Enhancing engraftment of islets using perioperative sodium 4-phenylbutyrate.
Primary nonfunction (PNF) adversely impacts islet transplantation. In addition to determining whether sodium 4-phenylbutyrate (4-SPB), an anti-inflammatory agent, reduces PNF, this study investigates how 4-SPB affects PNF. Streptozotocin-induced diabetic C57BL/6 mice, that received 75 syngeneic islets underneath left subrenal space, were fed twice daily of either 4-SPB at 500 mg/kg body weight or isotonic saline (NaCl) from 2 days before through 7 days after transplantation. The graft was removed at days 3, 10 and 84 following transplantation. At 68 h following transplantation, serum levels of interleukin-1beta (IL-1beta) were 2.2+/-0.4 and 0.4+/-0.2 pmol/L (n=6, p<0.005) for NaCl and 4-SPB groups, respectively. Graft genetic expression of IL-1beta was significantly suppressed in 4-SPB group (p<0.01). At day 10, the blood glucose levels were 22.7+/-1.0 and 17.1+/-1.7 mmol/L (n=12, p<0.05) and graft insulin contents (IC) were 35.0+/-8.3 and 107.6+/-29.7 pmol (n=12, p<0.05) for NaCl and 4-SPB groups, respectively. Moreover, the 4-SPB group had a shorter temporary hyperglycemia (15+/-2, n=21 vs. 25+/-2 days, n=19, p=0.001) and a higher cumulative cure rate of diabetes (p<0.001) than the NaCl group. In-vitro studies indicated that 4-SPB did not impact the islets function. These experimental results demonstrated that perioperative administration of 4-SPB decreased serum level and graft genetic expression of IL-1beta and attenuated PNF, which enhanced islet engraftment in a syngeneic transplantation mouse model.
Hsu
Brend Ray-Sea
BR
Division of Endocrinology and Metabolism, Department of Internal Medicine, Chang-Gung Memorial Hospital, Lin-Kou Medical Center, 5 Fu-Shin St. Kwei-Shan County, Tao-Yuan Hsien, Taiwan. bh0658@adm.cgmh.org.tw <bh0658@adm.cgmh.org.tw>
Chen
Szu-Tah
ST
Fu
Shin-Huei
SH
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000493:pharmacokinetics; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000235:genetics / Q000601:surgery*; D015870:Gene Expression / Q000187:drug effects; D006085:Graft Survival / Q000187:drug effects*; D007328:Insulin / Q000378:metabolism; D053583:Interleukin-1beta / Q000097:blood / Q000235:genetics; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D016381:Islets of Langerhans Transplantation; D007975:Leukotriene B4 / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009566:Nitrates / Q000097:blood; D009573:Nitrites / Q000097:blood; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism; D010654:Phenylbutyrates / Q000008:administration & dosage / Q000494:pharmacology*; D011453:Prostaglandins / Q000097:blood
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001786:Blood Glucose; D007328:Insulin; D053583:Interleukin-1beta; D009566:Nitrates; D009573:Nitrites; D010654:Phenylbutyrates; D011453:Prostaglandins; D007975:Leukotriene B4; C075773:4-phenylbutyric acid