Insulin Resistance Atherosclerosis Study (IRAS)

BACKGROUND:

An association between overt diabetes and cardiovascular disease has been observed in multiple studies among populations across the world. The reason for this excess are only partly understood. In recent years, several studies have suggested that elevations in levels of insulin or insulin resistance are important risk factors for cardiovascular disease, not only in diabetic patients but also among those with normal or subclinical abnormalities in glucose tolerance.

Many reasons exist to investigate the role of insulin and insulin resistance in the development of cardiovascular disease. Insulin has effects on multiple metabolic pathways and has been shown to promote development of atherosclerotic lesions in animals. In addition, levels of insulin and insulin resistance are correlated with multiple abnormalities in other cardiovascular disease risk factors such as elevations in blood pressure, dyslipidemia, and alterations in coagulation factors.

It is particularly important to determine whether these associations are strongest with levels of insulin or of insulin resistance since this information will be valuable both for studies aimed at localizing the site of the defect and in developing new therapeutic interventions. Despite evidence from population studies, it is difficult to explain the excess of cardiovascular disease in diabetics solely as a consequence of elevations in insulin levels. Recent, small studies suggest that the risk previously associated with hyperinsulinemia may be correlated more strongly with increases in insulin resistance. Insulin resistance continues to increase as glucose levels increase, even in the presence of decreasing insulin secretion. Such observations may help to explain the higher risk of cardiovascular disease in overt diabetics. More detailed assessments of the role of insulin resistance in altering cardiovascular disease risk factors are also needed. Prior to the IRAS study, direct measures of insulin resistance had not been performed in population studies. The continuation of IRAS for an additional five years will provide the first longitudinal data on insulin resistance as a cardiovascular disease risk factor.

The IRAS was proposed by staff and approved by the Clinical Applications and Prevention Advisory Committee in May, 1990. The Request for Applications was released in November, 1990. Awards were first made in September, 1991. The study was extended for an additional five years in September, 1995 and in August, 1999.

DESIGN NARRATIVE:

The study population was selected to insure adequate numbers of participants within gender and glucose tolerance groups (normoglycemia, impaired glucose tolerance, and non-insulin dependent diabetes mellitus). IRAS is the first large epidemiologic study to include detailed measurements of insulin sensitivity and secretion. During the first four years of funding, the IRAS investigators successfully designed and implemented the first phase of the study--a cross-sectional evaluation of 1,625 participants. Cohort examinations began in October, 1992 and were completed in April, 1994. Insulin resistance was assessed directly using the frequently sampled intravenous glucose tolerance test with minimal model analysis. Intimal-medial carotid artery wall thickness, an indicator of atherosclerosis, was measured using B-mode ultrasonography. Prevalent cardiovascular disease was assesed by questionnaire and resting electrocardiography.

The IRAS was renewed in September, 1995 for an additional five years through July, 1999 for the prospective follow-up and reexamination of the cohort. The renewal period consisted of three phases. During the first phase (years 05 and 06), the investigators conducted a substudy to address the measurement of insulin sensitivity in individuals with NIDDM. This substudy evaluated several alternate techniques for measuring insulin sensitivity in approximately 115 non-IRAS volunteers with NIDDM. In addition, all IRAS participants were contacted annually for incident cardiovascular and other major health events. During the second phase (years 07 and 08), a follow-up examination of the IRAS cohort was conducted with the goal of determining predictors of changes in insulin sensitivity, cardiovascular risk factors, measures of atherosclerosis development, and incident cardiovascular events. Additionally, throughout the first four years, there was a continued major effort devoted to the analysis and reporting of the cross-sectional data from the first IRAS examination. The final phase (year 09) included analysis and reporting of the longitudinal results.

Since existing measures of insulin resistance do not appear to measure exactly the same thing, substudies have been conducted to compare insulin resistance measurement techniques and enable the IRAS data to be related to other studies in the literature. A decision has been made to continue the frequently sampled intravenous glucose tolerance test (FSIGT) as the vascular resistance measure in the IRAS. The FSIGT is compared with other measures of insulin resistance in diabetics.

The IRAS was renewed in August 1999 through July 2005 as the IRAS Family Study. The purpose was to identify the genetic determinants of insulin resistance and abdominal obesity and to determine the extent to which insulin resistance, visceral adiposity, and metabolic cardiovascular disease risk factors share common genetic influences. Families of African-American and Hispanic background were enrolled using participants of the original IRAS study as index cases. Approximately 1,280 additional family members were recruited to the study for a total of 1,440 participants. Insulin resistance was measured using the frequently sampled intravenous glucose tolerance test, and abdominal obesity was measured using computed tomography. Metabolic cardiovascular disease risk factors were also assessed. A panel of 370 micro satellite markers were genotyped to provide data for a genome-wide scan to detect chromosomal regions containing quantitative trait loci (QTLs) that influenced phenotypic variation for insulin resistance and visceral adiposity.

The study which has been extended through December, 2008 targets the further exploration of genomic regions and positional cloning of genes contributing to variation in adiposity and glucose homeostasis. Positional candidate genes will be identified. The original cohort will be re-contacted to repeat some of the primary phenotypes for measures of change (abdominal CT scan and fasting insulin) and add several important new phenotypes to add depth to the assessment of adiposity and glucose homeostasis (total body fat by DXA and adipocytokines, including adiponectin and soluble TNF-alpha receptors 1 and 2). A panel of nutritional, dietary, and eating behaviors will be assessed to study the genetic effects. Using the existing genome scan data and variance-components-based linkage analysis methods, regions of the genome will be detected that contribute to variation in these new phenotypes and in the change phenotypes