A new view of the beta cell

Ahnfelt-Rønne, Jonas; Hecksher‐Sørensen, Jacob; Schäffer, Lauge; Madsen, Ole

doi:10.1007/s00125-012-2609-y

Cited by 4 publications

(3 citation statements)

References 18 publications

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“…One of the most promising approaches is the positron emission tomography (PET). However, PET is very challenging due to the heterogenous distribution and the small number of β -cells throughout the pancreas [7]. Another highly promising method was presented by Brom and co-workers who traced β -cells in humans by SPECT and could demonstrate, at least in a rat model, that the results correlated with β -cell mass [8].…”

Section: Discussionmentioning

confidence: 99%

Automated Assessment of β-Cell Area and Density per Islet and Patient Using TMEM27 and BACE2 Immunofluorescence Staining in Human Pancreatic β-Cells

et al. 2014

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In this study we aimed to establish an unbiased automatic quantification pipeline to assess islet specific features such as β-cell area and density per islet based on immunofluorescence stainings. To determine these parameters, the in vivo protein expression levels of TMEM27 and BACE2 in pancreatic islets of 32 patients with type 2 diabetes (T2D) and in 28 non-diabetic individuals (ND) were used as input for the automated pipeline. The output of the automated pipeline was first compared to a previously developed manual area scoring system which takes into account the intensity of the staining as well as the percentage of cells which are stained within an islet. The median TMEM27 and BACE2 area scores of all islets investigated per patient correlated significantly with the manual scoring and with the median area score of insulin. Furthermore, the median area scores of TMEM27, BACE2 and insulin calculated from all T2D were significantly lower compared to the one of all ND. TMEM27, BACE2, and insulin area scores correlated as well in each individual tissue specimen. Moreover, islet size determined by costaining of glucagon and either TMEM27 or BACE2 and β-cell density based either on TMEM27 or BACE2 positive cells correlated significantly. Finally, the TMEM27 area score showed a positive correlation with BMI in ND and an inverse pattern in T2D. In summary, automated quantification outperforms manual scoring by reducing time and individual bias. The simultaneous changes of TMEM27, BACE2, and insulin in the majority of the β–cells suggest that these proteins reflect the total number of functional insulin producing β–cells. Additionally, β–cell subpopulations may be identified which are positive for TMEM27, BACE2 or insulin only. Thus, the cumulative assessment of all three markers may provide further information about the real β–cell number per islet.

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Section: Discussionmentioning

confidence: 99%

Automated Assessment of β-Cell Area and Density per Islet and Patient Using TMEM27 and BACE2 Immunofluorescence Staining in Human Pancreatic β-Cells

et al. 2014

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“…(Ligand). Peptides targeting the GLP-1R are promising candidates for use in -cell imaging because (i) they should target the cells with high specificity [44][45][46][47][48][49][50][51][52][53][54][55], given the abundant expression of these receptors on native islet cells [56], and (ii) they are safe and already used in the clinic for treatment of T2DM. Among these, exendin-4, found in the saliva of the Gila monster [57], binds to the extracellular domain of GLP-1R with pM affinity [58].…”

Section: Tools and Targets For Imaging Of -Cell Massmentioning

confidence: 99%

Pancreatic β‐cell imaging in humans: fiction or option?

