In Vivo Imaging of Endogenous Pancreatic β-Cell Mass in Healthy and Type 1 Diabetic Subjects Using <sup>18</sup>F-Fluoropropyl-Dihydrotetrabenazine and PET

Normandin, Marc D.; Petersen, Kitt Falk; Ding, Yu‐Shin; Lin, Shu-fei; Naik, Sarita; Fowles, Krista; Skovronsky, Daniel; Herold, Kevan C.; McCarthy, Timothy J.; Calle, Roberto A.; Carson, Richard E.; Treadway, Judith L.; Cline, Gary W.

doi:10.2967/jnumed.111.100545

Cited by 108 publications

(107 citation statements)

References 34 publications

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“…To date, no other radiotracer tested for BCM determination has shown such large maximum differences between healthy individuals and patients with type 1 diabetes, nor has such a high interindividual variability of the uptake been reported previously [37][38][39][40][41][42][43][44]. A recent study in healthy individuals and patients with type 1 diabetes, involving PET after injection of [ 18 F]fluoropropyl-dihydrotetrabenazine ([ 18 F]FP-(+)-DTBZ), showed a maximum difference in pancreatic uptake of <40% [45]. The difference in binding potential between patients with type 1 diabetes and healthy individuals was not greater than 50% [45].…”

Section: Discussionmentioning

confidence: 99%

“…A recent study in healthy individuals and patients with type 1 diabetes, involving PET after injection of [ 18 F]fluoropropyl-dihydrotetrabenazine ([ 18 F]FP-(+)-DTBZ), showed a maximum difference in pancreatic uptake of <40% [45]. The difference in binding potential between patients with type 1 diabetes and healthy individuals was not greater than 50% [45]. Moreover, a recent publication showed that expression of vesicular monoamine transporter 2 (VMAT2) in pancreatic polypeptide cells causes overestimation of the BCM in type 1 diabetes, as determined by PET measurements [46].…”

Section: Discussionmentioning

confidence: 99%

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Non-invasive quantification of the beta cell mass by SPECT with 111In-labelled exendin

et al. 2014

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Aims/hypothesis A reliable method for in vivo quantification of pancreatic beta cell mass (BCM) could lead to further insight into the pathophysiology of diabetes. The glucagonlike peptide 1 receptor, abundantly expressed on beta cells, may be a suitable target for imaging. We investigated the potential of radiotracer imaging with the GLP-1 analogue exendin labelled with indium-111 for determination of BCM in vivo in a rodent model of beta cell loss and in patients with type 1 diabetes and healthy individuals. MethodsThe targeting of 111 In-labelled exendin was examined in a rat model of alloxan-induced beta cell loss. Rats were injected with 15 MBq 111 In-labelled exendin and single photon emission computed tomography (SPECT) acquisition was performed 1 h post injection, followed by dissection, biodistribution and ex vivo autoradiography studies of pancreatic sections. BCM was determined by morphometric analysis after staining with an anti-insulin antibody. For clinical evaluation SPECT was acquired 4, 24 and 48 h after injection of 150 MBq 111 In-labelled exendin in five patients with type 1 Maarten Brom and Wietske Woliner-van der Weg contributed equally to this study. Diabetologia (2014) 57:950-959 DOI 10.1007 diabetes and five healthy individuals. The tracer uptake was determined by quantitative analysis of the SPECT images. Results In rats, 111 In-labelled exendin specifically targets the beta cells and pancreatic uptake is highly correlated with BCM. In humans, the pancreas was visible in SPECT images and the pancreatic uptake showed high interindividual variation with a substantially lower uptake in patients with type 1 diabetes. Conclusions/interpretation These studies indicate that 111 Inlabelled exendin may be suitable for non-invasive quantification of BCM.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Non-invasive quantification of the beta cell mass by SPECT with 111In-labelled exendin

et al. 2014

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“…5A and B). Noninvasive imaging of pancreatic b-cell mass and function has been applied in normal and diabetic patients (Normandin et al 2012), but the accuracy of this approach needs to be further evaluated. The ratio of b-cells to non-b endocrine cells was unchanged after RYGB in the present study (Fig.…”

Section: Discussionmentioning

confidence: 99%

Pancreatic hyperplasia after gastric bypass surgery in a GK rat model of non-obese type 2 diabetes

Zhou

Qian

et al. 2015

Journal of Endocrinology

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Gastric bypass surgery produces clear antidiabetic effects in a substantial proportion of morbidly obese patients. In view of the recent trend away from 'bariatric' surgery and toward 'metabolic' surgery, it is important to elucidate the enhancing effect of bypass surgery on pancreatic b-cell mass, which is related to diabetes remission in non-obese patients. We investigated the effects of gastric bypass surgery on glycemic control and other pancreatic changes in a spontaneous non-obese type 2 diabetes Goto-Kakizaki rat model. Significant improvements in postprandial hyperglycemia and plasma c-peptide level were observed when glucose was administered orally post-surgery. Other important events observed after surgery were enhanced first phase insulin secretion in a in site pancreatic perfusion experiment, pancreatic hyperplasia, improved islet structure (revealed by immunohistochemical analysis), striking increase in b-cell mass, slight increase in ratio of b-cell area to total pancreas area, and increased number of small islets closely related to exocrine ducts. No notable changes were observed in ratio of b-cell to non-b endocrine cell area, b-cell apoptosis, or b-cell proliferation. These findings demonstrate that gastric bypass surgery in this rat model increases endocrine cells and pancreatic hyperplasia, and reflect the important role of the gastrointestinal system in regulation of metabolism. Key Words" type 2 diabetes mellitus " gastric bypass surgery

