Effects of cyclosporin on autoimmune diabetes induced in mice by streptozotocin: beta cell-toxicity and rebound of insulitis after cessation of treatment.
We have investigated the effects of an oral cyclosporin (CsA) treatment on "autoimmune" diabetes induced in CD1 male mice by 5 low doses (40 mg/kg/day) of streptozotocin (SZ). CsA (50, 25, or 12.5 mg/kg/day) induced significant hyperglycaemia and insulinopenia by the 3rd day after the last SZ injection, whereas mice receiving SZ only remained non diabetic at that time. Enhancement of SZ-induced diabetes by CsA was thus noted. Mice receiving CsA and SZ displayed a significantly higher number of degranulated and necrotic beta cells. Similarly, CsA enhanced "toxic" diabetes produced by a single high dose of SZ. Furthermore, mice treated with CsA alone displayed glucose intolerance, insulinopenia, and high pancreatic CsA content. These abnormalities were reversed by 2 weeks after CsA withdrawal. Islets isolated from CsA treated mice displayed in vitro decreased stimulated insulin secretion. During the period of administration, CsA led to a decrease of Lyt 1 +/Lyt 2 + ratio in spleen cells and prevented the insulitis in low dose SZ-treated mice. However, at CsA withdrawal, a rebound of insulitis occurred with a higher intensity. Immunohistochemical phenotyping on frozen pancreatic sections revealed that Lyt 1 + lymphocytes predominated on Lyt 2 + cells in the rebound insulitis. In this model: (1) CsA impairs glucose stimulated insulin release and alters beta cells. This reversible toxic effect accounts for enhancement of SZ-induced diabetes; (2) insulitis was slackened by CsA but developed, as a rebound, with CsA withdrawal associated with a prominence of Lyt 1 + lymphocytes.
Sai
P
P
Laboratoire de diabétologie, Faculté de Médecine, Nantes.
Maugendre
D
D
Loreal
O
O
Maurel
C
C
Pogu
S
S
D000818:Animals; D001327:Autoimmune Diseases / Q000473:pathology*; D001786:Blood Glucose / Q000032:analysis; D003524:Cyclosporins / Q000633:toxicity*; D003921:Diabetes Mellitus, Experimental / Q000276:immunology / Q000473:pathology*; D007515:Islets of Langerhans / Q000187:drug effects / Q000473:pathology*; D008297:Male; D051379:Mice; D009000:Monocytes / Q000166:cytology; D009336:Necrosis; D013601:T-Lymphocytes / Q000145:classification / Q000187:drug effects / Q000276:immunology
D001786:Blood Glucose; D003524:Cyclosporins