SPECT-OPT multimodal imaging enables accurate evaluation of radiotracers for β-cell mass assessments

Eter, Wael A.; Parween, Saba; Joosten, Lieke; Frielink, Cathelijne; Eriksson, Maria; Brom, Maarten; Ahlgren, Ulf; Gotthardt, Martin

doi:10.1038/srep24576

Cited by 12 publications

(7 citation statements)

References 14 publications

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“…Previous work demonstrated the mechanism and the specificity of tracers targeting GLP-1R for insulin-positive β-cells in the pancreas 13, 28, 29. Several studies showed that the specific accumulation of radiolabeled exendin-derivatives enabled the detection of islet β-cells clusters in control and diabetic murine models even in viable cells with insulin content below the detection limits of current immunohistochemical methods 13, 30, 31. Here, we demonstrated that the uptake of our PET tracer by the pancreatic insulinomas is colocalized with insulin-secreting cells expressing GLP-1R.…”

Section: Discussionmentioning

confidence: 99%

PET/MRI enables simultaneous in vivo quantification of β-cell mass and function

Michelotti¹,

Bowden²,

Küppers³

et al. 2020

Theranostics

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Non-invasive imaging of β-cells represents a desirable preclinical and clinical tool to monitor the change of β-cell mass and the loss of function during pre-diabetic stages. Although it is widely accepted that manganese (Mn) ions are actively gated by voltage-dependent calcium channels (VDCC) in response to glucose metabolism, little is known on its specificity in vivo for quantification of islet β-cell function using Mn and magnetic resonance imaging (MRI). On the other hand, glucagon-like-peptide-1 receptor (GLP-1R) represents a validated target for the estimation of β-cell mass using radiolabeled exendin-4 (Ex4) and positron emission tomography (PET). However, a multiparametric imaging workflow revealing β-cell mass and function quantitatively is still missing.Methods: We developed a simultaneous PET/MRI protocol to comprehensively quantify in vivo changes in β-cell mass and function by targeting, respectively, GLP-1R and VDCC coupled with insulin secretion. Differences in the spatial distribution of Mn and radiolabeled Ex4 were monitored overtime in native and transgenic pancreata, characterized by spontaneous pancreatic neuroendocrine tumor development. Follow-up with mass spectrometry imaging (MSI) and autoradiography allowed the ex vivo validation of the specificity of Mn and PET tracer uptake and the detection of endogenous biometals, such as calcium and zinc, throughout the endocrine and exocrine pancreas.Results: Our in vivo data based on a volumetric PET/MRI readout for native pancreata and insulinomas connects uptake of Mn measured at early imaging time points to high non-specific binding by the exocrine tissue, while specific retention was only found 24 h post injection. These results are supported by cross-validation of the spatial distribution of exogenous 55Mn and endogenous 44Ca and 64Zn as well with the specific internalization of the radiolabeled peptide targeting GLP-1R.Conclusion: Simultaneous PET/MR imaging of the pancreas enabled the comprehensive in vivo quantification of β-cell function and mass using Mn and radiolabeled Ex4. Most important, our data revealed that only late time-point measurements reflect the Mn uptake in the islet β-cells, while early time points detect non-specific accumulation of Mn in the exocrine pancreas.

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Section: Discussionmentioning

confidence: 99%

PET/MRI enables simultaneous in vivo quantification of β-cell mass and function

Michelotti¹,

Bowden²,

Küppers³

et al. 2020

Theranostics

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“…Some groups, including ours, are developing radiolabeled exendin derivatives 5–8,16,17 . However, most of the previous reports have used SPECT scan not with living mice but with resected pancreata 18,19 , and longitudinal observation of BCM has not been achieved. In order to enable longitudinal observation, we established an analytical method using SPECT imaging of living mice to quantify pancreatic uptake of [ 111 In]Ex4 9 ; we reported a correlation between pancreatic uptake and BCM and also a longitudinal decrease in BCM in NOD mice, an animal model of type 1 diabetes 10 .…”

Section: Discussionmentioning

confidence: 99%

Investigation of the preservation effect of canagliflozin on pancreatic beta cell mass using SPECT/CT imaging with 111In-labeled exendin-4

