The pancreatic beta cell surface proteome

Stützer, Ina; Esterházy, Daria; Stoffel, Markus

doi:10.1007/s00125-012-2531-3

Cited by 23 publications

(25 citation statements)

References 100 publications

(110 reference statements)

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“…In light of these statements, a new potential physiologic role of BACE2 in the pancreas emerges. It is known that BACE2 cleaves and regulates a broad set of β‐cell–enriched substrates, including transmembrane protein 27 (TMEM27) (22) and 2 proteins of the seizure 6 protein family (SEZ6L and SEZ6L2) (34, 35). In particular, TMEM27 is a transmembrane protein found at lower levels of expression in the islets of patients with diabetes compared to healthy controls and whose down‐regulation in the islets of rats treated with tungstate, exhibiting decreased insulin secretion in response to glucose, has also been described (36).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of BACE2 counteracts hIAPP‐induced insulin secretory defects in pancreatic β‐cells

et al. 2014

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BACE2 (b-site APP-cleaving enzyme 2) is a protease localized in the brain, where it appears to play a role in the development of Alzheimer disease (AD). It is also found in the pancreas, although its biologic function is not fully known. Amyloidogenic diseases, including AD and type 2 diabetes mellitus (T2D), share the accumulation of abnormally folded and insoluble proteins that interfere with cell function. Islet amyloid polypeptide (IAPP) deposits are a key pathogenic feature of T2D. Within this context, we found by global gene expression profiling that BACE2 was up-regulated in the rat pancreatic b-cell line INS1E stably transfected with human IAPP gene (hIAPP-INS1E). Glucose-stimulated insulin secretion (GSIS) in hIAPP-INS1E cells was 30% lower than in INS1E cells. Additionally, INS1E cells transfected with a transient overexpression of BACE2 showed a 60% decrease in proliferation, a 3-fold increase in reactive oxygen species production, and a 25% reduction in GSIS compared to control cells. Remarkably, silencing of endogenous BACE2 in hIAPP-INS1E cells resulted in a significant improvement in GSIS (3-fold increase vs. untransfected cells), revealing the significant role of BACE2 expression in b-cell function. Thus, BACE2 inhibition may be useful to recover insulin secretion in hIAPP-INS1E defective cells and may be proposed as a therapeutic target for T2D.-Alcarraz-Vizán, G., Casini, P., Cadavez, L., Visa, M., Montane, J., Servitja, J.-M., Novials, A. Inhibition of BACE2 counteracts hIAPP-induced insulin secretory defects in pancreatic b-cells. FASEB J. 29, 95-104 (2015). www.fasebj.org Key Words: amylin • BACE activity • secretase • type 2 diabetes INSULIN SECRETION DEFICIENCY plays a critical role in the onset of type 2 diabetes mellitus (T2D). It is well known that the progressive loss of b-cell mass and function are key features of the manifestation of the underlying disease (1). One of the main factors involved in the process of pancreatic b-cell deterioration is the accumulation of pancreatic amyloid deposits (2), which are considered a hallmark of T2D (3, 4). Because islet amyloid deposits colocalize with areas of b-cell degeneration, the process of amyloidosis has been strongly associated with a progressive loss of pancreatic b-cell mass and therefore with the pathology of T2D (5). Islet amyloid deposits are mainly composed by islet amyloid polypeptide (IAPP), a small peptide physiologically produced by pancreatic b-cells and cosecreted with insulin in response to different secretagogue stimuli (6, 7).The process of ordered aggregation into amyloid fibrils is a common event in many cell-degenerative diseases, such as Alzheimer disease (AD) and other local or systemic amyloidoses (8-10). A number of studies show that the toxicity of the amyloidogenic peptides lies in the oligomeric intermediates rather than in the mature fibrils. Thus, the conversion of a normally soluble protein into amyloid structures can allow for gained toxic function, providing a common mechanism by which amyloid contr...

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Section: Discussionmentioning

confidence: 99%

Inhibition of BACE2 counteracts hIAPP‐induced insulin secretory defects in pancreatic β‐cells

et al. 2014

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“…Ectodomain shedding of cell adhesion molecules can regulate their adhesive properties or signaling functions and be induced during natural processes such as protein turnover, cell division, differentiation, and morphological alterations linked to development as well as stress and tissue injury (65). For example, proteinuria that develops during preeclampsia is induced by nephrin shedding from podocytes as a result of endothelin-1 release from endothelial glomerular cells (66).…”

Section: Discussionmentioning

confidence: 99%

Kin of IRRE-like Protein 2 Is a Phosphorylated Glycoprotein That Regulates Basal Insulin Secretion

