Jin Jian, Lim Sun Woo, Jin Long, Yu Ji Hyun, Kim Hyun Seon, Chung Byung Ha, Yang Chul Woo
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.
Korean J Intern Med. 2017 Mar;32(2):314-322. doi: 10.3904/kjim.2015.394. Epub 2016 Sep 30.
BACKGROUND/AIMS: 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).
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.
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.
MET has different effects on hyperglycemia caused by TAC and SRL. The discrepancy between these drugs is related to their different mechanisms causing DM.
背景/目的：二甲双胍（MET）是2型糖尿病（DM）的一线用药；其对免疫抑制剂治疗所致移植后新发糖尿病的影响尚不清楚。我们比较了MET对他克莫司（TAC）或西罗莫司（SRL）所致糖尿病的影响。
通过给大鼠注射TAC（1.5mg/kg）或SRL（0.3mg/kg）2周诱导糖尿病，再注射MET（200mg/kg）2周。使用腹腔内葡萄糖耐量试验（IPGTT）并通过测量血浆胰岛素浓度、胰岛大小和葡萄糖刺激的胰岛素分泌（GSIS）来评估MET对TAC或SRL所致糖尿病的影响。比较了MET对TAC和SRL处理的胰岛中MET的药理学靶点单磷酸腺苷激活蛋白激酶（AMPK）表达的影响。
IPGTT显示，与溶剂对照组相比，TAC和SRL均诱导高血糖并降低血浆胰岛素浓度。将MET添加到SRL中可逆转这些变化，但添加到TAC中则不能。TAC可使胰岛细胞大小减小，而SRL则不会，但添加MET对两组的胰岛细胞大小均无影响。MET可显著增加SRL处理的大鼠的GSIS，但对TAC处理的大鼠则无此作用。TAC不影响AMPK表达，但SRL处理的胰岛中AMPK表达显著降低。添加MET可恢复SRL处理的胰岛中的AMPK表达，但不能恢复TAC处理的胰岛中的AMPK表达。
MET对TAC和SRL所致高血糖有不同影响。这些药物之间的差异与其导致糖尿病的不同机制有关。
