? Matrix metalloproteinases (MMPs) are a family of zinc-dependent proteinases that are involved in the breakdown and remodeling of extracellular matrix (ECM). Dysregulation of MMP activity has been implicated in many pathologic processes characterized by degradation of connective tissue matrices, including rheumatoid arthritis, periodontal disease and metastatic cancer. Recent studies both in vitro and in animal models of diabetes suggest that hyperglycemia-mediated alterations in MMP secretion, activation or action may also contribute to the development of diabetes-related complications including diabetic retinopathy and nephropathy. Based on these findings one can hypothesize that the mesangial accumulation and renal hypertrophy characteristic of diabetic nephropathy may result from reduced matrix degradation caused by a hyperglycemia-mediated suppression of renal MMP activity. In fact, preliminary clinical data from our laboratory confirm that in children with type 1 DM, serum MMP-2 concentrations are suppressed in the face of uncontrolled hyperglycemia, yet normalize with near-normalization of blood glucose levels. In the present study, we propose to investigate the hypothesis that MMPs are involved in the pathogenesis of diabetic nephropathy by measuring concentrations of specific MMPs (MMP-2, -8 and -9), concentrations of the naturally occurring inhibitors of MMPs (Tissue Inhibitor of Matrix Metalloproteinases, TIMP-1 and -2), and concentrations of the MMP-activated growth factor, insulin-like growth factor-I (IGF-I) in the serum and urine of patients with type 1 DM. We will examine levels of MMPs, TIMPs, and IGF-I in these biologic fluids among diabetic patient subgroups, ages 14-40 years, chosen to represent various time points in the natural history of d abet c nephropathy. Moreover, we will examine the correlation between observed differences in MMPFl'lMP/IGFconcentrations and differences in glycemic control at the time of study, as indicated by HbA1 c measurements and concurrent (72 hour) Continuous Subcutaneous Glucose Monitoring (CGMS). We anticipate that this study will provide preliminary evidence to establish a link between dysregulation of MMP activity and the pathogenesis of nephropathy in type 1 DM. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK062999-04
Application #
6893319
Study Section
Special Emphasis Panel (ZRG1-MDCN-1 (05))
Program Officer
Meyers, Catherine M
Project Start
2002-09-30
Project End
2008-04-30
Budget Start
2005-05-01
Budget End
2008-04-30
Support Year
4
Fiscal Year
2005
Total Cost
$322,500
Indirect Cost
Name
Arkansas Children's Hospital Research Institute
Department
Type
DUNS #
002593692
City
Little Rock
State
AR
Country
United States
Zip Code
72202
Thrailkill, K M; Jo, C-H; Cockrell, G E et al. (2012) Determinants of undercarboxylated and carboxylated osteocalcin concentrations in type 1 diabetes. Osteoporos Int 23:1799-806
Thrailkill, Kathryn M; Jo, Chan-Hee; Cockrell, Gael E et al. (2011) Enhanced excretion of vitamin D binding protein in type 1 diabetes: a role in vitamin D deficiency? J Clin Endocrinol Metab 96:142-9
Thrailkill, Kathryn M; Moreau, Cynthia S; Cockrell, Gael E et al. (2010) Disease and gender-specific dysregulation of NGAL and MMP-9 in type 1 diabetes mellitus. Endocrine 37:336-43
Thrailkill, Kathryn M; Clay Bunn, R; Fowlkes, John L (2009) Matrix metalloproteinases: their potential role in the pathogenesis of diabetic nephropathy. Endocrine 35:1-10
Thrailkill, Kathryn M; Nimmo, Teresa; Bunn, R Clay et al. (2009) Microalbuminuria in type 1 diabetes is associated with enhanced excretion of the endocytic multiligand receptors megalin and cubilin. Diabetes Care 32:1266-8
Thrailkill, Kathryn M; Bunn, Robert C; Moreau, Cynthia S et al. (2007) Matrix metalloproteinase-2 dysregulation in type 1 diabetes. Diabetes Care 30:2321-6
Thrailkill, Kathryn; Cockrell, Gael; Simpson, Pippa et al. (2006) Physiological matrix metalloproteinase (MMP) concentrations: comparison of serum and plasma specimens. Clin Chem Lab Med 44:503-4
Thrailkill, Kathryn M; Moreau, Cindy S; Cockrell, Gael et al. (2005) Physiological matrix metalloproteinase concentrations in serum during childhood and adolescence, using Luminex Multiplex technology. Clin Chem Lab Med 43:1392-9