THE ROLE OF 12-LIPOXYGENASE IN PANCREATIC BETA-CELLS (REVIEW)

Leukocyte type 12-lipoxygenase (12-LO) catalyzes the conversion of ara chidonic acid (AA; C20:4) to 12-hydroperoxyeicosatetraenoic acid (12-H PETE) and linoleic acid (LA; C18:2) to 13-hydroperoxyoctadecadienoic a cid (13-HPODE). Previous studies have demonstrated that 12-LO, but not 5- or 15-lipoxygenase (5-LO, 15-LO respectively), is specifically exp ressed in pancreatic beta-cells and is involved in regulating glucose- stimulated insulin secretion. Lipoxygenase products also have been lin ked with inflammatory pathways in endothelial cells, kidney mesangial cells, inflammatory bowel disease, and corneal epithelial cells. There fore, 12-LO may play a role in cytokine mediated inflammation in pancr eatic beta-cells (i.e. beta-cell dysfunction and cytotoxicity). Cytoki nes such as IL-1 beta stimulate both de novo 12-LO protein synthesis a nd enzyme activity in pancreatic beta-cells. The products generated by 12-LO may ultimately be involved in cellular events that lead to lipi d peroxidation. Hydroperoxide and free radical production in beta-cell s can activate intracellular signaling pathways that lead to cell deat h or may directly damage mitochondrial and plasma membranes. Increased 12-LO expression has also been found in islets from prediabetic Zucke r fatty rats, a model that demonstrates insulin secretory defects simi lar to human type 2 diabetes. In this review, we present an overview o f the 12-LO pathway in regulating glucose-stimulated insulin secretion in beta-cells as well as more recent data which supports the hypothes is that the 12-LO pathway participates in cytokine mediated beta-cell dysfunction and cytotoxicity.