Diabetes is extraordinarily prevalent in older adults, the most rapidly growing yet vulnerable portion of the US population, and it dramatically increases the risks of cardiovascular disease (CVD) and congestive heart failure (CHF) in this age group. Despite marked effects of aging on fat mass and distribution, little is known about the pathways that lead to diabetes and the mechanisms by which diabetes leads to CVD in older adults. Emerging evidence implicates two key candidate pathways in diabetes and CVD - the adipocyte-hepatocyte axis in the development of diabetes, and the advanced glycation endproduct (AGE)-profibrosis pathway in CVD complications. Few population-based cohort studies have sufficient numbers of participants, duration, stored specimens, measures of comorbidity, and confirmed outcomes to comprehensively examine these pathways in older adults. We propose an integrated, multi-institutional evaluation of determinants and consequences of diabetes in older adults, using a well-defined, large, and carefully followed cohort of 5,888 older men and women - the Cardiovascular Health Study (CHS). CHS has over 15 years of adjudicated follow-up, including repeated clinic visits with measures of anthropometrics, medication use, subclinical vascular disease, blood and urine biomarkers, and systematic ascertainment of CVD events. We propose to use this rich resource to examine prospectively (1) the associations of adipocyte- and liver-derived products (total and high-molecular-weight adiponectin, fatty-acid binding protein 4, free fatty acids, and fetuin-A) with incident diabetes, (2) the concomitant and potentially divergent associations of these markers with CVD, and (3) the associations of advanced glycation end-products and profibrotic markers (transforming growth factor 2, procollagen III N-terminal peptide) with microvascular and clinical CVD. CHS, with over 350 individuals with incident diabetes, over 725 with prevalent diabetes, nearly 1,300 cases of CVD, and over 2,500 deaths, provides a unique opportunity for our interdisciplinary team of new investigators to evaluate the associations of these candidate pathways with the risks of diabetes and CVD with power, methodological rigor, and cost and specimen efficiency. The findings will advance scientific knowledge and direct future research on diabetes and CVD in older adults, and may lead to novel strategies for prevention and treatment of these disorders that have reached epidemic proportions in elders.

Public Health Relevance

Diabetes is particularly common among older persons;the most rapidly growing segment of the population. Older persons are at highest risk of cardiovascular disease, and diabetes is a major contributing factor. However, our understanding of the determinants and cardiovascular consequences of diabetes in older persons is incomplete, as this age-group is substantially understudied in prior research. The results of this integrated research will provide novel insights to the pathogenesis and cardiovascular consequences of diabetes in older persons, and will inform new avenues for prevention and treatment in this vulnerable and growing population.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL094555-04
Application #
8321549
Study Section
Kidney, Nutrition, Obesity and Diabetes (KNOD)
Program Officer
Olson, Jean
Project Start
2009-09-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2014-06-30
Support Year
4
Fiscal Year
2012
Total Cost
$1,294,893
Indirect Cost
$166,134
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
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Jiang, Z Gordon; de Boer, Ian H; Mackey, Rachel H et al. (2016) Associations of insulin resistance, inflammation and liver synthetic function with very low-density lipoprotein: The Cardiovascular Health Study. Metabolism 65:92-9
Karas, Maria G; Yee, Laura M; Biggs, Mary L et al. (2016) Measures of Body Size and Composition and Risk of Incident Atrial Fibrillation in Older People: The Cardiovascular Health Study. Am J Epidemiol 183:998-1007
Mukamal, Kenneth J; Tremaglio, Joseph; Friedman, David J et al. (2016) APOL1 Genotype, Kidney and Cardiovascular Disease, and Death in Older Adults. Arterioscler Thromb Vasc Biol 36:398-403
Brutsaert, Erika F; Shitole, Sanyog; Biggs, Mary Lou et al. (2016) Relations of Postload and Fasting Glucose With Incident Cardiovascular Disease and Mortality Late in Life: The Cardiovascular Health Study. J Gerontol A Biol Sci Med Sci 71:370-7
Aroner, Sarah A; St-Jules, David E; Mukamal, Kenneth J et al. (2016) Fetuin-A, glycemic status, and risk of cardiovascular disease: The Multi-Ethnic Study of Atherosclerosis. Atherosclerosis 248:224-9
Kim, F; Biggs, M L; Kizer, J R et al. (2016) Brain natriuretic peptide and insulin resistance in older adults. Diabet Med :
Ix, Joachim H; Biggs, Mary L; Mukamal, Kenneth et al. (2015) Urine Collagen Fragments and CKD Progression-The Cardiovascular Health Study. J Am Soc Nephrol 26:2494-503

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