Yesildag

Bock

Herrmanns

et al. 2015

Journal of Biological Chemistry

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Background: Surface proteins fine-tune insulin secretion from pancreatic ␤-cells. Results: Kirrel2 is regulated by multiple post-translational modifications, and its expression influences basal insulin secretion. Conclusion: Kirrel2 expression is tightly regulated by phosphorylation and suppresses basal insulin secretion. Significance: Genetic and biochemical characterization of Kirrel2 in pancreatic ␤-cells reveals insight into regulation of protein stability and insulin secretion. Direct interactions among pancreatic ␤-cells via cell surface proteins inhibit basal and enhance stimulated insulin secretion.Here, we functionally and biochemically characterized Kirrel2, an immunoglobulin superfamily protein with ␤-cell-specific expression in the pancreas. Our results show that Kirrel2 is a phosphorylated glycoprotein that co-localizes and interacts with the adherens junction proteins E-cadherin and ␤-catenin in MIN6 cells. We further demonstrate that the phosphosites Tyr 595-596 are functionally relevant for the regulation of Kirrel2 stability and localization. Analysis of the extracellular and intracellular domains of Kirrel2 revealed that it is cleaved and shed from MIN6 cells and that the remaining membrane spanning cytoplasmic domain is processed by ␥-secretase complex. Kirrel2 knockdown with RNA interference in MIN6 cells and ablation of Kirrel2 from mice with genetic deletion resulted in increased basal insulin secretion from ␤-cells, with no immediate influence on stimulated insulin secretion, total insulin content, or whole body glucose metabolism. Our results show that in pancreatic ␤-cells Kirrel2 localizes to adherens junctions, is regulated by multiple post-translational events, including glycosylation, extracellular cleavage, and phosphorylation, and engages in the regulation of basal insulin secretion.Pancreatic ␤-cells sense fluctuations in metabolic demand, particularly minute changes in circulating glucose levels, and uniquely respond by secreting adequate amounts of insulin to regulate glucose homeostasis and metabolism (1). Loss of ␤-cell mass or impairment of normal insulin secretion results in diabetes, the most common metabolic disease in man that is characterized by hyperglycemia over a prolonged period (1). Hence, uncovering molecular mechanisms underlying normal ␤-cell function as well as those that lead to its dysfunction is crucial for understanding the pathology of diabetes and developing novel approaches for its treatment.During embryonic development, scattered ␤-cells aggregate with other ␤-cells and endocrine cells into small clusters that subsequently mature through a series of morphogenetic events to form endocrine micro-organs of the pancreas termed islets of Langerhans (2, 3). In pancreatic islets, several surface proteins mediate direct communication among ␤-cells and their neighbors (4). These integral membrane proteins selectively interact to adopt one or more of the following functions: establishment of adhesive links among adjacent cells (5, 6); assistance in the formation o...

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“…This led to an increase in accessibility of the biotherapeutic molecule to the binding site ). This result could be explained by the presence of zwitterionic molecules on the nanoparticles, caused by the bound insulin and N-linked glycoproteins on the rat b cells that self-assembled some structural motifs into polymer F2 (24,25). The negative surface charge of MIPs varied between -20 and -33 mV and contained the hydrophilic functionalities on the MIP binding sites and the negatively charged side chains.…”

Section: Synthesis and Characterization Of Mipsmentioning

confidence: 99%

Biomimetic insulin-imprinted polymer nanoparticles as a potential oral drug delivery system

2017

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In this study, we investigate molecularly imprinted polymers (MIPs), which form a three-dimensional image of the region at and around the active binding sites of pharmaceutically active insulin or are analogous to b cells bound to insulin. This approach was employed to create a welldefined structure within the nanospace cavities that make up functional monomers by cross-linking. The obtained MIPs exhibited a high adsorption capacity for the target insulin, which showed a significantly higher release of insulin in solution at pH 7.4 than at pH 1.2. In vivo studies on diabetic Wistar rats showed that the fast onset within 2 h is similar to subcutaneous injection with a maximum at 4 h, giving an engaged function responsible for the duration of glucose reduction for up to 24 h. These MIPs, prepared as nanosized material, may open a new horizon for oral insulin delivery.

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The pancreatic beta cell surface proteome

Cited by 23 publications

References 100 publications

Inhibition of BACE2 counteracts hIAPP‐induced insulin secretory defects in pancreatic β‐cells

Inhibition of BACE2 counteracts hIAPP‐induced insulin secretory defects in pancreatic β‐cells

Kin of IRRE-like Protein 2 Is a Phosphorylated Glycoprotein That Regulates Basal Insulin Secretion

Biomimetic insulin-imprinted polymer nanoparticles as a potential oral drug delivery system

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