title: Microarray analysis of isolated human islet transcriptome in type 2 diabetes and the role of the ubiquitin-proteasome system in pancreatic beta cell dysfunction.
abstract: To shed light on islet cell molecular phenotype in human type 2 diabetes (T2D), we studied the transcriptome of non-diabetic (ND) and T2D islets to then focus on the ubiquitin-proteasome system (UPS), the major protein degradation pathway. We assessed gene expression, amount of ubiquitinated proteins, proteasome activity, and the effects of proteasome inhibition and prolonged exposure to palmitate. Microarray analysis identified more than one thousand genes differently expressed in T2D islets, involved in many structures and functions, with consistent alterations of the UPS. Quantitative RT-PCR demonstrated downregulation of selected UPS genes in T2D islets and beta cell fractions, with greater ubiquitin accumulation and reduced proteasome activity. Chemically induced reduction of proteasome activity was associated with lower glucose-stimulated insulin secretion, which was partly reproduced by palmitate exposure. These results show the presence of many changes in islet transcriptome in T2D islets and underline the importance of the association between UPS alterations and beta cell dysfunction in human T2D.
authors.affiliation: Department of Clinical and Experimental Medicine, Islet Cell Laboratory, University of Pisa, Pisa 56124, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Bugliani
authors.forename: Robin
authors.initials: R
authors.lastname: Liechti
authors.forename: Hwanju
authors.initials: H
authors.lastname: Cheon
authors.forename: Mara
authors.initials: M
authors.lastname: Suleiman
authors.forename: Lorella
authors.initials: L
authors.lastname: Marselli
authors.forename: Clare
authors.initials: C
authors.lastname: Kirkpatrick
authors.forename: Franco
authors.initials: F
authors.lastname: Filipponi
authors.forename: Ugo
authors.initials: U
authors.lastname: Boggi
authors.forename: Ioannis
authors.initials: I
authors.lastname: Xenarios
authors.forename: Farooq
authors.initials: F
authors.lastname: Syed
authors.forename: Laurence
authors.initials: L
authors.lastname: Ladriere
authors.forename: Claes
authors.initials: C
authors.lastname: Wollheim
authors.forename: Myung-Shik
authors.initials: MS
authors.lastname: Lee
authors.forename: Piero
authors.initials: P
authors.lastname: Marchetti
mesh_terms: D000368:Aged; D000818:Animals; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D010168:Palmitates / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000494:pharmacology; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D059467:Transcriptome / Q000235:genetics*; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism*; D057149:Ubiquitinated Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D007328:Insulin; D010168:Palmitates; D061988:Proteasome Inhibitors; D025801:Ubiquitin; D057149:Ubiquitinated Proteins; D046988:Proteasome Endopeptidase Complex