Urinary MMP activity biomarkers for early diabetic renal dysfunction

描述(由申请人提供)：糖尿病的严重发病率和死亡率源于其并发症，如肾功能损害、加速的心血管疾病和视力丧失。血管重构异常是糖尿病大血管和微血管并发症的重要组成部分。控制高血糖和其他代谢因素，如血脂异常，可以改善或延缓糖尿病并发症；然而，肾脏和心血管并发症的易感性在个体之间以及1型糖尿病(T1D)和2型糖尿病(T2D)之间差异很大，这不能完全用代谢控制措施来解释。糖尿病血管重塑相关活动的检测将是预测糖尿病患者发生肾脏或心血管并发症的风险和监测治疗反应的重要且具有生物学意义的临床工具。基质金属蛋白酶(MMPs)在多种疾病中伴随着异常的血管生成和血管重塑。尿液中可检测到基质金属蛋白酶活性，并已被证明是预测癌症和血管畸形患者的分期和预后的有用的临床筛查。因此，进行了临床前研究，验证了尿液基质金属蛋白酶活性可能是预示与糖尿病相关的肾小球或血管改变的敏感生物标志物的假设。结果发现，在糖尿病肾病动物模型中，尿液中有明显的基质金属蛋白酶活性升高并先于微量白蛋白尿，而其他基质金属蛋白酶活性则预示着糖尿病促进动脉粥样硬化的血管生成阶段。先导性临床研究发现糖尿病患者尿液中的基质金属蛋白酶活性升高，与年龄和性别相匹配的非糖尿病对照组相比，患有T2D和T1D的青少年患者的基质金属蛋白酶活性增强，这对本研究具有直接意义。这项建议的目标是进行一项今天的辅助研究，以确定特定的尿液基质金属蛋白酶活性是否可以预测T2D青少年肾脏损害的早期迹象，并被控制高血糖或各种糖尿病治疗方法所改变。特别是，已知的基质金属蛋白酶成员的调节剂--噻唑烷二酮可以抑制尿液基质金属蛋白酶的活性并减缓肾脏损害进展的可能性与今日的研究直接相关，在该研究中，参与者被随机分为单独服用二甲双胍，或与罗格列酮或生活方式改变联合使用。今天的研究有随机前后微量白蛋白尿、胰岛素抵抗和储存尿量的重要指标，这些指标可以与尿液基质金属蛋白酶活性进行比较，以实现这些目标。这项建议的结果将验证对糖尿病患者临床上可获得的尿液进行快速、非侵入性筛选，以分层风险、诊断早期进展为微量白蛋白尿并为改善临床结果而量身定做的治疗。 公共卫生相关性：需要新的临床工具来确定糖尿病患者，尽管高血糖得到了很好的控制，但他们容易更快地进展为肾损害。对与早期肾损害或胰岛素抵抗有关的酶活性的敏感检测可以提醒提供者增加可能预防或减少这些并发症的治疗。

DESCRIPTION (provided by applicant): Significant morbidity and mortality of diabetes results from its complications of renal impairment, accelerated cardiovascular disease, and loss of vision. Abnormal vascular remodeling are integral components of diabetic macro-vascular and micro-vascular complications. Control of hyperglycemia and other metabolic factors such as dyslipidemia may ameliorate or delay diabetic complications; however, the susceptibilities for renal and cardiovascular complications vary widely between individuals and between type 1 diabetes (T1D) and type 2 diabetes (T2D), which are not entirely explained by measures of metabolic control. Detection of activities associated with vascular remodeling in diabetes would be an important and biologically relevant clinical tool to predict the risks of individuals with diabetes to develop renal or cardiovascular complications and to monitor treatment response. Matrix metalloproteinases (MMP) accompany dysregulated angiogenesis and vascular remodeling in a variety of diseases. MMP activities can be detected in urine and have been shown to be clinically useful screens that predict stage and prognosis in patients with cancer and vascular malformations. Preclinical studies were therefore conducted that tested the hypothesis that urinary MMP activities might be sensitive biomarkers that herald glomerular or vascular alterations associated with diabetes. Results identified distinct urine MMP activities that were increased and preceded microalbuminuria in animal models of diabetic nephropathy, while other MMP activities predicted diabetic enhanced angiogenic stages of atherosclerosis. Pilot clinical studies have detected increased urinary MMP activities in human subjects with diabetes, and of direct importance for this proposal, MMP activities are enhanced in adolescents with T2D and T1D compared to age and gender-matched control subjects without diabetes. The goals of this proposal are to conduct a TODAY ancillary study to determine whether specific urinary MMP activities predict early signs of renal impairment in T2D youth and are modified by control of hyperglycemia or by various treatments for diabetes. In particular, the possibility that a thiazolidinedione, known regulators of MMP members, can inhibit urine MMP activities and slow progression of renal impairment has direct relevance to the TODAY study, in which participants were randomized to metformin alone, or in combination with rosiglitazone or lifestyle modification. The TODAY Study has important measures of microalbuminuria, insulin resistance and stored urine before and after randomization that are amenable for comparisons with urine MMP activities to accomplish these aims. Outcomes of this proposal will validate a rapid non-invasive screen of clinically accessible urine from patients with diabetes to stratify risk, diagnose early progression to microalbuminuria and tailor therapy for improved clinical outcomes. PUBLIC HEALTH RELEVANCE: New clinical tools are needed to identify individuals with diabetes whom are prone to progress more rapidly to renal impairment despite good control of hyperglycemia. Sensitive detection for the appearance of enzyme activities that are involved in early renal impairment or insulin resistance could alert providers to add treatments that might prevent or reduce these complications.