Mice lacking the poly(ADP-ribose) polymerase gene are resistant to pancreatic beta-cell destruction and diabetes development induced by streptozocin

Abstract

Human type 1 diabetes results from the selective destruction of insulin-producing pancreatic beta cells during islet inflammation. Cytokines and reactive radicals released during this process contribute to beta-cell death. Here we show that mice with a disrupted gene coding for poly (ADP-ribose) polymerase (PARP-/- mice) are completely resistant to the development of diabetes induced by the beta-cell toxin streptozocin. The mice remained normoglycemic and maintained normal levels of total pancreatic insulin content and normal islet ultrastructure. Cultivated PARP-/- islet cells resisted streptozocin-induced lysis and maintained intracellular NAD+ levels. Our results identify NAD+ depletion caused by PARP activation as the dominant metabolic event in islet-cell destruction, and provide information for the development of strategies to prevent the progression or manifestation of the disease in individuals at risk of developing type 1 diabetes.

Genetic control of non obese diabetic mice susceptibility to high-dose streptozotocin-induced diabetes

“…Whereas PARP-1 activation and subsequent NAD + depletion have been implicated as a major mechanism of HDS-induced pancreatic beta-cell destruction [27,28,29], we did not detect any linkage of NOD HDSsusceptiblity to the D1Mit36 (92.3 cM) and D1Mit407 (101.5 cM) markers surrounding the corresponding gene at 98.6 cM in chromosome 1. This result is not really surprising since our previous studies showed that, in the NOD mouse, PARP-1 activation was not required for HDS-induced diabetes [6].…”

The mechanisms of alloxan- and streptozotocin-induced diabetes

“…Also, mice deficient in PARP are resistant to beta cell death mediated by streptozotocin, in spite of DNA fragmentation. The absence of PARP prevents the depletion of the cofactor NAD + and the subsequent loss of ATP [84,[88][89][90] and thus cell death.…”

Little evidence of transdifferentiation of bone marrow-derived cells into pancreatic beta cells

“…Multiple subdiabetogenic doses of STZ provoke different changes in the pancreas from a single injection of a diabetogenic dose of STZ [17,18,19] and enable us to observe the re-organization of pancreatic beta cells [20]. Thus, multiple low doses of STZ are considered to create a good model for observing regeneration after beta-cellspecific injury.…”