Urinary MMP activity biomarkers for early diabetic renal dysfunction

描述（由申请人提供）：糖尿病的发病率和死亡率很高，其并发症包括肾脏损害、心血管疾病加速和视力丧失。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）之间存在很大差异，这并不能完全通过代谢控制措施来解释。检测与糖尿病患者血管重构相关的活动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和生物学相关的临床工具。基质金属蛋白酶（MMP）在多种疾病中伴随血管生成和血管重塑失调。MMP活性可以在尿液中检测到，并且已被证明是预测癌症和血管畸形患者的分期和预后的临床有用筛查。因此进行了临床前研究，以验证尿MMP活性可能是预示肾小球或血管改变与糖尿病相关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MMP活性明显升高，并先于微量白蛋白尿，而其他MMP活性预测糖尿病增强的动脉粥样硬化血管生成阶段。前期临床研究发现糖尿病患者尿中MMP活性增加，与年龄和性别匹配的非糖尿病对照组相比，T2D和T1D青少年患者的MMP活性增强，这对该建议具有直接重要性。本提案的目的是进行一项辅助研究，以确定特定的尿MMP活动是否可以预测T2D青年肾脏损害的早期迹象，并通过控制高血糖或各种糖尿病治疗来改变。特别是，噻唑烷二酮，已知的MMP成员的调节因子，可以抑制尿MMP活性和减缓肾功能损害的进展的可能性与TODAY研究直接相关，在该研究中，参与者被随机分配到单用二甲双胍，或与罗格列酮或生活方式改变联合使用。TODAY研究在随机化前后对微量白蛋白尿、胰岛素抵抗和储存尿进行了重要的测量，可以与尿液MMP活性进行比较，以实现这些目标。该提案的结果将验证糖尿病患者临床可获得尿液的快速无创筛查，以分层风险，诊断微量白蛋白尿的早期进展并定制治疗以改善临床结果。

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.