BLOCKADE OF RECEPTOR CLEAVAGE IN DIABETES MELLITUS WITH AN MMP INHIBITOR

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 在该提案中，我们将测试新的假设，即降低活化MMP水平（通过长期多西环素给药）有助于恢复胰岛素受体的完整性，并改善患有DM 2的肥胖人群中的糖尿病指标。我们在患有DM 2的肥胖男性和女性中的具体目标是确定： 1. 与对照组相比，患有DM 2的肥胖受试者的血液和组织中MMP水平和活性升高。 2. 与安慰剂相比，给予12周的多西环素在血液和组织中更大程度地抑制MMP。 3. 与安慰剂相比，多西环素治疗后胰岛素受体裂解受到抑制。 4. 与安慰剂相比，多西环素改善了糖尿病的标准测量。 我们的假设如下： 1. 与对照相比，患有肥胖症和DM 2的受试者的血液和组织中MMP活性和胰岛素受体裂解将更大（目的1）。 2. 与安慰剂相比，向患有肥胖症和DM 2的人类受试者施用多西环素将降低MMP水平和胰岛素受体裂解（目的2和3）。 3. 与安慰剂相比，强力霉素给药将改善糖尿病的指标（目标4）。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. In this proposal, we will test the novel hypothesis that reduction of activated MMP levels (by chronic doxycycline administration) serves to restore insulin receptor integrity and improves measures of diabetes in an obese population of human subjects with DM2. Our specific aims in obese men and women with DM2 are to determine if: 1. MMP levels and activity are elevated in blood and tissue of obese subjects with DM2 compared to controls. 2. Doxycycline administered for 12 weeks suppresses MMPs to a greater extent in blood and tissue compared to placebo. 3. Insulin receptor cleavage is inhibited after treatment with doxycycline compared to placebo. 4. Doxycycline improves standard measures of diabetes compared to placebo. Our hypotheses are as follows: 1. MMP activity and insulin receptor cleavage will be greater in blood and tissue of subjects with obesity and DM2 compared to controls (Aim 1). 2. Doxycycline administration to human subjects with obesity and DM2 will decrease MMP levels and insulin receptor cleavage compared to placebo (Aims 2 and 3). 3. Doxycycline administration will improve measures of diabetes when compared to placebo (Aim 4).