Futility of attempts to detect and quantify beta cells by PET imaging in the pancreas: why it is time to abandon the approach

Alavi, Abass; Werner, Thomas

doi:10.1007/s00125-018-4676-1

Cited by 14 publications

(11 citation statements)

References 33 publications

(44 reference statements)

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“…In addition to analyzing human b cells ex vivo, there is great need to identify and visualize b cells non-invasively in vivo. Although reduced b cell mass is an accepted feature of diabetes progression, current knowledge has originated from postmortem analysis since there are no effective methods to quantify b cell mass non-invasively in humans (Alavi and Werner, 2018;Laurent et al, 2015). This limitation has greatly hindered our understanding of disease risk and progression and prevents the evaluation of interventions designed to preserve or increase b cell mass.…”

Section: Introductionmentioning

confidence: 99%

Ectonucleoside Triphosphate Diphosphohydrolase-3 Antibody Targets Adult Human Pancreatic β Cells for In Vitro and In Vivo Analysis

et al. 2019

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Section: Introductionmentioning

confidence: 99%

Ectonucleoside Triphosphate Diphosphohydrolase-3 Antibody Targets Adult Human Pancreatic β Cells for In Vitro and In Vivo Analysis

et al. 2019

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“…However, clinical studies of BCM are currently limited to cross-sectional studies in which the pancreas is obtained from autopsy or operation. Although there are a few arguments regarding the feasibility of the clinical implementation on BCM quantification (9)(10)(11)(12)(13), the study of how BCM changes over time would provide a deeper understanding of the pathophysiology of diabetes and could be used to develop a scale to evaluate the efficacy of antidiabetic drugs in preserving or increasing BCM.…”

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confidence: 99%

Noninvasive longitudinal quantification of β‐cell mass with [¹¹¹In]‐labeled exendin‐4

et al. 2019

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Currently, quantifying β‐cell mass (BCM) requires harvesting the pancreas. In this study, we investigated a potential noninvasive method to quantify BCM changes longitudinally using [Lys12(111In‐BnDTPA‐Ahx)] exendin‐4 ([111In]‐Ex4) and single‐photon emission computed tomography (SPECT). We used autoradiography and transgenic mice expressing green fluorescent protein under the control of mouse insulin 1 gene promotor to evaluate the specificity of [111In]‐Ex4 toward β cells. Using nonobese diabetic (NOD) mice, we injected [111In]‐Ex4 (3.0 MBq) intravenously and performed SPECT 30 min later, repeating this at a 2‐wk interval. After the second scan, we harvested the pancreas and calculated BCM from immunohistochemically stained pancreatic sections. Specific accumulation of [111In]‐Ex4 in β cells was confirmed by autoradiography, with a significant correlation (r = 0.94) between the fluorescent and radioactive signal intensities. The radioactive signal from the pancreas in the second SPECT scan significantly correlated (r = 0.89) with BCM calculated from the immunostained pancreatic sections. We developed a regression formula to estimate BCM from the radioactive signals from the pancreas in SPECT scans. BCM can be quantified longitudinally and noninvasively by SPECT imaging with [111In]‐Ex4. This technique successfully demonstrated longitudinal changes in BCM in NOD mice before and after onset of hyperglycemia.—Fujita, N., Fujimoto, H., Hamamatsu, K., Murakami, T., Kimura, H., Toyoda, K., Saji, H., Inagaki, N. Noninvasive longitudinal quantification of β‐cell mass with [111In]‐labeled exendin‐4. FASEB J. 33, 11836‐11844 (2019). http://www.fasebj.org

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“…The use of radiolabeled PET/SPECT-based probes for BCM quantification is a contentious field, with concerns that relatively poor spatial resolution is a substantial limitation for accurate b-cell imaging. Since exocrine pancreas also expresses GLP-1R, PET/SPECT cannot distinguish whether the radioactivity is originating from b-cells or exocrine cells, thereby skewing the accuracy of BCM quantification (36,37). However, as Gotthardt et al pointed out, the key influencing factor for successful b-cell quantification using PET is not spatial resolution but ensuring that the radioactive signal observed is exclusively from b-cells (38).…”

Section: Discussionmentioning

confidence: 99%

Blocking of Glucagonlike Peptide-1 Receptors in the Exocrine Pancreas Improves Specificity for β-Cells in a Mouse Model of Type 1 Diabetes

et al. 2019

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The diabetes community has long desired an imaging agent to quantify the number of insulin-secreting β-cells, beyond just functional equivalents (insulin secretion), to help diagnose and monitor early stages of both type 1 and type 2 diabetes mellitus. Loss in the number of β-cells can be masked by a compensatory increase in function of the remaining cells. Since β-cells form only about 1% of the pancreas and decrease as the disease progresses, only a few imaging agents, such as exendin, have demonstrated clinical potential to detect a drop in the already scarce signal. However, clinical translation of imaging with exendin has been hampered by pancreatic uptake that is higher than expected in subjects with long-term diabetes who lack β-cells. Exendin binds glucagonlike peptide-1 receptor (GLP-1R), previously thought to be expressed only on β-cells, but recent studies report low levels of GLP-1R on exocrine cells, complicating β-cell mass quantification. Methods: Here, we used a GLP-1R knockout mouse model to demonstrate that exocrine binding of exendin is exclusively via GLP-1R (∼1,000/cell) and not any other receptor. We then used lipophilic Cy-7 exendin to selectively preblock exocrine GLP-1R in healthy and streptozotocininduced diabetic mice. Results: Sufficient receptors remain on βcells for subsequent labeling with a fluorescent-or 111 In-exendin. Conclusion: Selective GLP-1R blocking, which improves contrast between healthy and diabetic pancreata and provides a potential avenue for achieving the long-standing goal of imaging β-cell mass in the clinic.

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Futility of attempts to detect and quantify beta cells by PET imaging in the pancreas: why it is time to abandon the approach

Cited by 14 publications

References 33 publications

Ectonucleoside Triphosphate Diphosphohydrolase-3 Antibody Targets Adult Human Pancreatic β Cells for In Vitro and In Vivo Analysis

Ectonucleoside Triphosphate Diphosphohydrolase-3 Antibody Targets Adult Human Pancreatic β Cells for In Vitro and In Vivo Analysis

Noninvasive longitudinal quantification of β‐cell mass with [¹¹¹In]‐labeled exendin‐4

Blocking of Glucagonlike Peptide-1 Receptors in the Exocrine Pancreas Improves Specificity for β-Cells in a Mouse Model of Type 1 Diabetes

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