One of the key challenges in type 1 diabetes (T1D) complications today is the vastly increased risk of coronary artery disease (CAD), compared to the general population. While more intensive glycemic, blood pressure and lipid control has decreased the rates of nephropathy and retinopathy, the gap in CAD risk between T1D and non-diabetic persons has persisted, unexplained by conventional risk factors. This proposed study will examine the role of novel factors in vascular complications of T1D that are not directly addressed by current preventive guidelines: insulin resistance, AGEs, oxidative stress, and endothelial dysfunction. Anticipated results will inform the design of trials to prevent premature CAD and further delay microvascular complications in patients with T1D. The Coronary Artery Calcification in Type 1 Diabetes (CACTI) study has followed 1416 adults (652 with T1D, 764 non-diabetic controls) aged 19-56 years at the baseline examination in 2000-2002, and re-examined after 3 and 6 years. The unique features of this cohort include: population-representativeness of the T1D and non- diabetic (Non-DM) subjects, large size, and availability of prospectively defined cardio-renal phenotypes. We are proposing a 12-year follow-up examination of this cohort. Coronary artery calcification (CAC), the main study outcome, is an excellent marker of CAD risk in the general population. This proposed study will significantly expand our knowledge concerning CAC associations with macro- and micro-vascular complications of T1D, and will help to develop alternative biomarkers that do not involve radiation and can be administered at point of care to identify those T1D patients at high risk.
Specific Aim 1 : Evaluate development and progression of subclinical coronary atherosclerosis over 12 years in these well characterized cohorts of T1D patients and Non-DM controls to: i) Determine if there is evidence for continued divergence of progression of subclinical atherosclerosis in these groups;ii) Evaluate novel risk factors;and iii) Explore additional non-invasive measurements of CAD. iv) Continue annual ascertainment of CAD events (including revascularization) and mortality in all study subjects.
Specific Aim 2 : In all subjects, continue prospective assessment of renal function, and: i) Determine whether renal complications independently predict CAC progression, and whether T1D patients without renal complications have increased risk of CAC ii) Assess additional, novel microvascular complications to estimate the global burden of microvascular complications and their association with CAC;iii) Evaluate novel risk markers (insulin resistance, AGEs, glycemic control and variability) as factors common to all complications.
Specific Aim 3 : Examine endothelium-specific mechanisms of micro and macrovascular complications in a subgroup of T1D and Non-DM subjects identified from the study cohorts with complications vs. without.

Public Health Relevance

The vastly increased risk of coronary artery disease (CAD) in people with type 1 diabetes (T1D) compared to the general population remains one of the key unanswered challenges. While more intensive glycemic, blood pressure and lipid control has decreased the rates of nephropathy and retinopathy, the gap in CAD risk between T1D and non-diabetic persons has persisted, unexplained by conventional risk factors. This proposed study will examine the role of novel factors in vascular complications of T1D that are not directly addressed by current preventive guidelines: insulin resistance, AGEs, oxidative stress, and endothelial dysfunction. Anticipated results will inform the design of trials to prevent premature CAD and further delay microvascular complications in patients with T1D.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL113029-01A1
Application #
8436645
Study Section
Kidney, Nutrition, Obesity and Diabetes (KNOD)
Program Officer
Wright, Jacqueline
Project Start
2013-06-01
Project End
2017-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
1
Fiscal Year
2013
Total Cost
$730,316
Indirect Cost
$240,811
Name
University of Colorado Denver
Department
Pediatrics
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
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