Effects of (-)15-deoxyspergualin on pancreatic islet B-cell function in vitro and on the development of diabetes after multiple low dose streptozotocin administration.
The effects of (-)15-deoxyspergualin (15-DS), a newly described immunosuppressive drug, have been investigated on diabetes induced in mice treated with multiple low-dose streptozotocin (multiple SZ). Male C3D2F1 mice were treated with either intraperitoneal injections of saline or 15-DS (2.5 mg/kg body weight) for a total of 10 days, starting during the first day of SZ administration (5 days; 40 mg/kg body weight). On day 14, 15-DS-treated animals were still normoglycaemic, whilst on day 21 there was only a partial reduction in the hyperglycaemia compared to that found in the saline treated animals receiving SZ. 15-DS did not prevent hyperglycaemia in the long run (day 35-63). Furthermore, morphological examinations of pancreatic glands suggested that the insulitis in the pancreatic islets was delayed in the 15-DS-treated animals. In control experiments mice were treated with 15-DS+ the vehicle for SZ. This regimen did not hamper the glucose homeostasis of the animals. In vitro effects of 15-DS were also examined. Isolated islets from C3D2F1 mice were cultured at different concentrations of 15-DS (0.1-10.0 mg/l). After one week in culture, islet insulin release, islet insulin and DNA content were measured. The islets looked fluffy after culture at the higher 15-DS concentrations (4.0-10.0 mg/l) and at 10 mM almost all of the islets disappeared. A dose-dependent reduction of glucose-stimulated insulin release could also be seen. In other experiments islets were exposed to SZ and subsequently cultured in the presence of 0.5 mM 15-DS, however, 15-DS could not prevent the reduction in insulin release due to SZ exposure. Since 15-DS influences macrophage functions, the presently observed protective effects against the multiple SZ-treatment could reflect a reduced local interleukin-1 production in the islet vicinity. Alternatively, a lowered interleukin-1 secretion could prevent the activation of other immune cells involved in the destruction of B-cells.
Strandell
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E
Department of Medical Cell Biology, Uppsala University, Sweden.
Andersson
A
A
Groth
C G
CG
Sandler
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S
D000818:Animals; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D005260:Female; D006146:Guanidines / Q000494:pharmacology*; D006943:Hyperglycemia / Q000188:drug therapy; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D013311:Streptozocin / Q000008:administration & dosage
D006146:Guanidines; D007166:Immunosuppressive Agents; D013311:Streptozocin; C037258:gusperimus