Urinary MMP activity biomarkers for early diabetic renal dysfunction

早期糖尿病肾功能不全的尿液 MMP 活性生物标志物

• 批准号: 8046269
• 负责人: KAREN Simpson MOULTON
• 金额: $ 20万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2012-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8046269
• 关键词: 2,4-thiazolidinedione; Acute Kidney Failure; Address; Adolescent; Adult; Age; Albuminuria; Ancillary Study; Animal Model; Appearance; Atherosclerosis; Behavior Therapy; Biological Assay; Biological Markers; Blindness; Blood Vessels; Cardiology; Cardiovascular Diseases; Cardiovascular system; Childhood; Clinical; Clinical Data; Clinical Investigator; Clinical Research; Clinical Trials; Colorado; Complex; Complications of Diabetes Mellitus; Detection; Diabetes Mellitus; Diabetic Angiopathies; Diabetic Nephropathy; Diagnosis; Diagnostic Neoplasm Staging; Disease; Doctor of Medicine; Doctor of Philosophy; Dyslipidemias; Early Diagnosis; Endocrinology; Epidemiology; Functional disorder; Future; Gelatinase A; Gender; Goals; Hyperglycemia; Impairment; Individual; Institution; Insulin Resistance; Insulin-Dependent Diabetes Mellitus; Kidney; Kidney Diseases; Lupus; MMP2 gene; MMP9 gene; Malignant Neoplasms; Matrix Metalloproteinases; Measures; Metabolic; Metabolic Control; Metalloproteases; Metformin; Microalbuminuria; Molecular Weight; Monitor; Morbidity - disease rate; Nephritis; Non-Insulin-Dependent Diabetes Mellitus; Operative Surgical Procedures; Outcome; Participant; Patients; Pediatric Hospitals; Pediatrics; Predictive Value; Predisposition; Proteins; Provider; Randomized; Research; Research Personnel; Risk; Source; Staging; Testing; Thiazolidinediones; Universities; Urine; Validation; Vascular remodeling; Youth; abstracting; angiogenesis; cardiovascular risk factor; clinical care; clinical material; diabetic; enzyme activity; high risk; human subject; improved; indexing; insulin sensitivity; kidney vascular structure; malformation; member; mortality; non-invasive monitor; outcome forecast; preclinical study; prevent; prognostic; rosiglitazone; stem; tool; translational study; treatment response; urinary; vascular bed; vascular endothelial dysfunction

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.

描述（由申请人提供）：糖尿病的显着发病率和死亡率是由其肾功能损害、加速心血管疾病和视力丧失的并发症引起的。异常血管重塑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（例如血脂异常）可能会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，这不能完全通过代谢控制措施来解释。检测与糖尿病血管重塑相关的活动将是一种重要且生物学相关的临床工具，可预测糖尿病患者发生肾脏或心血管并发症的风险并监测治疗反应。 基质金属蛋白酶 (MMP) 伴随多种疾病中的血管生成失调和血管重塑。 MMP 活性可以在尿液中检测到，并已被证明是临床上有用的筛选，可预测癌症和血管畸形患者的分期和预后。因此，进行了临床前研究，测试了以下假设：尿液 MMP 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。结果发现，在糖尿病肾病动物模型中，尿液中 MMP 活性明显增加，且先于微量白蛋白尿，而其他 MMP 活性则预测糖尿病增强的动脉粥样硬化血管生成阶段。试点临床研究已检测到患有糖尿病的人类受试者的尿液 MMP 活性增加，并且与该提案直接重要的是，与年龄和性别匹配的非糖尿病对照受试者相比，患有 T2D 和 T1D 的青少年的 MMP 活性增强。 该提案的目标是进行一项 TODAY 辅助研究，以确定特定的尿液 MMP 活性是否可以预测 T2D 青少年肾损伤的早期迹象，并通过控制高血糖或通过各种糖尿病治疗来改变。特别是，噻唑烷二酮（MMP 成员的已知调节剂）可以抑制尿液 MMP 活性并减缓肾功能损害的进展，这与 TODAY 研究直接相关，在该研究中，参与者被随机分配到单独使用二甲双胍，或与罗格列酮或生活方式联合使用修改。 TODAY 研究对随机化前后的微量白蛋白尿、胰岛素抵抗和储存尿液进行了重要测量，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对糖尿病患者临床可获取尿液的快速无创筛查，以对风险进行分层，诊断微量白蛋白尿的早期进展，并调整治疗以改善临床结果。 公共卫生相关性：需要新的临床工具来识别糖尿病患者，尽管高血糖控制良好，但这些患者仍容易更快地进展为肾功能损害。对与早期肾功能损害或胰岛素抵抗相关的酶活性的出现进行灵敏检测，可以提醒提供者添加可能预防或减少这些并发症的治疗方法。