Inhibition of dipeptidyl peptidase IV with sitagliptin (MK0431) prolongs islet graft survival in streptozotocin-induced diabetic mice
Inhibition of dipeptidyl peptidase IV with sitagliptin (MK0431) prolongs islet graft survival in streptozotocin-induced diabetic mice
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DOI：
10.2337/db07-1639
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发表时间：
2008-05-01
期刊：
影响因子：
7.7
通讯作者：
McIntosh, Christopher H. S.
中科院分区：
文献类型：
--
作者：
Kim, Su-Jin;Nian, Cuilan;McIntosh, Christopher H. S.
抗氧化剂-二肽基肽酶-IV（DPP-TV）抑制剂已被引入作为2型糖尿病的治疗剂。它们通过阻断肠促胰岛素激素胰高血糖素样肽-1（GLP-1）和葡萄糖依赖性促胰岛素多肽（GIP）的降解而部分发挥作用，从而增加活性激素的循环水平。除了促胰岛素作用外，GLP-1和GIP还促进β细胞增殖和存活，DPP-IV抑制剂在啮齿动物2型糖尿病模型中发挥类似作用。研究目的是确定DPP-IV抑制剂治疗是否延长移植胰岛的存活，并确定正电子发射断层扫描（PET）是否适用于量化抑制对胰岛质量的影响。在链脲佐菌素（STZ）诱导的1型糖尿病小鼠模型中，通过代谢研究和microPET成像来确定（西格列汀）对血糖控制和功能性胰岛质量的影响。1型糖尿病小鼠模型显示血浆DPP-IV水平升高，而服用MK 0431饮食的小鼠血浆DPP-IV水平基本上受到抑制。在STZ诱导的糖尿病小鼠中，残留的β细胞量极低，尽管MK 0431饮食增加了活性GLP-1水平，但对血糖控制无显著影响。胰岛移植后，正常饮食喂养的小鼠迅速失去了调节血糖的能力，反映了次优的胰岛移植。相比之下，MK 0431组在整个研究过程中完全调节血糖，PET成像显示MK 0431对胰岛移植物大小具有深远的保护作用。结论：在1型糖尿病动物模型中，用DPP-IV抑制剂治疗可以延长胰岛移植物保留。
OBJECTIVE-Dipeptidyl peptidase-IV (DPP-TV) inhibitors have been introduced as therapeutics for type 2 diabetes. They partially act by blocking degradation of the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), thus increasing circulating levels of active hormones. In addition to their insulinotropic actions, GLP-1 and GIP also promote beta-cell proliferation and survival, and DPP-IV inhibitors exert similar effects in rodent type 2 diabetes models. The study objective was to establish whether DPP-IV inhibitor treatment prolonged survival of transplanted islets and to determine whether positron emission tomography (PET) was appropriate for quantifying the effect of inhibition on islet mass.RESEARCH DESIGN & METHODS-Effects of the DPP-IV inhibitor MK0431 (sitagliptin) on glycemic control and functional islet mass in a streptozotocin (STZ)-induced type 1 diabetes mouse model were determined with metabolic studies and microPET imaging.RESULTS-The type 1 diabetes mouse model exhibited elevated plasma DPP-IV levels that were substantially inhibited in mice on an MK0431 diet. Residual beta-cell mass was extremely low in STZ-induced diabetic mice, and although active GLP-1 levels were increased by the MK0431 diet, there were no significant effects on glycemic control. After islet transplantation, mice fed normal diet rapidly lost their ability to regulate blood glucose, reflecting the suboptimal islet transplant. By contrast, the MK0431 group fully regulated blood glucose throughout the study, and PET imaging demonstrated a profound protective effect of MK0431 on islet graft size.CONCLUSIONS-Treatment with a DPP-IV inhibitor can prolong islet graft retention in an animal model of type 1 diabetes.