Mechanisms linking glucotoxicity to the development of insulin resistance: a role for the endoplasmic reticulum stress

Iadicicco, Claudia (2010) Mechanisms linking glucotoxicity to the development of insulin resistance: a role for the endoplasmic reticulum stress. [Tesi di dottorato] (Inedito)

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Abstract

Aims/hypothesis: Glucosamine, generated during hyperglycaemia, causes insulin resistance in different cells. Here we sought to evaluate the possible role of ER stress in the induction of insulin-resistance by glucosamine in skeletal muscle cells. Methods: Real-time RT-PCR analysis, 2-deoxy-D-glucose uptake and western blot analysis were carried out in rat and human muscle cell lines. Results: Glucosamine treatment causes both in rat and human myotubes a significant increase in the expression of the ER stress markers BIP, XBP1 and ATF6. In addition, glucosamine impairs insulin-stimulated 2-deoxyglucose uptake both in rat and human myotubes. Interestingly, pre-treatment of both rat and human myotubes with the chemical chaperones PBA or TUDCA, completely prevents the effect of glucosamine on both ER stress induction and insulin-induced glucose uptake. Glucosamine treatment reduces GLUT4 mRNA and protein levels and the mRNA levels of the main regulators of GLUT4 gene, MEF2A and PGC1α, both in rat and human myotubes. Again, PBA or TUDCA pre-treatment prevents glucosamine-induced inhibition of GLUT4, MEF2A and PGC1α. Finally, we show that overexpression of ATF6 is sufficient to inhibit the expression of Glut4, Mef2a and Pgc1a and that ATF6 silencing with a specific siRNA is sufficient to completely prevent glucosamine-induced inhibition of Glut4, Mef2a and Pgc1a in skeletal muscle cells. Conclusions/interpretation: In this work we show that glucosamine-induced ER stress causes insulin-resistance both in human and rat myotubes and impairs GLUT4 expression and insulin-induced glucose uptake via an ATF6-dependent decrease of the Glut4 regulators Mef2a and Pgc1a

Tipologia di documento:Tesi di dottorato
Parole chiave:Glucotoxicity, insulin resistance, ER stress
Settori scientifico-disciplinari MIUR:Area 06 Scienze mediche > MED/13 ENDOCRINOLOGIA
Coordinatori della Scuola di dottorato:
Coordinatore del Corso di dottoratoe-mail (se nota)
Avvedimento, Vittorio Enricoavvedim@unina.it
Tutor della Scuola di dottorato:
Tutor del Corso di dottoratoe-mail (se nota)
Beguinot, Francescobeguino@unina.it
Stato del full text:Accessibile
Data:26 Novembre 2010
Numero di pagine:80
Istituzione:Università degli studi di Napoli Federico II
Dipartimento o Struttura:Biologia e patologia cellullare e molecolare "L. Califano"
Tipo di tesi:Dottorato
Stato dell'Eprint:Inedito
Scuola di dottorato:Medicina molecolare
Denominazione del dottorato:Patologia e fisiopatologia molecolare
Ciclo di dottorato:23
Numero di sistema:7982
Depositato il:10 Dicembre 2010 11:32
Ultima modifica:23 Giugno 2011 13:33

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