MAJOR SPECIES-DIFFERENCES BETWEEN HUMANS AND RODENTS IN THE SUSCEPTIBILITY TO PANCREATIC BETA-CELL INJURY

被引:251
作者
EIZIRIK, DL [1 ]
PIPELEERS, DG [1 ]
LING, ZD [1 ]
WELSH, N [1 ]
HELLERSTROM, C [1 ]
ANDERSSON, A [1 ]
机构
[1] FREE UNIV BRUSSELS, DEPT METAB & ENDOCRINOL, B-1090 BRUSSELS, BELGIUM
关键词
NITRIC OXIDE; STREPTOZOTOCIN; ALLOXAN; INSULIN-DEPENDENT DIABETES MELLITUS;
D O I
10.1073/pnas.91.20.9253
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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 mu M) 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 tells 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 damaged (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.
引用
收藏
页码:9253 / 9256
页数:4
相关论文
共 25 条
[2]   IT WAS A VERY GOOD YEAR FOR DNA-REPAIR [J].
CLEAVER, JE .
CELL, 1994, 76 (01) :1-4
[3]   DOES NITRIC-OXIDE MEDIATE AUTOIMMUNE DESTRUCTION OF BETA-CELLS - POSSIBLE THERAPEUTIC INTERVENTIONS IN IDDM [J].
CORBETT, JA ;
MCDANIEL, ML .
DIABETES, 1992, 41 (08) :897-903
[4]  
EISENBARTH GS, 1986, NEW ENGL J MED, V314, P1360
[5]   CYTOKINES SUPPRESS HUMAN ISLET FUNCTION IRRESPECTIVE OF THEIR EFFECTS ON NITRIC-OXIDE GENERATION [J].
EIZIRIK, DL ;
SANDLER, S ;
WELSH, N ;
CETKOVICCVRLJE, M ;
NIEMAN, A ;
GELLER, DA ;
PIPELEERS, DG ;
BENDTZEN, K ;
HELLERSTROM, C .
JOURNAL OF CLINICAL INVESTIGATION, 1994, 93 (05) :1968-1974
[6]   FUNCTIONAL RESTORATION OF CULTURED MOUSE PANCREATIC-ISLETS AFTER INVITRO EXPOSURE TO ALLOXAN [J].
EIZIRIK, DL ;
SANDLER, S .
PHARMACOLOGY & TOXICOLOGY, 1988, 63 (05) :396-399
[7]   REPAIR OF PANCREATIC BETA-CELLS - A RELEVANT PHENOMENON IN EARLY IDDM [J].
EIZIRIK, DL ;
SANDLER, S ;
PALMER, JP .
DIABETES, 1993, 42 (10) :1383-1391
[8]   PROLONGED EXPOSURE OF HUMAN PANCREATIC-ISLETS TO HIGH GLUCOSE-CONCENTRATIONS INVITRO IMPAIRS THE BETA-CELL FUNCTION [J].
EIZIRIK, DL ;
KORBUTT, GS ;
HELLERSTROM, C .
JOURNAL OF CLINICAL INVESTIGATION, 1992, 90 (04) :1263-1268
[9]   PREFERENTIAL REDUCTION OF INSULIN PRODUCTION IN MOUSE PANCREATIC-ISLETS MAINTAINED IN CULTURE AFTER STREPTOZOTOCIN EXPOSURE [J].
EIZIRIK, DL ;
SANDLER, S ;
WELSH, N ;
HELLERSTROM, C .
ENDOCRINOLOGY, 1988, 122 (04) :1242-1249
[10]   CORRELATION BETWEEN NITRIC-OXIDE FORMATION DURING DEGRADATION OF ORGANIC NITRATES AND ACTIVATION OF GUANYLATE-CYCLASE [J].
FEELISCH, M ;
NOACK, EA .
EUROPEAN JOURNAL OF PHARMACOLOGY, 1987, 139 (01) :19-30