title: Altered expression of uncoupling protein 2 in GLP-1-producing cells after chronic high glucose exposure: implications for the pathogenesis of diabetes mellitus.
abstract: Glucagon-like peptide-1 (GLP-1) is a gut L-cell hormone that enhances glucose-stimulated insulin secretion. Several approaches that prevent GLP-1 degradation or activate the GLP-1 receptor are being used to treat type 2 diabetes mellitus (T2DM) patients. In T2DM, GLP-1 secretion has been suggested to be impaired, and this defect appears to be a consequence rather than a cause of impaired glucose homeostasis. However, although defective GLP-1 secretion has been correlated with insulin resistance, little is known about the direct effects of chronic high glucose concentrations, which are typical in diabetes patients, on GLP-1-secreting cell function. In the present study, we demonstrate that glucotoxicity directly affects GLP-1 secretion in GLUTag cells chronically exposed to high glucose. Our results indicate that this abnormality is associated with a decrease in ATP production due to the elevated expression of mitochondrial uncoupling protein 2 (UCP2). Furthermore, UCP2 inhibition using small interfering RNA (siRNA) and the application of glibenclamide, an ATP-sensitive potassium (KATP(+)) channel blocker, reverse the GLP-1 secretion defect induced by chronic high-glucose treatment. These results show that glucotoxicity diminishes the secretory responsiveness of GLP-1-secreting cells to acute glucose stimulation. We conclude that the loss of the incretin effect, as observed in T2DM patients, could at least partially depend on hyperglycemia, which is typical in diabetes patients. Such an understanding may not only provide new insight into diabetes complications but also ultimately contribute to the identification of novel molecular targets within intestinal L-cells for controlling and improving endogenous GLP-1 secretion.
authors.affiliation: Department of Clinical and Experimental Medicine, Garibaldi-Nesima Hospital, University of Catania, Catania, Italy; and.
authors.forename: Francesca
authors.initials: F
authors.lastname: Urbano
authors.affiliation: Department of Clinical and Experimental Medicine, Garibaldi-Nesima Hospital, University of Catania, Catania, Italy; and.
authors.forename: Agnese
authors.initials: A
authors.lastname: Filippello
authors.affiliation: Department of Clinical and Experimental Medicine, Garibaldi-Nesima Hospital, University of Catania, Catania, Italy; and.
authors.forename: Antonino
authors.initials: A
authors.lastname: Di Pino
authors.affiliation: Department of BioMedical Sciences and BioTechnology, section of Biology and Genetics Giovanni Sichel, Unit of Molecular, Genome and Complex Systems BioMedicine, University of Catania, Catania, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Barbagallo
authors.affiliation: Department of Clinical and Experimental Medicine, Garibaldi-Nesima Hospital, University of Catania, Catania, Italy; and.
authors.forename: Stefania
authors.initials: S
authors.lastname: Di Mauro
authors.affiliation: Department of Clinical and Experimental Medicine, Garibaldi-Nesima Hospital, University of Catania, Catania, Italy; and.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Pappalardo
authors.affiliation: Department of Clinical and Experimental Medicine, Garibaldi-Nesima Hospital, University of Catania, Catania, Italy; and.
authors.forename: Agata Maria
authors.initials: AM
authors.lastname: Rabuazzo
authors.affiliation: Department of BioMedical Sciences and BioTechnology, section of Biology and Genetics Giovanni Sichel, Unit of Molecular, Genome and Complex Systems BioMedicine, University of Catania, Catania, Italy fpurrell@unict.it.
authors.forename: Michele
authors.initials: M
authors.lastname: Purrello
authors.affiliation: Department of Clinical and Experimental Medicine, Garibaldi-Nesima Hospital, University of Catania, Catania, Italy; and.
authors.forename: Francesco
authors.initials: F
authors.lastname: Purrello
authors.affiliation: Department of Clinical and Experimental Medicine, Garibaldi-Nesima Hospital, University of Catania, Catania, Italy; and.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Piro
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism*; D005947:Glucose / Q000633:toxicity*; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism; D007473:Ion Channels / Q000096:biosynthesis*; D051379:Mice; D024101:Mitochondrial Proteins / Q000096:biosynthesis*; D016133:Polymerase Chain Reaction; D034741:RNA, Small Interfering / Q000235:genetics; D014162:Transfection; D000071246:Uncoupling Protein 2
chemical_list: D007473:Ion Channels; D024101:Mitochondrial Proteins; D034741:RNA, Small Interfering; C000604390:Ucp2 protein, mouse; D000071246:Uncoupling Protein 2; D052216:Glucagon-Like Peptide 1; D005947:Glucose
keywords: ATP; UCP2; glucagon-like peptide-1; gut hormones; incretins; intestinal L-cell; metabolism