Agonist of growth hormone-releasing hormone as a potential effector for survival and proliferation of pancreatic islets
Agonist of growth hormone-releasing hormone as a potential effector for survival and proliferation of pancreatic islets
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DOI：
10.1073/pnas.1005098107
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发表时间：
2010-07-13
影响因子：
11.1
通讯作者：
Bornstein, Stefan R.
中科院分区：
文献类型：
--
作者：
Ludwig, Barbara;Ziegler, Christian G.;Bornstein, Stefan R.
胰岛细胞移植迫切需要通过刺激胰岛细胞增殖和/或延长胰岛细胞存活来扩大β细胞质量的治疗策略。不同生长因子对胰岛的控制为增加β细胞质量提供了一个潜在的场所。在本研究中，我们展示了生长激素释放激素（GHRH）受体的生物活性剪接变异体-1 （SV-1）在大鼠胰岛素瘤（INS-1）细胞以及大鼠和人胰岛中的表达。在INS-1细胞的体外研究中，GHRH激动剂JI-36显著增加了细胞增殖，减少了细胞凋亡。在48-72 h后，JI-36增加了离体大鼠胰岛的大小和葡萄糖刺激的胰岛素分泌。在超微结构水平上，激动剂JI-36处理的INS-1细胞显示出代谢活跃的刺激状态，细胞质增加。与GHRH拮抗剂MIA-602共孵育可逆转激动剂JI-36的作用，表明该激动剂具有特异性。在体内，通过将大鼠胰岛移植到链脲佐菌素诱导的糖尿病非肥胖糖尿病-严重联合免疫缺陷（NOD-SCID）小鼠的肾包膜下来评估胰岛的功能。与未治疗的胰岛相比，经GHR Hagonist JI-36治疗的胰岛能够更早、更持久地达到正常血糖。此外，与移植未经治疗的胰岛的糖尿病动物相比，接受激动剂JI-36治疗的胰岛动物对i.p.葡萄糖耐量试验（IPGTT）的胰岛素反应与正常健康小鼠相当。总之，我们的研究提供了证据，表明GHRH激动剂是一种很有前途的药物治疗方法，旨在促进糖尿病患者胰岛移植物的生长和增殖。
Therapeutic strategies for transplantation of pancreatic islet cells are urgently needed to expand beta-cell mass by stimulating islet cell proliferation and/or prolonging islet cell survival. Control of the islets by different growth factors provides a potential venue for augmenting beta-cell mass. In the present study, we show the expression of the biologically active splice variant-1 (SV-1) of growth hormone-releasing hormone (GHRH) receptor in rat insulinoma (INS-1) cells as well as in rat and human pancreatic islets. In studies in vitro of INS-1 cells, the GHRH agonist JI-36 caused a significant increase in cell proliferation and a reduction of cell apoptosis. JI-36 increased islet size and glucose-stimulated insulin secretion in isolated rat islets after 48-72 h. At the ultrastructural level, INS-1 cells treated with agonist JI-36 revealed a metabolic active stimulation state with increased cytoplasm. Coincubation with the GHRH antagonist MIA-602 reversed the actions of the agonist JI-36, indicating the specificity of this agonist. In vivo, the function of pancreatic islets was assessed by transplantation of rat islets under the kidney capsule of streptozotocin-induced diabetic non-obese diabetic-severe combined immunodeficiency (NOD-SCID) mice. Islets treated with GHR Hagonist JI-36 were able to achieve normoglycemia earlier and more consistently than untreated islets. Furthermore, in contrast to diabetic animals transplanted with untreated islets, insulin response to an i.p. glucose tolerance test (IPGTT) in animals receiving islets treated with agonist JI-36 was comparable to that of normal healthy mice. In conclusion, our study provides evidence that agonists of GHRH represent a promising pharmacological therapy aimed at promoting islet graft growth and proliferation in diabetic patients.