Diabetes is associated with a several-fold increased risk for atherosclerotic vascular disease. A major contributor to the increased risk is the well-known fact that blood of diabetic patients tends to form blood clots more easily than blood of non-diabetic individuals. The tissue factor (TF) pathway of blood coagulation, which is the primary physiological mechanism of initiation of blood coagulation, has therefore become of intense interest. We have recently shown that high glucose and high insulin, but especially the combination of high glucose and high insulin (HI/HG), greatly increased membrane-bound tissue factor procoagulant activity (TF-PCA) in blood of normal volunteers and increased further the already elevated circulating TF- PCA in patients with type 2 diabetes (T2DM). Moreover, we have found that raising glucose and insulin levels in healthy subjects to levels commonly seen in patients with T2DM, increased circulating TF-PCA 8.6- fold within 24 h and that somatostatin (SMS) almost completely inhibited this HG/HI induced increase in TF- PCA with only a modest reduction (~28%) in the TF-antigen. The current proposal has two major objectives. Objective 1 is to expand our studies to conditions with chronically elevated glucose and/or insulin levels, i.e., to patients with T1DM, T2DM, IGT and insulin resistant, non-diabetic individuals. Specifically, we plan to investigate effects of acutely worsening and improving glycemic control and of longterm lowering of insulin resistance on TF-PCA and TF-antigen. Objective 2 is to determine the nature and the origin of basal, HG/HI stimulated and of SMS suppressed circulating TF-PCA and protein in blood of healthy volunteers and of patients with T2DM. We hypothesize, that HG/HI induces an increase in circulating microparticles (MP) which are highly procoagulant, bearTF and segregate from various cells, including monocytes, platelets and endothelial cells. We will enumerate MP, their cellular origin and procoagulant activity. We hypothesize that SMS inhibits HG/HI-induced MP formation. We hope that continuation of the successful collaboration between the PI, who has many years of experience in diabetes and the Co-Pi, who is a well-known expert in the area of blood coagulation, will provide new information on the nature of the coagulation disorder known to exist in T2DM and will help to reduce their risk for vascular accidents.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK058895-08
Application #
7825339
Study Section
Clinical and Integrative Diabetes and Obesity Study Section (CIDO)
Program Officer
Jones, Teresa L Z
Project Start
2002-04-01
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
8
Fiscal Year
2010
Total Cost
$437,973
Indirect Cost
Name
Temple University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
057123192
City
Philadelphia
State
PA
Country
United States
Zip Code
19122
Singh, Anamika; Boden, Guenther; Rao, A Koneti (2015) Tissue factor and Toll-like receptor (TLR)4 in hyperglycaemia-hyperinsulinaemia. Effects in healthy subjects, and type 1 and type 2 diabetes mellitus. Thromb Haemost 113:750-8
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Rao, A Koneti; Freishtat, Robert J; Jalagadugula, Gauthami et al. (2014) Alterations in insulin-signaling and coagulation pathways in platelets during hyperglycemia-hyperinsulinemia in healthy non-diabetic subject. Thromb Res 134:704-10
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Boden, Guenther (2012) Does inhibition of *-cell proliferation by free fatty acid in mice explain the progressive failure of insulin secretion in type 2 diabetes? Diabetes 61:560-1
Li, Ke; Li, Ling; Yang, Mengliu et al. (2012) The effects of fibroblast growth factor-21 knockdown and over-expression on its signaling pathway and glucose-lipid metabolism in vitro. Mol Cell Endocrinol 348:21-6
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