Sakuma Y, Ricordi C, Miki A, Yamamoto T, Mita A, Barker S, Damaris R M, Pileggi A, Yasuda Y, Yada T, Ichii H
Cell Transplant Center, Diabetes Research Institute, University of Miami Leonard M. Miller School of Medicine, Miami, Florida 33136, USA.
Transplant Proc. 2009 Jan-Feb;41(1):343-5. doi: 10.1016/j.transproceed.2008.10.064.
Pituitary adenylate cyclase-activating polypeptide (PACAP) is an islet substance serving as an intra-islet amplifier of glucose-induced insulin secretion similar to exendin-4. It has been reported that systemic administration of PACAP maintained beta-cell mass, delayed the onset of hyperglycemia, and protected beta cells from glucose toxicity. Moreover, PACAP increases glucose-stimulated insulin release in vitro and in vivo. In this study, we investigated the possibility of PACAP use in human islet transplantation.
Human islets were cultured in the presence or absence of PACAP (10(-12) mol/L) for 48 hours. We assessed beta-cell viability using FACS, cellular composition analysis by iCys/LSC, and glucose-stimulated insulin secretion. In vivo, islets were transplanted beneath the kidney capsule of Streptozotocin-induced diabetic immunodeficient mice. An intravenous glucose tolerance test (IVGTT) was also performed in the presence or absence of PACAP (Peptide International, Louisville, Ky, United States; 1.3 nmol/kg).
There were significant improvements in terms of beta-cell viability and cellular composition between islets cultured with or without PACAP, respectively (P < .05). Moreover, glucose-stimulated insulin secretion significantly improved in islets cultured with PACAP compared with controls, respectively (P < .05). Treatment of recipient mice with PACAP resulted in beneficial effects on insulin secretion (PACAP vs control, 13.2 vs 1.9 mU/L), in IVGTT. However, no significant difference was observed in glucose levels between the 2 groups.
Our study indicated that PACAP significantly improved beta-cell viability and survival during culture, and increased insulin secretion in vitro and in vivo. However, blood glucose levels in vivo after an IVGTT did not significantly improve, probably due to increased glucagon secretion from alpha cells. PACAP supplementation to culture medium could be of assistance to improve clinical islet transplantation outcomes.
垂体腺苷酸环化酶激活多肽（PACAP）是一种胰岛物质，与艾塞那肽-4类似，可作为胰岛内葡萄糖诱导胰岛素分泌的放大器。据报道，全身给予PACAP可维持β细胞质量，延缓高血糖的发生，并保护β细胞免受葡萄糖毒性。此外，PACAP在体外和体内均可增加葡萄糖刺激的胰岛素释放。在本研究中，我们探讨了PACAP用于人类胰岛移植的可能性。
将人类胰岛在有或无PACAP（10⁻¹² mol/L）的情况下培养48小时。我们使用流式细胞术评估β细胞活力，通过iCys/LSC进行细胞组成分析，并检测葡萄糖刺激的胰岛素分泌。在体内，将胰岛移植到链脲佐菌素诱导的糖尿病免疫缺陷小鼠的肾包膜下。在有或无PACAP（美国肯塔基州路易斯维尔市Peptide International公司；1.3 nmol/kg）的情况下，还进行了静脉葡萄糖耐量试验（IVGTT）。
分别在有或无PACAP培养的胰岛之间，β细胞活力和细胞组成有显著改善（P <.05）。此外，与对照组相比，用PACAP培养的胰岛中葡萄糖刺激的胰岛素分泌显著改善（P <.05）。在IVGTT中，用PACAP治疗受体小鼠对胰岛素分泌有有益影响（PACAP组与对照组，分别为13.2 vs 1.9 mU/L）。然而，两组之间的血糖水平未观察到显著差异。
我们的研究表明，PACAP在培养过程中显著改善了β细胞活力和存活率，并在体外和体内增加了胰岛素分泌。然而，IVGTT后体内血糖水平未显著改善，可能是由于α细胞分泌的胰高血糖素增加所致。在培养基中补充PACAP可能有助于改善临床胰岛移植结果。
