Imaging inflammation of the pancreatic islets in type 1 diabetes

Denis, Maria C; Mahmood, Umar; Benoist, Christophe; Mathis, Diane; Weissleder, Ralph

doi:10.1073/pnas.0404307101

Cited by 172 publications

(154 citation statements)

References 31 publications

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“…Moore et al, using superparamagnetic-particle-labeled T cells (via a CLIO-Tat peptide or major histocompatibility complex tetramer peptide complexes), were able to clearly demonstrate the presence of infiltrating T cells during the evolution of β-cell destruction [10,11]. MRI has also been used to visualize peri-islet vascular leakage due to insulitis using superparamagnetic nanobeads [21].…”

Section: Introductionmentioning

confidence: 99%

Visualizing pancreatic β-cell mass with [11C]DTBZ

Simpson

Souza

Witkowski

et al. 2006

Nuclear Medicine and Biology

109

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Abstractβ-Cell mass (BCM) influences the total amount of insulin secreted, varies by individual and by the degree of insulin resistance, and is affected by physiologic and pathologic conditions. The islets of Langerhans, however, appear to have a reserve capacity of insulin secretion and, overall, assessments of insulin and blood glucose levels remain poor measures of BCM, β-cell function and progression of diabetes. Thus, novel noninvasive determinations of BCM are needed to provide a quantitative endpoint for novel therapies of diabetes, islet regeneration and transplantation. Built on previous gene expression studies, we tested the hypothesis that the targeting of vesicular monoamine transporter 2 (VMAT2), which is expressed by β cells, with [ 11 C]dihydrotetrabenazine ([ 11 C]DTBZ), a radioligand specific for VMAT2, and the use of positron emission tomography (PET) can provide a measure of BCM. In this report, we demonstrate decreased radioligand uptake within the pancreas of Lewis rats with streptozotocininduced diabetes relative to their euglycemic historical controls. These studies suggest that quantitation of VMAT2 expression in β cells with the use of [ 11 C]DTBZ and PET represents a method for noninvasive longitudinal estimates of changes in BCM that may be useful in the study and treatment of diabetes.

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Section: Introductionmentioning

confidence: 99%

Visualizing pancreatic β-cell mass with [11C]DTBZ

Simpson

Souza

Witkowski

et al. 2006

Nuclear Medicine and Biology

109

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show abstract

“…The in-depth projection of the scanned volume reveals the perfusive intra-islet, perivascular sympathetic innervation in addition to the peri-islet axons and fibres encircling the adjacent arterioles. Furthermore, our optical method also revealed remodelling of the sympathetic innervation due to streptozotocin (STZ)-induced microcirculatory injury and lymphocytic infiltration in the non-obese diabetic (NOD) mouse model in the early phase of insulitis [24][25][26][27]. In this report, the development of our islet imaging approach and the functional and pathophysiological implications of the neurovascular network in health and disease are presented and discussed.…”

Section: Introductionmentioning

confidence: 99%

3-D imaging and illustration of the perfusive mouse islet sympathetic innervation and its remodelling in injury

Chiu

Hua

et al. 2012

Diabetologia

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Aims/hypothesis Sympathetic nerves influence islet hormone levels in the circulation. Insights into islet sympathetic innervation and its remodelling in diabetes may impact future therapeutics. However, standard immunohistochemistry and microtome-based microscopy cannot provide an integral view of the islet neurovascular complex. We prepared transparent islet specimens to investigate the spatial relationship between sympathetic nerves, blood vessels and islet cells in normal, streptozotocin-injected and non-obese diabetic mouse models. Methods Cardiac perfusion of fluorescent lectin was used to label pancreatic blood vessels. Tyrosine hydroxylase and nuclear staining were used to reveal islet sympathetic innervation and microstructure. Optical clearing (i.e. use of immersion solution to reduce scattering) was applied to enable 3-dimensional confocal microscopy of islets to visualise the sympathetic neurovascular complex in space. Results Unlike previously reported morphology, we observed perfusive intra-islet, perivascular sympathetic innervation, in addition to peri-islet contacts of sympathetic nerves with alpha cells and sympathetic fibres encircling the adjacent arterioles. The intra-islet axons became markedly prominent in streptozotocin-injected mice (2 weeks after injection). In non-obese diabetic mice, lymphocytic infiltration remodelled the peri-islet sympathetic axons in early insulitis. Conclusions/interpretation We have established an imaging approach to reveal the spatial features of mouse islet sympathetic innervation. The neurovascular complex and sympathetic nerve-alpha cell contact suggest that sympathetic nerves modulate islet hormone secretion through blood vessels, in addition to acting directly on alpha cells. In islet injuries, sympathetic nerves undergo different remodelling in response to different pathophysiological cues.

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“…In the progression of type 1 diabetes, although the role of pericytes is not understood, vascular swelling and leakage have been imaged in insulitis and used as an indicator of islet inflammation in NOD mice [20,21]. Whether or not the vascular damage induces remodelling of pericytes is the topic for investigation in this research.…”

Section: Introductionmentioning

confidence: 99%

Plasticity of Schwann cells and pericytes in response to islet injury in mice

et al. 2013

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Aims/hypothesis Islet Schwann (glial) cells and pericytes are the microorgan's accessory cells positioned at the external and internal boundaries facing the exocrine pancreas and endothelium, respectively, adjacent to the endocrine cells. Plasticity of glial cells and pericytes is shown in the glial scar formation after injury to the central nervous system. It remains unclear whether similar reactive cellular responses occur in insulitis. We applied three-dimensional (3D) histology to perform qualitative and quantitative analyses of the islet Schwann cell network and pericytes in normal, streptozotocin-injected (positive control of gliosis) and NOD mouse models. Methods Vessel painting paired with immunostaining of mouse pancreatic tissue was used to reveal the islet Schwann cells and pericytes and their association with vasculature. Transparent islet specimens were prepared by optical clearing to facilitate 3D confocal microscopy for panoramic visualisation of the tissue networks.Results In-depth microscopy showed that the islet Schwann cell network extends from the peri-islet domain into the core. One week after streptozotocin injection, we observed intraislet perivascular gliosis and an increase in pericyte density. In early/moderate insulitis in the NOD mice, perilesional gliosis occurred at the front of the lymphocytic infiltration with atypical islet Schwann cell morphologies, including excessive branching and perivascular gliosis. Meanwhile, pericytes aggregated on the walls of the feeding arteriole at the peri-and intralesional domains with a marked increase in surface marker density. Conclusions/interpretationThe reactive cellular responses demonstrate plasticity and suggest a stop-gap mechanism consisting of the Schwann cells and pericytes in association with the islet lesion and vasculature when injury occurs.

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Imaging inflammation of the pancreatic islets in type 1 diabetes

Cited by 172 publications

References 31 publications

Visualizing pancreatic β-cell mass with [11C]DTBZ

Visualizing pancreatic β-cell mass with [11C]DTBZ

3-D imaging and illustration of the perfusive mouse islet sympathetic innervation and its remodelling in injury

Plasticity of Schwann cells and pericytes in response to islet injury in mice

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