Individuals with type 1 diabetes (T1D) are at greatly increased risk of coronary artery disease (CAD) compared to the general population, despite only minor differences in traditional lipid and other cardiovascular risk factors. Although generally elevated in T1D patients, high density lipoprotein cholesterol (HDL-C) levels still inversely predict CAD risk. Surprisingly, analyses of the 18-year follow-up of our Epidemiology of Diabetes Complications (EDC) study showed an increased CAD incidence with highly elevated (>80 mg/dL) HDL-C in women, in whom no progressive protection above 50 mg/dL was noted. In men, the original strong inverse relationship held throughout the range of HDL-C levels, though only two had HDL-C above 80 mg/dL. We therefore hypothesize that these apparently contradictory findings of elevated risk in the presence of high HDL- C reflect impaired HDL functionality in T1D. Indeed, the hypothesis of dysfunctional HDL-C in terms of its most critical activity, reverse cholesterol transport, has long been proposed in T1D, although it has not been formally tested using currently available novel measures of HDL function. The recently reported association between the Haptoglobin (Hp) 2 allele and CAD incidence in diabetes is also thought, at least partially, to relate to impaired HDL function, i.e. impaired reverse cholesterol transport, in these individuals. Hp is an acute phase plasma protein whose main function is to bind free hemoglobin, thereby inhibiting heme iron release and thus reducing hemoglobin-induced oxidative tissue damage. In T1D, we showed a significantly increased CAD risk with Hp 2-2 and a linear trend toward increased risk with the number of Hp 2 alleles. Additionally, in our HapE intervention study, HDL-mediated cholesterol efflux decreased linearly with the number of Hp 2 alleles, whereas vitamin E improved efflux among Hp 2-2 carriers. Given these data, our aim, using novel sophisticated methods, is to determine: a) whether HDL function (sterol efflux) is impaired in T1D compared to non-diabetic controls (overall and by gender); b) the ability of HDL function to predict CAD in T1D by gender; and c) to what extent HDL function explains the reported Hp- CAD association in T1D. We thus propose to quantify HDL efflux capacity with macrophages using a well- validated assay, and complement these studies with state-of-the art quantification of the concentration/size of HDL particles and HDL's protein cargo (providing information on HDL's anti-inflammatory and anti-oxidative properties). The proteomic analyses, though more exploratory in nature, will provide data on HDL's anti- inflammatory/anti-oxidative properties, which would be of great interest as inflammation/oxidative stress play a role in atherosclerosis development and as Hp is an acute phase protein with anti-oxidative properties. With this research we therefore aim to further our understanding of factors that influence HDL's cardioprotective effects in patients with T1D and shed light on gender differences as well as the mechanisms underlying the increased CAD risk associated with the Hp 2 allele in this population.
The observations of a) greatly increased CAD risk in type 1 diabetes compared to the general population despite often elevated HDL-C and b) no gender differences in CAD risk in type 1 diabetes despite higher HDL- C in women, has led to the hypothesis that HDL is dysfunctional. The Haptoglobin 2 allele - CAD association in diabetes is also thought to, at least partially, relate to impaired HDL function. Our proposal to study factors that influence HDL's cardioprotective effects in type 1 diabetes will shed light on the mechanisms underlying the overall increased CAD risk in this population, the lack of a gender difference in risk, as well as risk associated with the Hp 2 allele, potentially providing the basi for future therapies.
