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利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 在这项建议中，我们将检验这一新的假设，即降低激活的基质金属蛋白酶水平(通过长期服用强力霉素)有助于恢复胰岛素受体的完整性，并改善患有DM2的肥胖人群中的糖尿病指标。我们对患有DM2的肥胖男性和女性的具体目标是确定是否： 1.与正常对照组相比，DM2肥胖组血液和组织中的基质金属蛋白酶水平和活性明显升高。 2.与安慰剂相比，服用12周的多西环素能更大程度地抑制血液和组织中的MMPs。 3.与安慰剂相比，多西环素治疗后胰岛素受体切割受到抑制。 4.与安慰剂相比，多西环素改善了糖尿病的标准指标。 我们的假设如下： 1.肥胖和2型糖尿病患者血液和组织中的基质金属蛋白酶活性和胰岛素受体裂解均高于对照组(目标1)。 2.与安慰剂(目标2和3)相比，对肥胖症患者和DM2患者使用多西环素可以降低基质金属蛋白酶水平和胰岛素受体裂解。 3.与安慰剂相比，服用多西环素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).