Unexpected sensitivity of nonobese diabetic mice with a disrupted poly(ADP-Ribose) polymerase-1 gene to streptozotocin-induced and spontaneous diabetes.
Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear enzyme that consumes NAD in response to DNA strand breaks. Its excessive activation seems particularly deleterious to pancreatic beta-cells, as exemplified by the complete resistance of PARP-1-deficient mice to the toxic diabetes induced by streptozotocin. Because of the possible implication of this enzyme in type 1 diabetes, many human trials using nicotinamide, an inhibitor of PARP-1, have been conducted either in patients recently diagnosed or in subjects highly predisposed to this disease. To analyze the role of this enzyme in murine type 1 diabetes, we introgressed a disrupted PARP-1 allele onto the autoimmune diabetes-prone nonobese diabetic (NOD) mouse strain. We showed that these mice were protected neither from spontaneous nor from cyclophosphamide-accelerated diabetes. Surprisingly they were also highly sensitive to the diabetes induced by a single high dose of streptozotocin, standing in sharp contrast with C57BL/6 mice that bear the same inactivated PARP-1 allele. Our results suggest that NOD mice are characterized not only by their immune dysfunction but also by a peculiarity of their islets leading to a PARP-1-independent mechanism of streptozotocin-induced beta-cell death.
Gonzalez
Cristina
C
Institut National de la Santé et de la Recherche Médicale, Unité 25, Hôpital Necker, Paris, France.
Ménissier De Murcia
Josiane
J
Janiak
Philip
P
Bidouard
Jean-Pierre
JP
Beauvais
Catherine
C
Karray
Saoussen
S
Garchon
Henri-Jean
HJ
Lévi-Strauss
Matthieu
M
D000818:Animals; D003520:Cyclophosphamide; D003921:Diabetes Mellitus, Experimental / Q000235:genetics* / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D005260:Female; D020022:Genetic Predisposition to Disease; D007515:Islets of Langerhans / Q000276:immunology / Q000473:pathology; D008214:Lymphocytes / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics*; D013047:Specific Pathogen-Free Organisms; D013154:Spleen / Q000276:immunology
D003520:Cyclophosphamide; D011065:Poly(ADP-ribose) Polymerases