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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
High Impact Research and Research Infrastructure Programs—Multi-Yr Funding (RC4)
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Special Emphasis Panel (ZDK1-GRB-N (O1))
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Flessner, Michael Francis
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University of Colorado Denver
Internal Medicine/Medicine
Schools of Medicine
United States
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McKittrick, Ian B; Bogaert, Yolanda; Nadeau, Kristen et al. (2011) Urinary matrix metalloproteinase activities: biomarkers for plaque angiogenesis and nephropathy in diabetes. Am J Physiol Renal Physiol 301:F1326-33