Hamamatsu

Fujimoto

Fujita

et al. 2019

Sci Rep

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Radiolabeled exendin derivatives are promising for non-invasive quantification of pancreatic beta cell mass (BCM); longitudinal observation of BCM for evaluation of therapeutic effects has not been achieved. The aim of this study is to demonstrate the usefulness of our developing method using [Lys12(111In-BnDTPA-Ahx)]exendin-4 to detect longitudinal changes in BCM. We performed a longitudinal study with obese type 2 diabetes model (db/db) mice administered canagliflozin, which is reported to preserve BCM. Six-week-old mice were assigned to a canagliflozin-administered group or a control group. Blood glucose levels of the canagliflozin group were significantly lower than those of the control group. Plasma insulin levels, insulin secretion during OGTT and insulin content in the pancreas were preserved in the canagliflozin group in comparison with those in the control group. According to SPECT/CT imaging analysis using [Lys12(111In-BnDTPA-Ahx)]exendin-4, pancreatic uptake was significantly decreased in the control group, whereas there was no significant change in the canagliflozin group. After nine weeks, both pancreatic uptake and BCM of the canagliflozin group were significantly higher than those of the control group, and a correlation between them was observed. In conclusion, our imaging method confirmed the BCM-preservation effect of canagliflozin, and demonstrated its potential for longitudinal evaluation of BCM.

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“…Owing to the possibility of calculating absolute islet numbers and even their individual volumes in pancreatic specimens labeled with islet-specific markers (see e.g., [72,73]), this technique may be considered as a gold standard against other imaging assessments. Indeed, we have shown that 111 Inexendin-3 SPECT imaging and OPT linearly correlates and both techniques are more reliable than histological assessment of β cell mass [74]. A recent standardized approach has been postulated to define criteria that β cell traces should fulfill [45].…”

Section: Box 3 Preclinical Approaches For β Cell Evaluation In Diabetesmentioning

confidence: 97%

Novel Strategies to Protect and Visualize Pancreatic β Cells in Diabetes

Gurzov

Ahlgren

et al. 2020

Trends in Endocrinology & Metabolism

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A common feature in the pathophysiology of different types of diabetes is the reduction of β cell mass and/or impairment of β cell function. Diagnosis and treatment of type 1 and type 2 diabetes is currently hampered by a lack of reliable techniques to restore β cell survival, to improve insulin secretion, and to quantify β cell mass in patients. Current new approaches may allow us to precisely and specifically visualize β cells in vivo and provide viable therapeutic strategies to preserve, recover, and regenerate β cells. In this review, we discuss recent protective approaches for β cells and the advantages and limitations of current imaging probes in the field. Type 1 and Type 2 Diabetes (T1D and T2D) as a β Cell Pathology T1D and T2D, although arising from different etiologies, are each associated with physical and/or functional loss of insulin-secreting β cells [1-3]. T1D is described as a heterogeneous inflammatory disease characterized by infiltration of the pancreatic islets with a number of autoimmune cells (CD4+ and CD8+ T cells, macrophages, dendritic cells, and B cells) [4]. Recent evidence suggests that progression of islet infiltrates promotes β cell dysfunction (reduced first-phase insulin response) and later β cell elimination, which ultimately results in the onset of diabetes. Interestingly, it is now clear that residual β cell mass can be found several years after diagnosis. Thus, a desired strategy for T1D treatment should suppress β cell autoimmunity, along with protection and restoration of the remaining β cell mass. Currently, there are no clinically approved interventional therapies for treating the underlying autoimmunity and boosting β cell survival in T1D. T2D, however, is characterized by insulin resistance following progressive decline in β cell function and accumulation of islet amyloid polypeptide (IAPP, or amylin) in the pancreatic islets [2,5]. The pathology is far more complex, as a recent study on newly diagnosed diabetic subjects postulates a reclassification into five distinct clusters based on the metabolic profile and risk of complications; three of the different cluster are currently considered T2D [6]. The treatment of T2D is mainly limited to metformin monotherapy as the initial strategy to improve insulin sensitivity. When the patient cannot control glycemia by lifestyle and metformin, a pharmacology approach to increase β cell resistance and function will be required, as an alternative to chronic exogenous insulin injections. Highlights Pancreatic β cell failure is characteristic to both T1D and T2D. The JAK-STAT pathway is a promising target to prevent autoimmune β cell destruction. Several strategies are currently being tested to improve insulin production in T2D: preventing β cell death/dysfunction, enhancing β cell proliferation, ameliorating β cell dedifferentiation, and inducing transdifferentiation into β like cells. Imaging and diagnostic tools are required to improve the efficacy of current therapeutic strategies aimed at restoring β cell function. Nanotechnology...

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SPECT-OPT multimodal imaging enables accurate evaluation of radiotracers for β-cell mass assessments

Cited by 12 publications

References 14 publications

PET/MRI enables simultaneous in vivo quantification of β-cell mass and function

PET/MRI enables simultaneous in vivo quantification of β-cell mass and function

Investigation of the preservation effect of canagliflozin on pancreatic beta cell mass using SPECT/CT imaging with 111In-labeled exendin-4

Novel Strategies to Protect and Visualize Pancreatic β Cells in Diabetes

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