VMAT2 gene expression and function as it applies to imaging β-cell mass

Harris, Paul E.; Ferrara, Caterina; Barba, Pasquale; Polito, Teresa; Freeby, Matthew; Maffei, Antonella

doi:10.1007/s00109-007-0242-x

Cited by 63 publications

(41 citation statements)

References 125 publications

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“…Ideally, two basic criteria should be met for adequate beta cell imaging [6]: (1) beta cells should retain the tracer 100-to 1,000-fold more than the exocrine cells; and (2) agents that label beta cell surface proteins should do this at high enough concentrations to overcome imaging signals arising from unbound tracer retained in the extracellular and vascular spaces, and from tracer bound to the other tissues surrounding the pancreas. Agents being tested currently for BCM imaging include glibenclamide [6], glucagon-like peptide 1 receptor [7,8], sulfonylurea receptor [6], vesicular monoamine transporter 2 (VMAT2) [9][10][11][12][13] and gangliosides [14]. Unfortunately, the uptake/binding of these agents to beta cells, compared with exocrine pancreas and non-beta cells, is insufficient to allow reliable imaging of the BCM [6,15].…”

Section: Introductionmentioning

confidence: 99%

“…Unfortunately, the uptake/binding of these agents to beta cells, compared with exocrine pancreas and non-beta cells, is insufficient to allow reliable imaging of the BCM [6,15]. For instance, the most promising beta cell marker, VMAT2, is produced in beta cells and monoaminergic neurons [10] but recent studies indicate that VMAT2 is also present in other islet cells besides beta cells [13]. Promising preliminary data were obtained with 11 C-labelled dihydrotetrabenazine (the PET ligand binding specifically to VMAT2) in streptozotocin (STZ)-induced diabetic Lewis rats [11] and in the BB-DP rat [12], but the data obtained in baboons [15] and in patients with longstanding type 1 diabetes [16] are not conclusive.…”

Section: Introductionmentioning

confidence: 99%

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A genomic-based approach identifies FXYD domain containing ion transport regulator 2 (FXYD2)γa as a pancreatic beta cell-specific biomarker

et al. 2010

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Aims/hypothesis Non-invasive imaging of the pancreatic beta cell mass (BCM) requires the identification of novel and specific beta cell biomarkers. We have developed a systems biology approach to the identification of promising beta cell markers. Methods We followed a functional genomics strategy based on massive parallel signal sequencing (MPSS) and microarray data obtained in human islets, purified primary rat beta cells, non-beta cells and INS-1E cells to identify promising beta cell markers. Candidate biomarkers were validated and screened using established human and macaque (Macacus cynomolgus) tissue microarrays.Results After a series of filtering steps, 12 beta cell-specific membrane proteins were identified. For four of the proteins we selected or produced antibodies targeting specifically the human proteins and their splice variants; all four candidates were confirmed as islet-specific in human D. Flamez and I. Roland contributed equally to this study. Electronic supplementary materialThe online version of this article

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A genomic-based approach identifies FXYD domain containing ion transport regulator 2 (FXYD2)γa as a pancreatic beta cell-specific biomarker

et al. 2010

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“…Previously developed β-cell-specific imaging agents have included labeled glucose analogs (or other small molecules) (1,2), antibodies (3), sulfonylureas (2,4), and vesicular monoamine transporter receptor agonists (5,6). In addition, a variety of transgenic strategies have been applied to mouse models (7,8).…”

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confidence: 99%

Accurate measurement of pancreatic islet β-cell mass using a second-generation fluorescent exendin-4 analog

