Low stress response enhances vulnerability of islet cells in diabetes-prone BB rats.
In islet cells isolated from normal outbred Wistar rats, the known high vulnerability of islet cells toward oxygen radicals or nitric oxide can be abolished by inducing a stress response, such as by heat shock. We show here that islet cells from diabetes-prone BB rats are unable to mount such a protective response. Islet cells from diabetes-prone BB rats without recognizable insulitis were heat stressed. Subsequently, cells were exposed to nitric oxide, to oxygen radicals, or to the beta-cell toxin streptozotocin. While prior heat shock substantially increased the survival of toxin-treated Wistar rat islet cells, no protective stress response was noted for islet cells from diabetes-prone BB rats. Islet cells from diabetes-resistant BB rats were protected by heat stress to the same extent as Wistar rats. A survey of four additional major histocompatibility complex (MHC)-disparate rat strains confirmed the existence of a low and high responder type to stress. Parallel analysis of heat shock protein (hsp)70 induction by Western blot showed a low and high hsp70 response phenotype. A high hsp70 response coincided with a protective stress response. The presence (or absence) of a protective stress response correlated with the preservation (or loss) of intracellular NAD+ in toxin-treated islet cells. The lack of a protective stress response in islet cells from diabetes-prone BB rats, but not in diabetes-resistant BB rats, may promote beta-cell lysis and autoantigen release, and hence could be important for initiation or propagation of the disease process.
Bellmann
K
K
Diabetes Research Institute at the University of Düsseldorf, Germany.
Hui
L
L
Radons
J
J
Burkart
V
V
Kolb
H
H
D000818:Animals; D002470:Cell Survival; D002478:Cells, Cultured; D006239:Haplotypes; D006360:Heat-Shock Proteins / Q000378:metabolism; D018869:Heat-Shock Response; D000949:Histocompatibility Antigens Class II / Q000235:genetics; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D008285:Major Histocompatibility Complex; D009599:Nitroprusside / Q000494:pharmacology; D051381:Rats; D011913:Rats, Inbred BB / Q000502:physiology*; D011916:Rats, Inbred F344 / Q000502:physiology; D017208:Rats, Wistar / Q000502:physiology; D013311:Streptozocin / Q000494:pharmacology; D014969:Xanthine Oxidase / Q000494:pharmacology
D006360:Heat-Shock Proteins; D000949:Histocompatibility Antigens Class II; D009599:Nitroprusside; D013311:Streptozocin; D014969:Xanthine Oxidase