Laurent

Vinet

Lamprianou

et al. 2015

Diabetes Obesity Metabolism

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Main Text (excl abstract, refs, figure legends, acknows) = 3992 words 2 Abbreviations, BCI, BCM, -cell imaging and mass, respectively; IMIDIA, Innovative Medicines Initiative in DIAbetes; MRI, magnetic resonance imaging; OPT, optical projection tomography; PET, positron emission tomography; SPECT, single photon emission computed tomography; VMAT, vesicular monoamine transporter; GLP1, glucagon-like peptide-1; PSA-NCAM, polysialylated neural cell adhesion molecule; SUR 1, sulfonylurea receptor 1; STZ, streptozotocin; T1D type 1 diabetes; T2D, type 2 diabetes; TMEM27, transmembrane protein 27; USPIO, ultrasmall superparamagnetic iron oxide 3 AbstractDiabetes mellitus is a growing worldwide epidemic currently affecting 1 in 12 adults.Treatment of disease complications typically consumes ~10% of healthcare budgets in developed societies. Whilst immune-mediated destruction of insulin-secreting pancreatic -cells is responsible for Type 1 diabetes, both the loss and dysfunction of these cells underlies the more prevalent Type 2 diabetes. The establishment of robust drug development programmes aiming at -cell restoration is still hampered by the absence of means to measure -cell mass prospectively in vivo, an approach which would provide new opportunities for understanding disease mechanisms and ultimately assigning personalized treatments. Here, we describe progress towards this goal achieved by the Innovative Medicines Initiative in DIAbetes (IMIDIA), a collaborative public-private consortium supported by the European Commission and dedicated resources of pharmaceutical companies. We compare several of the available imaging modalities and molecular targets and provide suggestions as to the likeliest to lead to tractable approaches and furthermore we discuss the simultaneous development of animal models that can be used to measure subtle changes in -cell mass, a prerequisite for validating the clinical potential of the different imaging tracers.4

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“…Second, the pancreas is surrounded by the gastrointestinal system and liver, , and therefore, probe uptake in the latter organs obscures visualization of the pancreas . Several receptors or proteins that are selectively expressed on β-cell membranes have been described as potentially useful targets for β-cell imaging, including sulfonylurea receptor 1 (SUR1), , vesicular monoamine transporter 2 (VMAT2), − membrane protein IC2, − or transmembrane protein 27 (TMEM27). , However, all these targets show limitations such as heterogeneous or non-β-cell-specific expression, low absolute uptake, or even unspecific accumulation of the tracer . To date, the most promising probes are based on agonists of the glucagon like peptide 1 receptor (GLP-1R) , with proven high specificity for β-cells; however, some concerns exist whether potential downregulation of the receptor may influence uptake of the tracer. , This downregulation may lead to an erroneously low quantification of β-cell number.…”

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confidence: 99%

Synthesis and Characterization of a Promising Novel FFAR1/GPR40 Targeting Fluorescent Probe for β-Cell Imaging

et al. 2016

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Diabetes affects an increasing number of patients worldwide and is responsible for a significant rise in healthcare expenses. Imaging of β-cells bears the potential to contribute to an improved understanding, diagnosis, and development of new treatment options for diabetes. Here, we describe the first small molecule fluorescent probe targeting the free fatty acid receptor 1 (FFAR1/GPR40). This receptor is highly expressed on β-cells, and was up to now unexplored for imaging purposes. We designed a novel probe by facile modification of the selective and potent FFAR1 agonist TAK-875. Effective and specific binding of the probe was demonstrated using FFAR1 overexpressing cells. We also successfully labeled FFAR1 on MIN6 and INS1E cells, two widely used β-cell models, by applying an effective amplification protocol. Finally, we showed that the probe is capable of inducing insulin secretion in a glucose-dependent manner, thus demonstrating that functional activity of the probe was maintained. These results suggest that our probe represents a first important step to successful β-cell imaging by targeting FFAR1. The developed probe may prove to be particularly useful for in vitro and ex vivo studies of diabetic cellular and animal models to gain new insights into disease pathogenesis.

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A new view of the beta cell

Cited by 4 publications

References 18 publications

Automated Assessment of β-Cell Area and Density per Islet and Patient Using TMEM27 and BACE2 Immunofluorescence Staining in Human Pancreatic β-Cells

Automated Assessment of β-Cell Area and Density per Islet and Patient Using TMEM27 and BACE2 Immunofluorescence Staining in Human Pancreatic β-Cells

Pancreatic β‐cell imaging in humans: fiction or option?

Synthesis and Characterization of a Promising Novel FFAR1/GPR40 Targeting Fluorescent Probe for β-Cell Imaging

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