Rosiglitazone protects the pancreatic beta-cell death induced by cyclosporine A.
The pathogenesis of post-transplant diabetes mellitus (PTDM) is thought to be partly related to the direct toxic effect of cyclosporine (CsA) on pancreatic beta-cells and the resultant decrease in insulin synthesis and secretion. Although rosiglitazone (Rosi) is an insulin sensitizer, recent data has shown that Rosi also directly protects against beta-cell dysfunction and death. This study was undertaken to clarify the effects of Rosi on CsA-induced beta-cell dysfunction and death. The deterioration in glucose tolerance caused by CsA administration was significantly improved by cotreatment with Rosi. The relative volume and absolute mass of beta-cells were significantly reduced by CsA, whereas combined treatment with Rosi had protective effects. Induction of beta-cell death and increased expression of endoplasmic reticulum (ER) stress markers (CHOP and spliced XBP-1) by CsA were rescued by Rosi. Thus, Rosi signaling directly modulates the ER stress response, promoting beta-cell adaptation and survival. Rosi might be an appropriate drug for preventing and treating CsA-induced PTDM.
Kim
Ji-Won
JW
Division of Endocrinology & Metabolism, Department of Internal Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
Yang
Ji-Hun
JH
Park
Heon-Seok
HS
Sun
Chenglin
C
Lee
Seung-Hwan
SH
Cho
Jae-Hyoung
JH
Yang
Chul Woo
CW
Yoon
Kun-Ho
KH
D000818:Animals; D016572:Cyclosporine / Q000009:adverse effects / Q000037:antagonists & inhibitors* / Q000633:toxicity; D019610:Cytoprotection; D003920:Diabetes Mellitus / Q000139:chemically induced / Q000517:prevention & control*; D005951:Glucose Tolerance Test; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000037:antagonists & inhibitors* / Q000633:toxicity; D007328:Insulin / Q000097:blood; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000473:pathology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077154:Rosiglitazone; D045162:Thiazolidinediones; D014180:Transplantation / Q000009:adverse effects
D007004:Hypoglycemic Agents; D007166:Immunosuppressive Agents; D007328:Insulin; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D016572:Cyclosporine