Major species differences between humans and rodents in the susceptibility to pancreatic beta-cell injury.
The ability of beta cells to endure assaults may be relevant in the development of insulin-dependent diabetes mellitus. This study examines the susceptibility of human pancreatic islets to agents that are cytotoxic for rodent beta cells--i.e., sodium nitroprusside (NP, a nitric oxide donor), streptozotocin (SZ), or alloxan. After 5-8 days in tissue culture, human or rodent islets were exposed for 14 h to NP (50-200 microM) or for 30 min to SZ or alloxan (1-3 mM). Glucose oxidation by human islets was not reduced by NP, but there was a dose-dependent inhibition in rat (40-90% inhibition; P < 0.001) and mouse (10-60% inhibition; P < 0.05) islet glucose oxidation. Glucose (16.7 mM)-induced insulin release by human islets was not impaired after a 30-min exposure to SZ or alloxan, at concentrations that inhibited insulin release from rat (30-80% inhibition; P < 0.001) or mouse (10-70% inhibition; P < 0.05) islets. The viability of human beta cells purified by flow cytometry was not affected by SZ or alloxan (5 mM), as judged 1 or 4 days after a 10-min exposure and subsequent culture; these conditions were cytotoxic for rat beta cells, with 65-95% (P < 0.01) dead beta cells after 4 days. Human islets transplanted under the kidney capsule of nude mice were not affected by in vivo alloxan exposure, as suggested by preserved graft morphology and insulin content, whereas the endogenous beta cells of the transplanted mice were severely damage (80% decrease in pancreatic insulin content and morphological signs of beta-cell destruction). Thus human beta cells are resistant to NP, SZ, or alloxan at concentrations that decrease survival and function of rat or mouse beta cells. These marked interspecies differences emphasize the relevance of repair and/or defense mechanisms in beta-cell destruction and raise the possibility that such differences may also be present among individuals of the same species.
Eizirik
D L
DL
Department of Medical Cell Biology, Uppsala University, Sweden.
Pipeleers
D G
DG
Ling
Z
Z
Welsh
N
N
Hellerström
C
C
Andersson
A
A
D000496:Alloxan / Q000633:toxicity; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D051379:Mice; D009599:Nitroprusside / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D013045:Species Specificity; D013311:Streptozocin / Q000633:toxicity; D014021:Tissue Preservation
D007328:Insulin; D009599:Nitroprusside; D013311:Streptozocin; D000496:Alloxan; D005947:Glucose