A5078496713- Pancreatic function and diabetes
- Trace Elements in Health
- Calcium signaling and nucleotide metabolism
- Diabetes Treatment and Management
- Adenosine and Purinergic Signaling
- Genetics and Neurodevelopmental Disorders
- Protein Tyrosine Phosphatases
- RNA modifications and cancer
- Folate and B Vitamins Research
- Iron Metabolism and Disorders
- RNA and protein synthesis mechanisms
- Diabetes and associated disorders
- Mitochondrial Function and Pathology
- Advanced biosensing and bioanalysis techniques
- Pancreatitis Pathology and Treatment
- Endoplasmic Reticulum Stress and Disease
- Ion Channels and Receptors
- ATP Synthase and ATPases Research
- Edible Oils Quality and Analysis
- Plant Molecular Biology Research
- Metabolism, Diabetes, and Cancer
- Pediatric Hepatobiliary Diseases and Treatments
- Vanadium and Halogenation Chemistry
- Inflammatory Bowel Disease
- Synthesis of Organic Compounds
Azienda Ospedaliera Nazionale SS. Antonio e Biagio e Cesare Arrigo
2021
King's College London
2014-2018
Imperial College London
2008-2017
Centre des Sciences du Goût et de l'Alimentation
2015
Hammersmith Hospital
2014
Indiana University School of Medicine
2014
Institute of Cell Biology
2013
Universidad de Londres
2012
Agruicultural Research Institute
2011
Università degli Studi del Piemonte Orientale “Amedeo Avogadro”
2006
Free fatty acids (FFA) cause apoptosis of pancreatic beta-cells and might contribute to beta-cell loss in type 2 diabetes via the induction endoplasmic reticulum (ER) stress. We studied here molecular mechanisms implicated FFA-induced ER stress initiation INS-1E cells, FACS-purified primary human islets exposed oleate and/or palmitate. Treatment with saturated unsaturated FFA led differential signaling. Palmitate induced more markedly activated IRE1, PERK ATF6 pathways, owing a sustained...
OBJECTIVE Zinc ions are essential for the formation of hexameric insulin and hormone crystallization. A nonsynonymous single nucleotide polymorphism rs13266634 in SLC30A8 gene, encoding secretory granule zinc transporter ZnT8, is associated with type 2 diabetes. We describe effects deleting ZnT8 gene mice explore action at-risk allele. RESEARCH DESIGN AND METHODS Slc30a8 null were generated backcrossed at least twice onto a C57BL/6J background. Glucose tolerance measured by intraperitoneal...
Pancreatic β cell dysfunction is pathognomonic of type 2 diabetes mellitus (T2DM) and driven by environmental genetic factors. responses to glucose incretins such as glucagon-like peptide-1 (GLP-1) glucose-dependent insulinotropic polypeptide (GIP) are altered in the disease state. While rodent cells act a coordinated syncytium drive insulin release, this property unexplored human islets. In situ imaging approaches were therefore used monitor real time islet dynamics underlying hormone...
Glucose induces insulin release from pancreatic β-cells by stimulating ATP synthesis, membrane depolarisation and Ca2+ influx. As well as activating ATP-consuming processes, cytosolic increases may also potentiate mitochondrial synthesis. Until recently, the ability to study role of transport in glucose-stimulated secretion has been hindered absence suitable approaches either suppress uptake into these organelles, or examine impact on β-cell excitability. Here, we have combined patch-clamp...
Current methods of monitoring insulin secretion lack the required spatial and temporal resolution to adequately map dynamics exocytosis native granules in intact cell populations three dimensions. Exploiting fact that contain a high level Zn 2+ , is coreleased with during secretion, we have developed fluorescent, surface-targeted zinc indicator for induced exocytotic release (ZIMIR). ZIMIR displayed robust fluorescence enhancement on chelation bound selectivity against Ca Mg . When added...
Zinc (Zn2+) ions are increasingly recognized as playing an important role in cellular physiology. Whereas the free Zn2+ concentration cytosol has been established to be 0.1-1 nM, subcellular organelles is not well-established. Here, we extend eCALWY family of genetically encoded Förster Resonance Energy Transfer (FRET) probes permit measurements endo(sarco)plasmic reticulum (ER) and mitochondrial matrix. Deployed a variety mammalian cell types, these reveal resting [Zn2+] values ∼300 pM,...