Reiner

Thurber

Gaglia³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

113

126

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The hallmark of type 1 diabetes is autoimmune destruction of the insulin-producing β-cells of the pancreatic islets. Autoimmune diabetes has been difficult to study or treat because it is not usually diagnosed until substantial β-cell loss has already occurred. Imaging agents that permit noninvasive visualization of changes in β-cell mass remain a high-priority goal. We report on the development and testing of a near-infrared fluorescent β-cell imaging agent. Based on the amino acid sequence of exendin-4, we created a neopeptide via introduction of an unnatural amino acid at the K 12 position, which could subsequently be conjugated to fluorophores via bioorthogonal copper-catalyzed click-chemistry. Cell assays confirmed that the resulting fluorescent probe (E4 ×12 -VT750) had a high binding affinity (∼3 nM). Its in vivo properties were evaluated using high-resolution intravital imaging, histology, whole-pancreas visualization, and endoscopic imaging. According to intravital microscopy, the probe rapidly bound to β-cells and, as demonstrated by confocal microscopy, it was internalized. Histology of the whole pancreas showed a close correspondence between fluorescence and insulin staining, and there was an excellent correlation between imaging signals and β-cell mass in mice treated with streptozotocin, a β-cell toxin. Individual islets could also be visualized by endoscopic imaging. In short, E4 ×12 -VT750 showed strong and selective binding to glucose-like peptide-1 receptors and permitted accurate measurement of β-cell mass in both diabetic and nondiabetic mice. This near-infrared imaging probe, as well as future radioisotope-labeled versions of it, should prove to be important tools for monitoring diabetes, progression, and treatment in both experimental and clinical contexts.

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“…44,45 to produce a significant amount of insulin. 49 The Diabetes control and complications trial (DCCT) found that 20 % of patients studied, who were within five years of diagnosis, had remaining endogenous insulin production as measured by C-peptide levels; 50 within the first five years after diagnosis, immunologic intervention can potentially save β-cell function and reduce reliance on insulin administration.…”

Section: Pancreatic Pathologymentioning

confidence: 99%

Understanding the Immunology of Type 1 Diabetes – An Overview of Current Knowledge and Perspectives for the Future

Piya¹,

Michels²

2010

European Endocrinology

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Type 1 diabetes is classified into two types by the American Diabetes Association; type 1A diabetes is the immune-mediated form and type 1B the non-immune mediated form of the disease, both leading to β-cell destruction and absolute insulin deficiency.It is estimated that approximately 1.5 million people in the US have type 1A diabetes. The incidence of type 1 diabetes is increasing worldwide at a rate of 3-5 % each year. Strikingly, it has doubled in each of the last two decades, children less than five years of age being the most commonly affected group. It was previously thought that the concordance rate for monozygotic twins with type 1 diabetes was relatively low (<50 %); however, following a cohort of monozygotic twins for longer than 50 years, the concordance rate for type 1 diabetes development is 66 %.A recent analysis of these long-term twin data indicates that there is no age at which an initially discordant monozygotic twin is no longer at risk, with some developing type 1 diabetes in the fourth and fifth decades of life. 17The major genetic determinant of type 1 diabetes is conferred by genes in the human leukocyte antigen (HLA) complex, which is divided into three regions: class I, II, and III. Alleles of the class II genes, DQ and DR (and to a lesser extent DP), are the most important determinants of type 1 diabetes. These major histocompatibility complex (MHC) class II molecules are expressed on antigen-presenting cells (macrophages, dendritic cells, and B cells) and present antigens to CD4+ T lymphocytes.DQ2 and DQ8 alleles are strongly associated with type 1 diabetes and more than 90 % of people with type 1A diabetes possess one or both of these genes, compared with 40 % of the US population in general.18 AbstractType 1 diabetes is a chronic autoimmune disease resulting from the immune destruction of insulin-producing β-cells in pancreatic islets.It is now a predicable disease in humans with the measurement of islet autoantibodies. Despite the ability to assess disease risk, there is no cure for type 1 diabetes and treatment requires lifelong insulin administration. Individuals with type 1 diabetes are at risk of long-term complications of the disease and the development of concomitant autoimmune disorders. Our understanding of the immunology of diabetes has increased greatly over the last decade at a basic science level, with translation to type 1 diabetes patients. Therapies are emerging to prevent beta cell destruction in these patients. This article centres around our current understanding of the immunology of type 1 diabetes, with a focus on immune intervention for the prevention and ultimate cure of the disease.

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VMAT2 gene expression and function as it applies to imaging β-cell mass

Cited by 63 publications

References 125 publications

A genomic-based approach identifies FXYD domain containing ion transport regulator 2 (FXYD2)γa as a pancreatic beta cell-specific biomarker

A genomic-based approach identifies FXYD domain containing ion transport regulator 2 (FXYD2)γa as a pancreatic beta cell-specific biomarker

Accurate measurement of pancreatic islet β-cell mass using a second-generation fluorescent exendin-4 analog

Understanding the Immunology of Type 1 Diabetes – An Overview of Current Knowledge and Perspectives for the Future

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