Markers and Mechanisms of Vascular Disease in Type II Diabetes
Status:
Completed
Trial end date:
2008-05-01
Target enrollment:
Participant gender:
Summary
OBJECTIVES: Vascular Disease is the leading cause of complications and death in patients with
diabetes. Risk markers and underlying mechanisms have not been fully elucidated, and may
differ from those in non-diabetic individuals. The unifying theme for the Program Project is
that hyperglycemia and insulin resistance alter a number of biological processes which
interact in vicious cycles to accelerate atherogenesis and are consequently major underlying
risk factors for vascular disease. The overall objectives are to define these unique
processes and to elucidate underlying biochemical, metabolic, and genetic determinants of
vascular disease complications in diabetes.
RESEARCH PLAN: Over the past 4 years, we have collaborated with the DCCT/EDIC Study Group,
and have made novel observations regarding vascular disease pathogenesis in Type 1 Diabetes.
This work has focused our studies on specific pathogenic processes. We will now study a Type
2 Diabetes cohort from the VA Cooperative Study, "Glycemic Control and the Complications of
Diabetes, Type 2", with high vascular disease event rates. These collaborations provide a
unique opportunity to address the pathogenesis of accelerated atherogenesis in the two main
types of diabetes, and will greatly augment the scientific knowledge that will be gained in
the conduct of these world-class prospective trials.
METHODS: The Program Project has 4 projects and 3 cores. Project 1 will assess lipoproteins,
glycoxidative stress, and inflammation as risk factors in studies involving Type 2 Diabetes
patients and cultured cell systems. Based on preliminary data from our initial studies Type 1
patients, changes in the NMR lipoprotein subclass profile will be emphasized.
Project 2 will elucidate interactions between inflammation, modifications of lipoproteins,
and autoimmunity in vascular disease risk. These novel concepts are also based upon exciting
preliminary data pertaining to LDL-antibody complexes.
Project 3 will pursue interesting preliminary data and define the role of the
kallikrein-kinin system in vascular disease complications, with effects on mitogenesis and
matrix production.
Project 4 will assess the role of the Insulin Resistance Syndrome and novel factors secreted
from adipocytes in the pathophysiology of biochemical risk factors and cardiovascular
complications.
Cores include an Administrative Core, a Biostatistics and Epidemiology Core which will link
with the trials data coordinating centers, and Molecular and Statistical Genetics Core.
Investigators will work in close collaboration with the VA Executive Committee, Study
Centers, the Hines Coordinating Center, and some of the other ancillary studies. All data
analysis involving clinical outcomes will be performed at the Hines Coordinating Center.
There is true synergism among the projects at both scientific and logistical levels. The
Program Project design allows for interactions among multidisciplinary investigators studying
the same cohort, which will define how multiple pathological processes interact at the level
of the arterial wall to promote atherosclerosis.
Details
Lead Sponsor:
US Department of Veterans Affairs VA Office of Research and Development