Accelerated arterial stiffening occurs in conditions of insulin resistance, such as hypertension, obesity, and type 2 diabetes (T2D). Arterial stiffness is an independent risk factor for cardiovascular disease (CVD). Importantly, women with T2D are at higher risk for stiffening than men. The underlying mechanisms that contribute to the sexual dimorphism in arterial stiffness are unknown. Diets rich in fructose elevate serum uric acid (SUA). In turn, high SUA and enhanced activation of xanthine oxidase (XO) are associated with vascular stiffness preferentially in women. Uric acid (UA) and XO activation result in inflammation, oxidative stress and endothelial dysfunction, all key events in the genesis of arterial stiffness. Conversely, lowering SUA with the XO inhibitor allopurinol reduces the incidence of stroke and cardiac events in humans. Our preliminary data in rodents demonstrate that a high-fructose diet promotes arterial stiffness more in female mice than males, whereas a reduction of uric acid with allopurinol reverses this phenomenon in females. In obese and insulin- resistant humans, we have shown that a low-fructose diet with weight loss has a greater impact in reducing pulse wave velocity (PWV), a marker of vascular stiffness, in women than men. Still, a critical unanswered question is whether lowering SUA and/or blocking XO will improve vascular stiffness in hyperuricemic T2D adults in the absence of weight loss. It is also unknown if such interventions will have a different effect on men and women. Hence, we hypothesize that SUA reduction (via pharmacological or dietary means) will improve arterial stiffness in T2D women to a greater extent than in T2D men treated in a similar fashion, and further, that this improvement will parallel decreased inflammation, oxidative stress and endothelial dysfunction. Two interventions will be undertaken with the primary outcome of improving PWV. Initially, age- and BMI-matched men and post-menopausal women, all with T2D, will be treated with allopurinol (20 men, 20 women) for 6 months, in order to reduce SUA concentrations to 6 mg/dL relative to placebo (10 men, 10 women). In a second intervention, dietary fructose will be restricted for a period of 6 months in T2D subjects who will maintain a stable weight (20 men, 20 women). At the beginning and end of both studies, measures of arterial stiffness will be combined with assessments of endothelial function, measurements of inflammation and oxidative stress.
In Aim 1, the team will determine if sex-related differences exist in the relationship between SUA levels and arterial stiffness (via PWV) in age-matched T2D men and post-menopausal women, and to what degree these differences are related to augmented oxidative stress, inflammation and endothelial dysfunction.
In Aim 2, the two strategies for reducing SUA (XO inhibition and fructose replacement with starch) will be compared, to determine the differential effect on vascular stiffness, between men and women. This proposal will bridge a critical knowledge gap about the pathophysiology of CVD, specifically in women, and will lead to pharmacologic and dietary strategies to reduce the unique risk of CVD in women with T2D.
Stiffness of the arteries is a risk factor for cardiovascular disease, and women with type 2 diabetes have more arterial stiffening than men with type 2 diabetes. Because the mechanisms contributing to this sex-related difference are not clear, in this project, we will explore the effect of elevated uric acid as a key factor contributing to arterial stiffness in type 2 diabetics; we will also test the effects of two interventions to reduce uric acid (low-fructose diet and allopurinol) on arterial stiffness. Successful completion of these studies could enable the development of therapeutic tools to prevent cardiovascular disease in diabetics, particularly in diabetic women.
