Tersey Sarah A, Carter Jeffery D, Rosenberg Lawrence, Taylor-Fishwick David A, Mirmira Raghavendra G, Nadler Jerry L
Department of Pediatrics, Indiana University, Indianapolis, USA ; Herman B Wells Center for Pediatric Research, Indiana University, Indianapolis, USA.
Department of Medicine, University of Virginia, Charlottesville, USA.
J Diabetes Mellitus. 2012 May 1;2(2):251-257. doi: 10.4236/jdm.2012.22040.
Type 1 diabetes mellitus results from the autoimmune and inflammatory destruction of insulin-producing islet β cells, rendering individuals devoid of insulin production. Recent studies suggest that combination therapies consisting of anti-inflammatory agents and islet growth-promoting factors have the potential to cause sustained recovery of β cell mass, leading to amelioration or reversal of type 1 diabetes in mouse models. In this study, we hypothesized that the combination of the anti-inflammatory agent lisofylline (LSF) with an active peptide fragment of islet neogenesis associated protein (INGAP peptide) would lead to remission of type 1 diabetes in the non-obese diabetic (NOD) mouse. We treated groups of spontaneously diabetic NOD mice with combinations of LSF, INGAP peptide, or control saline parenterally for up to 6 weeks. Our results demonstrate that the mice receiving combined treatment with LSF and INGAP peptide exhibited partial remission of diabetes with increased plasma insulin levels. Histologic assessment of pancreata in mice receiving combined therapy revealed the presence of islet insulin staining, increased β cell replication, and evidence of Pdx1-positivity in ductal cells. By contrast, diabetic animals showed severe insulitis with no detectible insulin or Pdx1 staining. We conclude that the novel combination treatment with LSF and INGAP peptide has the potential to ameliorate hyperglycemia in the setting of established type 1 diabetes via the recovery of endogenous β cells and warrant further studies.
1型糖尿病是由产生胰岛素的胰岛β细胞发生自身免疫性和炎症性破坏所致，导致个体无法产生胰岛素。最近的研究表明，由抗炎剂和促进胰岛生长的因子组成的联合疗法有可能使β细胞量持续恢复，从而在小鼠模型中改善或逆转1型糖尿病。在本研究中，我们假设抗炎剂利索茶碱（LSF）与胰岛新生相关蛋白的活性肽片段（INGAP肽）联合使用将使非肥胖糖尿病（NOD）小鼠的1型糖尿病得到缓解。我们将自发糖尿病的NOD小鼠分组，通过腹腔注射给予LSF、INGAP肽或对照生理盐水的组合，持续6周。我们的结果表明，接受LSF和INGAP肽联合治疗的小鼠出现了糖尿病部分缓解，血浆胰岛素水平升高。对接受联合治疗的小鼠胰腺进行组织学评估发现存在胰岛胰岛素染色、β细胞复制增加以及导管细胞中Pdx1阳性的证据。相比之下，糖尿病动物表现出严重的胰岛炎，没有可检测到的胰岛素或Pdx1染色。我们得出结论，LSF和INGAP肽的新型联合治疗有可能通过恢复内源性β细胞来改善已确诊的1型糖尿病患者的高血糖，值得进一步研究。
