Effects of metformin on hyperglycemia in an experimental model of tacrolimus- and sirolimus-induced diabetic rats.
OBJECTIVE
Metformin (MET) is a first-line drug for type 2 diabetes mellitus (DM); its effect on new-onset diabetes after transplantation caused by immunosuppressant therapy is unclear. We compared the effects of MET on DM caused by tacrolimus (TAC) or sirolimus (SRL).


METHODS
DM was induced by injection of TAC (1.5 mg/kg) or SRL (0.3 mg/kg) for 2 weeks in rats, and MET (200 mg/kg) was injected for 2 more weeks. The effects of MET on DM caused by TAC or SRL were evaluated using an intraperitoneal glucose tolerance test (IPGTT) and by measuring plasma insulin concentration, islet size, and glucose-stimulated insulin secretion (GSIS). The effects of MET on the expression of adenosine monophosphate-activated protein kinase (AMPK), a pharmacological target of MET, were compared between TAC- and SRL-treated islets.


RESULTS
IPGTT showed that both TAC and SRL induced hyperglycemia and reduced plasma insulin concentration compared with vehicle. These changes were reversed by addition of MET to SRL but not to TAC. Pancreatic islet cell size was decreased by TAC but not by SRL, but addition of MET did not affect pancreatic islet cell size in either group. MET significantly increased GSIS in SRL- but not in TAC-treated rats. AMPK expression was not affected by TAC but was significantly decreased in SRL-treated islets. Addition of MET restored AMPK expression in SRL-treated islets but not in TAC-treated islets.


CONCLUSIONS
MET has different effects on hyperglycemia caused by TAC and SRL. The discrepancy between these drugs is related to their different mechanisms causing DM.
Transplant Research Center, College of Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea.|Convergent Research Consortium for Immunologic Disease, College of Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea.
Jian
J
Jin
Transplant Research Center, College of Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea.|Convergent Research Consortium for Immunologic Disease, College of Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea.
Sun Woo
SW
Lim
Transplant Research Center, College of Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea.|Convergent Research Consortium for Immunologic Disease, College of Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea.
Long
L
Jin
Transplant Research Center, College of Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea.|Division of Nephrology, Department of Internal Medicine, College of Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea.
Ji Hyun
JH
Yu
Transplant Research Center, College of Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea.|Division of Nephrology, Department of Internal Medicine, College of Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea.
Hyun Seon
HS
Kim
Convergent Research Consortium for Immunologic Disease, College of Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea.|Division of Nephrology, Department of Internal Medicine, College of Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea.
Byung Ha
BH
Chung
Transplant Research Center, College of Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea.|Convergent Research Consortium for Immunologic Disease, College of Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea.|Division of Nephrology, Department of Internal Medicine, College of Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea.
Chul Woo
CW
Yang
D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced* / Q000188:drug therapy* / Q000503:physiopathology; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D007515:Islets of Langerhans / Q000187:drug effects / Q000503:physiopathology; D016030:Kidney Transplantation / Q000009:adverse effects; D008687:Metformin / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020123:Sirolimus / Q000009:adverse effects; D016559:Tacrolimus / Q000009:adverse effects
D007004:Hypoglycemic Agents; D007166:Immunosuppressive Agents; D008687:Metformin; D020123:Sirolimus; D016559:Tacrolimus
Metformin; New onset diabetes after transplantation; Sirolimus; Tacrolimus
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