Until now, research investigations employing the Wynn Database information have concentrated primarily on a sub-set of the data that relates to an occupational cohort of 1192 individuals, studied between 1971 and 2000 - the Heart Disease and Diabetes Research Indicators in a Screened Cohort (HDDRISC) study. Analyses of HDDRISC study data have resulted in 25 peer-reviewed, published studies of relationships between metabolic risk factors and of their relationships to cardiovascular and cancer mortality and diabetes outcomes (1-25). Key findings from analyses of HDDRISC sub-study data include: 1) demonstration of the marked decline in beta cell insulin output as fasting plasma glucose increases towards diabetic levels (9); 2) discovery of associations between instability and progressive change in HDL cholesterol, uric acid, erythrocyte sedimentation rate and insulin sensitivity and cardiovascular disease outcomes (14, 15); and 3) prediction of death from either cardiovascular disease or cancer by inflammation markers measured over 20 years prior to death (20).

Insulin sensitivity and secretion in men and pre-and post-menopausal women

The sex steroids, oestradiol and testosterone significantly affect tissue sensitivity to insulin and beta cell function. A core investigative procedure used by the Wynn Group from 1965 through to the late 1990s was the intravenous glucose tolerance test (IVGTT) which can provide widely-used measures of both insulin sensitivity and beta cell function. IVGTT data in the Wynn Database offers an opportunity to explore sex steroid-associated variation in key physiological determinants of glucose metabolism by comparing groups of pre- and postmenopausal women and men. A preliminary review of IVGTT data held in the Wynn Database has identified Wynn database information on over 9,000 IVGTTs suitable for such an analysis.

Does individual variability in metabolic risk indicators relate to mortality outcomes?

Metabolic risk factors for cardiovascular disease are generally evaluated on the basis of single measurements. However, preliminary studies in the course of the HDDRISC study have shown that increased variability in risk factor levels may indicate increased risk of adverse health outcomes. Studies of relationships between metabolic instability and clinical outcomes are limited, primarily due to the costs and the logistic challenges of undertaking the serial metabolic assessments necessary. The Wynn Database holds data for multiple serial evaluations in single individuals of a variety of metabolic risk indicators. Around 2,000 participants have information on fasting plasma glucose and insulin and serum lipids from which measures of metabolic instability may be derived. With mortality outcomes in each individual, it will be possible to explore further the clinical implications of metabolic variation.

Can oral glucose tolerance test glucose and insulin profile features provide novel information regarding caridovascular mortality risks?

The risk of developing cardiovascular disease is increased in impaired glucose tolerance and diabetes but there may be further variations in risk among normoglycaemic individuals. There is, currently, interest in the possibility that sub-clinical variations in oral glucose tolerance test (OGTT) glucose and insulin profiles may have health implications. However, investigations into this possibility have been limited by lack of suitable data and of clinical outcome information. In a Wynn Database pilot analysis of 397 normoglycaemic individuals participating in the HDDRISC study (unpublished), we have used cluster analysis of OGTT glucose and insulin measurement sets to classify key profile features into 10 discrete categories. Independently of individual characteristics, insulin resistance and beta cell function, associations were found between profile features and lipid and blood pressure risk factors for cardiovascular disease, including diastolic blood pressure, triglycerides, insulin and HDL cholesterol. The complete Wynn database can provide OGTT glucose and insulin profile information for 7107 individuals. These data can provide for a substantially expanded analysis of relationships between OGTT profile features and cardiovascular disease risk factors and, with mortality follow-up for each participant, could enable profile features to be related to risk and cause of death.

Does the metabolic response to oral contraceptive use relate to subsequent mortality and cause of death?

 There have been many studies of the effects of oral contraceptive use on mortality in cohorts of women who, on recruitment, were either taking or not taking oral contraceptives. These studies identified increased risks of venous thromboembolic and arterial disease associated with oral contraceptive use. Combined oral contraceptives can have marked adverse effects on glucose and lipid homeostasis that are consistent with these risks. However, no study has investigated the relationship between metabolic response to oral contraceptve use and long-term mortality.  With the Wynn Database, relationships between oral contraceptive-induced changes in metabolic risk indicators and mortality can be studied in 3311 women who were oral contraceptive users at the time of receiving an OGTT. As a reference group, there are 4,996 women aged 45 or less who were not oral contraceptive users at the time of receiving an OGTT.