH. Optical sectioning deep inside live embryos by selective plane illumination microscopy. Science 2004;305:1007–9.

    Article  PubMed  CAS  Google Scholar 

  48. Huisken J, Stainier DY. Even fluorescence excitation by multidirectional selective plane illumination microscopy (mSPIM). Opt Lett 2007;32:2608–10.

    Article  PubMed  Google Scholar 

  49. Dewitt L. Morphology and Physiology of the Areas of Langerhans in some Vertebrates. J Exp Med 1906;8:193–239.

    Article  PubMed  CAS  Google Scholar 

  50. Holmberg D, Ahlgren U. Imaging the pancreas: from ex vivo to non-invasive technology. Diabetologia 2008;51:2148–54.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

The authors are grateful to Dr. J. Gilthorpe and Dr. J. Sharpe for valuable comments on the manuscript.

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Correspondence to Ulf Ahlgren .

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Ahlgren, U., Gotthardt, M. (2010). Approaches for Imaging Islets: Recent Advances and Future Prospects. In: Islam, M. (eds) The Islets of Langerhans. Advances in Experimental Medicine and Biology, vol 654. Springer, Dordrecht. https://doi.org/10.1007/978-90-481-3271-3_3

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