Use of the PET ligand florbetapir for in vivo imaging of pancreatic islet amyloid deposits in hIAPP transgenic mice
Islet amyloid deposits contribute to beta cell dysfunction and death in most individuals with type 2 diabetes but non-invasive methods to determine the presence of these pathological protein aggregates are currently not available. Therefore, we examined whether florbetapir, a radiopharmaceutical agent used for detection of amyloid-β deposits in the brain, also allows identification of islet amyloid in the pancreas.
Saturation binding assays were used to determine the affinity of florbetapir for human islet amyloid polypeptide (hIAPP) aggregates in vitro. Islet amyloid-prone transgenic mice that express hIAPP in their beta cells and amyloid-free non-transgenic control mice were used to examine the ability of florbetapir to detect islet amyloid deposits in vitro, in vivo and ex vivo. Mice or mouse pancreases were subjected to autoradiographic, histochemical and/or positron emission tomography (PET) analyses to assess the utility of florbetapir in identifying islet amyloid.
In vitro, florbetapir bound synthetic hIAPP fibrils with a dissociation constant of 7.9 nmol/l. Additionally, florbetapir bound preferentially to amyloid-containing hIAPP transgenic vs amyloid-free non-transgenic mouse pancreas sections in vitro, as determined by autoradiography (16,475 ± 5581 vs 5762 ± 575 density/unit area, p < 0.05). In hIAPP transgenic and non-transgenic mice fed a high-fat diet for 1 year, intravenous administration of florbetapir followed by PET scanning showed that the florbetapir signal was significantly higher in amyloid-laden hIAPP transgenic vs amyloid-free non-transgenic pancreases in vivo during the first 5 min of the scan (36.83 ± 2.22 vs 29.34 ± 2.03 standardised uptake value × min, p < 0.05). Following PET, pancreases were excised and florbetapir uptake was determined ex vivo by γ counting. Pancreatic uptake of florbetapir was significantly correlated with the degree of islet amyloid deposition, the latter assessed by histochemistry (r = 0.74, p < 0.001).
Florbetapir binds to islet amyloid deposits in a specific and quantitative manner. In the future, florbetapir may be useful as a non-invasive tool to identify islet amyloid deposits in humans.
KeywordsAmyloid Diabetes Florbetapir Islet PET
Human islet amyloid polypeptide
Positron emission tomography
Standardised uptake value
We thank M. Peters, B. Barrow, D. Hackney, P. Bergquist and J. Wilkins-Gutierrez (all Seattle Institute for Biomedical and Clinical Research, Seattle, WA, USA) for excellent technical assistance provided during these studies. We thank M. F. Hogan and S. Zraika (both Department of Medicine, VA Puget Sound Health Care System and University of Washington, Seattle, WA, USA) for critical review of the data generated in this study. Some data from this study were presented at the American Diabetes Association 77th Scientific Sessions in 2017.
ATT acquired data, analysed/interpreted data and wrote the manuscript. DTM, JRW, TWH, KC, YG-L and PJG acquired data, analysed/interpreted data and reviewed/revised the manuscript. KBB and GA analysed/interpreted data and reviewed/revised the manuscript. SEK, DS and RLH designed the study, analysed/interpreted data and reviewed/revised the manuscript. All authors approved the final version of the manuscript to be published. ATT and RLH are responsible for the integrity of the work as a whole.
This work was supported by the Lilly Research Laboratories Early Discovery and Development Research Awards Program (to RLH), Department of Veterans Affairs (BX001060 to SEK), National Institutes of Health (F32DK107022 to ATT and Diabetes Research Center P30DK017047), American Diabetes Association (7-11-MN-28 to SEK) and the University of Washington (Dick and Julia McAbee Fellowship to DTM).
Duality of interest
This work was supported in part by an investigator-initiated research proposal from Lilly Research Laboratories (to RLH). SEK consulted for Eli Lilly & Co. during the performance of this study but did not receive compensation. At the time of the research, KC, Y-GL and GA were employees of Avid Radiopharmaceuticals, Inc., a subsidiary of Eli Lilly & Co. and PJG, KBB and DS were employees of and shareholders in Eli Lilly & Co. All other authors declare that there was no duality of interest associated with their contribution to this manuscript. The study sponsor was involved in the design of the study, collection and analysis of data, and editing the report. The sponsor was not involved in interpretation of data, writing the report or the decision to submit the report for publication.
- 1.Westermark P, Grimelius L (1973) The pancreatic islet cells in insular amyloidosis in human diabetic and non-diabetic adults. Acta Pathol Microbiol Scand 81:291–300Google Scholar
- 6.Davalli AM, Perego L, Bertuzzi F et al (2008) Disproportionate hyperproinsulinemia, β-cell restricted prohormone convertase 2 deficiency, and cell cycle inhibitors expression by human islets transplanted into athymic nude mice: insights into nonimmune-mediated mechanisms of delayed islet graft failure. Cell Transplant 17:1323–1336CrossRefPubMedGoogle Scholar
- 7.Westermark P, Wernstedt C, Wilander E, Hayden DW, O’Brien TD, Johnson KH (1987) Amyloid fibrils in human insulinoma and islets of Langerhans of the diabetic cat are derived from a neuropeptide-like protein also present in normal islet cells. Proc Natl Acad Sci U S A 84:3881–3885CrossRefPubMedPubMedCentralGoogle Scholar
- 28.Romano M, Buratti E (2013) Florbetapir F 18 for brain imaging of β-amyloid plaques. Drugs Today (Barc) 49:181–193Google Scholar