Protein tyrosine phosphatases (PTPs) are key enzymes in cellular regulation. The 107 human PTPs regulated by redox signalling, phosphorylation, dimerisation, and proteolysis. Recent findings of very strong inhibition some zinc ions at concentrations relevant a environment suggest yet another mechanism One the most extensively investigated is PTP1B (PTPN1). It regulates insulin leptin signalling pathway implicated cancer obesity/diabetes. development novel assay conditions to investigate...
Zn2+ is an important cofactor for insulin biosynthesis and storage in pancreatic β-cells. Correspondingly, polymorphisms the SLC30A8 gene, encoding secretory granule transporter ZnT8, are associated with type 2 diabetes risk. Using a genetically engineered (FRET)-based sensor (eCALWY-4), we show here that elevated glucose time-dependently increases free cytosolic ([Zn2+]cyt) mouse These changes become highly significant (853 ± 96 pm versus 452 42 pm, p < 0.001) after 24 h increased...
Zinc is an important micronutrient, essential in the diet to avoid a variety of conditions associated with malnutrition such as diarrhoea and alopecia. Lowered circulating levels zinc are also found diabetes mellitus, condition which affects one twelve adult population whose treatments consume approximately 10 % healthcare budgets. Zn2+ ions for huge range cellular functions and, specialised pancreatic β-cell, storage insulin within secretory granule. Correspondingly, genetic variants...
Zinc transporter 8 (ZnT8), encoded by SLC30A8, is chiefly expressed within pancreatic islet cells, where it mediates zinc (Zn(2+)) uptake into secretory granules. Although a common nonsynonymous polymorphism (R325W), which lowers activity, associated with increased type 2 diabetes (T2D) risk, rare inactivating mutations in SLC30A8 have been reported to protect against T2D. Here, we generate and characterize new mouse models explore the impact on glucose homeostasis of graded changes ZnT8...
Wolfram syndrome is an autosomal recessive disorder characterized by neurodegeneration and diabetes mellitus. The gene responsible for the (WFS1) encodes endoplasmic reticulum (ER)-resident transmembrane protein that involved in regulation of unfolded response (UPR), intracellular ion homeostasis, cyclic adenosine monophosphate production insulin biosynthesis secretion. In this study, single cell Ca2+ imaging with fura-2 direct measurements free cytosolic ATP concentration ([ATP]CYT)...
Pancreatic β cells are electrically excitable and respond to elevated glucose concentrations with bursts of Ca2+ action potentials due the activation voltage-dependent channels (VDCCs), which leads exocytosis insulin granules. We have examined possible role nicotinic acid adenine dinucleotide phosphate (NAADP)-mediated release from intracellular stores during stimulus-secretion coupling in primary mouse pancreatic cells. NAADP-regulated channels, likely two-pore (TPCs), recently been shown...
SLC30A8 encodes a zinc transporter ZnT8 largely restricted to pancreatic islet β- and α-cells, responsible for accumulation into secretory granules. Although common variants, believed reduce activity, increase type 2 diabetes risk in humans, rare inactivating mutations are protective. To investigate the role of Slc30a8 control glucagon secretion, was inactivated selectively α-cells by crossing mice with alleles floxed at exon 1 animals expressing Cre recombinase under pre-proglucagon...
Hypoxic damage complicates islet isolation for transplantation and may contribute to beta cell failure in type 2 diabetes. Polymorphisms the SLC30A8 gene, encoding secretory granule zinc transporter 8 (ZnT8), influence diabetes risk, conceivably by modulating cytosolic Zn(2+) levels. We have therefore explored role of ZnT8 response hypoxia pancreatic cells.
While the majority of phosphatases are metalloenzymes, prevailing model for reactions catalyzed by protein tyrosine does not involve any metal ion, yet both cations and oxoanions affect their enzymatic activity. Mg2+ Zn2+ activate inhibit, respectively, phosphatase 1B (PTP1B). Molecular dynamics simulations, metadynamics, quantum chemical calculations in combination with experimental investigations demonstrate that compete same binding site active only closed conformation enzyme its...
NAADP is a second messenger that releases Ca2+ from intracellular stores. Surprisingly, it has been recently shown extracellular application of capable inducing release. This particularly important since the only mammalian enzymes known to catalyze synthesis this are located extracellularly. In present manuscript, we have investigated whether cells possess transport system transporting highly charged molecule into cells. Indeed, in RBL-2H3 cells, rat basophilic cell line, and SK-N-BE...