engleski

Role of amylin in pancreatic beta-cell death

Amylin is a 37-amino acid peptide that is co-synthesized, co-stored and co-secreted with insulin in pancreatic beta-cells. Amylin is the major component of islet amyloid found in the pancreas of >90% patients with type 2 diabetes mellitus, and the increase of the pancreatic amyloid deposits correlates with the gradual destruction of beta-cells. In this study we addressed the question whether the mechanism underlying induction of islet beta– cell death by human amylin involves activation of mitogen-activated protein kinase (MAPK) family members and/or the caspase machinery. We employed rat insulinoma RINm5F cells, a well-established model cell line for studying pancreatic islet beta-cells. Nanomolar concentrations of human amylin promoted death of RINm5F cells in a time- and in a concentration-dependent manner. Morphological changes of membrane and chromatin integrity suggested that cells were predominantly dying by the process of apoptosis. Human amylin induced strong and sustained phosphorylation of stress kinases, c-Jun N-terminal kinase (JNK) and p38 MAPK, and significant activation of caspase-3, that preceded cell death. Correlative inhibition of JNK activation by immunosuppressive drug FK506 as well as direct inhibition of p38 MAPK activation by SB 203580, significantly suppressed procaspase-3 processing and the extent of amylin-induced cell death. Moreover, simultaneous pretreatment with both FK506 and SB 203580 or with caspase-3 inhibitor Ac-DEVD-CHO alone almost completely abolished procaspase-3 processing and cell death. Thus, our results suggest that amylin-induced apoptosis of RINm5F cells proceeds through strong and sustained activation of JNK and p38 MAPK followed by caspase-3 activation.

amylin; apoptosis

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