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Glucosamine-induced alterations of mitochondrial function in pancreatic -cells: possible role of protein glycosylation

Unità Operativa di Medicina Interna, Laboratorio di Medicina Molecolare, Dipartimento di Scienze della Senescenza, Urologiche e Neurologiche, Università di Catania, Ospedale Cannizzaro, 95126 Catania, Italy

Submitted 15 July 2003 ; accepted in final form 11 May 2004

Chronic exposure of rat pancreatic islets and INS-1 insulinoma cells to glucosamine (GlcN) produced a reduction of glucose-induced (22.2 mM) insulin release that was associated with a reduction of ATP levels and ATP/ADP ratio compared with control groups. To further evaluate mitochondrial function and ATP metabolism, we then studied uncoupling protein-2 (UCP2), F₁-F₀-ATP-synthase, and mitochondrial membrane potential, a marker of F₁-F₀-ATP-synthase activity. UCP2 protein levels were unchanged after chronic exposure to GlcN on both pancreatic islets and INS-1 -cells. Due to the high number of cells required to measure mitochondrial F₁-F₀-ATP-synthase protein levels and mitochondrial membrane potential, we used INS-1 cells, and we found that chronic culture with GlcN increased F₁-F₀-ATP-synthase protein levels but decreased glucose-stimulated changes of mitochondrial membrane potential. Moreover, F₁-F₀-ATP-synthase was highly glycosylated, as demonstrated by experiments with N-glycosidase F and glycoprotein staining. Tunicamycin (an inhibitor of protein N-glycosylation), when added with GlcN in the culture medium, was able to partially prevent all these negative effects on insulin secretion, adenine nucleotide content, mitochondrial membrane potential, and protein glycosylation. Thus we suggest that GlcN-induced pancreatic -cell toxicity might be mediated by reduced cell energy production. An excessive protein N-glycosylation of mitochondrial F₁-F₀-ATP-synthase might lead to cell damage and secretory alterations in pancreatic -cells.

insulin release; adenine nucleotides; uncoupling protein-2; tunicamycin; F₁-F₀-adenosine triphosphate synthase

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