Roles of poly(ADP-ribose) polymerase activation in the pathogenesis of diabetes mellitus and its complications.
Activation of poly(ADP-ribose) polymerase (PARP) plays a role in the pathogenesis of beta-cell necrosis that occurs in response to autoimmune disease associated with Type I diabetes. In addition, PARP activation also plays a role in the pathogenesis of endothelial injury that underlies the ethiology of various diabetic complications (vasculopathy, cardiomyopathy, retinopathy, neuropathy), which develop on the basis of chronically elevated circulating glucose levels in diabetes. Both during the pathogenesis of diabetes and during the pathogenesis of diabetic complications, free radical and oxidant production leads to DNA strand-breakage which activates the nuclear enzyme PARP and initiates an energy consuming, inefficient cellular metabolic cycle with transfer of the ADP-ribosyl moiety of NAD+ to protein acceptors. These processes lead to the functional impairment of the affected cells (beta-cells or vascular endothelial cells, respectively). PARP also promotes the activation of various pro-inflammatory signal transduction pathways. During the last two decades, a growing number of experimental studies demonstrated the beneficial effects PARP inhibition in various models of diabetes and diabetic complications. The current review provides an overview of the experimental evidence implicating PARP as a causative factor in the pathogenesis of diabetes and diabetic complications in vitro and in vivo.
Szabó
Csaba
C
Inotek Pharmaceuticals Corporation, Suite 419 E, 100 Cummings Center, Beverly, MA 01915, USA. szabocsaba@aol.com
D000818:Animals; D017209:Apoptosis; D004249:DNA Damage; D048909:Diabetes Complications / Q000201:enzymology / Q000209:etiology*; D003920:Diabetes Mellitus / Q000201:enzymology / Q000209:etiology*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D006801:Humans; D007515:Islets of Langerhans / Q000473:pathology; D009249:NADP / Q000378:metabolism; D009569:Nitric Oxide / Q000502:physiology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000502:physiology*
D004791:Enzyme Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D009569:Nitric Oxide; D009249:NADP; D011065:Poly(ADP-ribose) Polymerases