Imaging of β-Cell Mass and Function

Ichise, Masanori; Harris, Paul E.

doi:10.2967/jnumed.109.068999

Cited by 40 publications

(29 citation statements)

References 31 publications

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“…Due to this low fraction of beta cells in the pancreas, a robust, non-invasive technique for monitoring and measuring BCM to predict disease onset has proven elusive[10, 13]. Currently, stimulated insulin secretion to indirectly measure the BCM showed success with healthy animal models but failed to predict the development of diabetes because of its limited ability to monitor BCM functionality[6, 14–15]. Other studies were able to correlate hyperglycemia only with large reductions in BCM[16–17].…”

Section: Introductionmentioning

confidence: 99%

Quantitative Impact of Plasma Clearance and Down-regulation on GLP-1 Receptor Molecular Imaging

Zhang

Thurber

2015

Mol Imaging Biol

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Purpose Quantitative molecular imaging of beta cell mass (BCM) would enable early detection and treatment monitoring of type-1 diabetes. The glucagon like peptide-1 (GLP-1) receptor is an attractive target due to its beta cell specificity and cell surface location. We quantitatively investigated the impact of plasma clearance and receptor internalization on targeting efficiency in healthy B6 mice. Procedures Four exenatide-based probes were synthesized that varied in molecular weight, binding affinity, and plasma clearance. The GLP-1 receptor internalization rate and in vivo receptor expression were quantified. Results Receptor internalization (54,000 receptors/cell in vivo) decreased significantly within minutes, reducing the benefit of a slower clearing agent. The multimers and albumin binding probes had higher kidney and liver uptake, respectively. Conclusions Slow plasma clearance is beneficial for GLP-1 receptor peptide therapeutics. However, for exendin-based imaging of islets, downregulation of the GLP-1 receptor and non-specific background uptake result in a higher TBR for fast-clearing agents.

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Section: Introductionmentioning

confidence: 99%

Quantitative Impact of Plasma Clearance and Down-regulation on GLP-1 Receptor Molecular Imaging

Zhang

Thurber

2015

Mol Imaging Biol

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“…Mass quantification with noninvasive approaches is important for basic science and clinical studies. 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 18 …”

Section: Discussionmentioning

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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“…Tetrabenazine (TBZ) and Dihydrotetrabenazine (DTBZ) specifically bind to the synaptic VMAT2 [51,52] and are approved for clinical use. Several groups showed the utility of these agents for targeting VMAT2 for BCM imaging in animal models [44][45][46][47][48][49].…”

Section: Nuclear Imaging Of Bcmmentioning

confidence: 99%

Translational Molecular Imaging of Diabetes

Wang

Moore

2013

Curr Radiol Rep

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Diabetes mellitus contributes to significant morbidity and mortality worldwide. Translational medicine and research facilitate the transition of in vitro and experimental animal research to human applications. Molecular imaging is one of the powerful tools for translational research in diabetes, which accelerates transition of laboratory hypotheses into the clinic. These imaging tools are also instrumental for furthering our understanding about the causes that trigger diabetes and facilitate its progression. Imaging of therapeutic response is yet another avenue that can be explored in our attempt to find a cure for this disease. In this review we briefly summarize molecular imaging studies that show promise for clinical translation. Emphasis is placed on imaging of endogenous and transplanted beta cell mass, including application of various imaging modalities and approaches. Finally, the review attempts to define the future role of these non-invasive imaging techniques in diabetes research and clinical care.

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Imaging of β-Cell Mass and Function

Cited by 40 publications

References 31 publications

Quantitative Impact of Plasma Clearance and Down-regulation on GLP-1 Receptor Molecular Imaging

Quantitative Impact of Plasma Clearance and Down-regulation on GLP-1 Receptor Molecular Imaging

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

Translational Molecular Imaging of Diabetes

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