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“…However, quantification of β-cell mass in vivo is relatively difficult due to the lack of reliable and noninvasive biomarkers for cells (24). Recently, the use of in vivo imaging techniques including positron-emission tomography (PET) and single-photon emission computed tomography (SPECT) with isotope-labeled ligands [such as In-labeled exendin] have been utilized in the field of human β-cell image studies (25)(26)(27). Likewise, BLI has been widely used with luciferase transgenic mice to evaluate β-cell mass under both normal and pathological conditions (17,28).…”

Section: R E S E a R C H A R T I C L Ementioning

confidence: 99%

“…In-labeled exendin] have been utilized in the field of human β-cell image studies (25)(26)(27). Likewise, BLI has been widely used with luciferase transgenic mice to evaluate β-cell mass under both normal and pathological conditions (17,28).…”

Section: F-fluoropropyl-(+)-dtbz and 111mentioning

confidence: 99%

Deletion of β-Arrestin2 in Mice Limited Pancreatic β-Cell Expansion under Metabolic Stress through Activation of the JNK Pathway

Lin

Zhao

Song

et al. 2016

Mol Med

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β-Arrestin2 (βarr2) is an adaptor protein that interacts with numerous signaling molecules and regulates insulin sensitivity. We reported previously that βarr2 was abundantly expressed in mouse pancreatic β-cells, and loss of βarr2 leads to impairment of acuteand late-phase insulin secretion. In the present study, we examined the dynamic changes of β-cell mass in barr2-deficient (barr2 -/-) mice in vivo and explored the underlying mechanisms involved. barr2-/-mice with exclusively luciferase overexpression in β-cellswere generated and fed a high-fat diet (HFD). β-Cell mass was determined by in vivo noninvasive bioluminescence imaging from 4 to 20 wks of age. Proliferation was measured by 5-bromo-2-deoxyuridine (BrdU) incorporation and fluorescence-activated cell sorter analysis. Quantitative real-time polymerase chain reaction (qRT-PCR) and immunoblotting were conducted for gene and protein expression. We found that β-cell mass was reduced dramatically in barr2 -/-mice at 12 wks old compared with that of their respective HFD-fed controls. The percentage of BrdU-and Ki67-positive cells reduced in islets from barr2 -/-mice. Exposure of barr2 -/-islets to high levels of glucose and free fatty acids (FFAs) exacerbated cell death, which was associated with upregulation of the JNK pathway in these islets. Conversely, overexpression of βarr2 amplified β-cell proliferation with a concomitant increase in cyclinD2 expression and a decrease in p21 expression and protected β-cells from glucose-and FFA-induced cell death through JNK-activation inhibition.In conclusion, βarr2 plays roles in regulation of pancreatic β-cell mass through the modulation of cell cycle regulatory genes and the inhibition of JNK activation induced by glucolipotoxity, which implicates a role for βarr2 in the development of type 2 diabetes. China. Phone: +86-21-24058657; Fax: 86-21-64368031; E-mail: wangchen@sjtu.edu.cn. Submitted June 24, 2015; Accepted for publication February 22, 2016; Published Online (www.molmed.org) February 29, 2016. R E S E A R C H A R T I C L EM O L M E D 2 2 : 7 4 -8 4 , 2 0 1 6 | L i n E T A L . | 7 5Histology Study and Morphometric Analyses Pancreases were removed from 16-wk-old barr2 +/+ and barr2 -/-mice, immediately weighed, fixed and embedded. To determine the count and area of islets, 8-10 randomly chosen sections per mouse that were separated by at least 100 μm were stained with hematoxylin and eosin (H&E). The entire pancreatic sections were scanned using a Nikon Eclipse Ni-E Microscope (Nikon), and a tile image of the tissue section was generated using the NIS-Elements AR 4.20 (Nikon). The fractional area of the islet in the pancreas, islet count per unit pancreatic area (islet density) and islet size were manually quantified using Image-Pro Plus 6.0 (Media Cybernetics), as described previously (21). The average of all the sections was taken as a measure for the entire organ. The total islet mass was calculated as pancreatic weight × mean fractional pancreatic islet area. For immunofluorescence analysis, pan...

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In Vivo Imaging of Endogenous Pancreatic β-Cell Mass in Healthy and Type 1 Diabetic Subjects Using ¹⁸F-Fluoropropyl-Dihydrotetrabenazine and PET

Cited by 108 publications

References 34 publications

Non-invasive quantification of the beta cell mass by SPECT with 111In-labelled exendin

Non-invasive quantification of the beta cell mass by SPECT with 111In-labelled exendin

Pancreatic hyperplasia after gastric bypass surgery in a GK rat model of non-obese type 2 diabetes

Deletion of β-Arrestin2 in Mice Limited Pancreatic β-Cell Expansion under Metabolic Stress through Activation of the JNK Pathway

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In Vivo Imaging of Endogenous Pancreatic β-Cell Mass in Healthy and Type 1 Diabetic Subjects Using 18F-Fluoropropyl-Dihydrotetrabenazine and PET

Cited by 108 publications

References 34 publications

Non-invasive quantification of the beta cell mass by SPECT with 111In-labelled exendin

Non-invasive quantification of the beta cell mass by SPECT with 111In-labelled exendin

Pancreatic hyperplasia after gastric bypass surgery in a GK rat model of non-obese type 2 diabetes

Deletion of β-Arrestin2 in Mice Limited Pancreatic β-Cell Expansion under Metabolic Stress through Activation of the JNK Pathway

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Product

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In Vivo Imaging of Endogenous Pancreatic β-Cell Mass in Healthy and Type 1 Diabetic Subjects Using ¹⁸F-Fluoropropyl-Dihydrotetrabenazine and PET