Perturbation of hyaluronan metabolism predisposes patients with type 1 diabetes mellitus to atherosclerosis

Abstract

Aims/hypothesis Cardiovascular disease contributes to mortality in type 1 diabetes mellitus, but the specific pathophysiological mechanisms remain to be established. We recently showed that the endothelial glycocalyx, a protective layer of proteoglycans covering the endothelium, is severely perturbed in type 1 diabetes, with concomitantly increased plasma levels of hyaluronan and hyaluronidase. In the present study, we evaluated the relationship between hyaluronan and hyaluronidase with carotid intima-media thickness (cIMT), an established surrogate marker for cardiovascular disease. Subjects and methods Non-smoking type 1 diabetes patients without micro-or macrovascular complications and matched controls were recruited and cIMT of both carotid arteries was measured. To evaluate the relationship between cIMT and hyaluronan and hyaluronidase as well as other parameters, uni-or multivariate regression analyses were performed. Results We included 99 type 1 diabetes patients (age 10-72 years) and 99 age-and sex-matched controls. Mean cIMT, HbA 1c , high sensitivity C-reactive protein, hyaluronan and hyaluronidase were significantly increased in type 1 diabetes vs controls. Plasma hyaluronan and hyaluronidase were correlated in type 1 diabetes. In univariate regression analyses, mean IMT was associated with plasma hyaluronan, age and male sex, whereas after multivariate analysis only age and sex remained statistically significant. Conclusions/interpretation We conclude that type 1 diabetes patients show structural changes of the arterial wall associated with increased hyaluronan metabolism. These data may lend further support to altered glycosaminoglycan metabolism in type 1 diabetes as a potential mechanism involved in accelerated atherogenesis.

Effects of Grape Seed Proanthocyanidin Extracts on Aortic Pulse Wave Velocity in Streptozocin Induced Diabetic Rats

“…1) In diabetes, macrovascular disease is the commonest cause of mortality and morbidity, and is responsible for a high incidence of vascular diseases such as stroke, myocardial infarction, and peripheral vascular diseases. 2,3) Macrovascular diseases are traditionally thought of as due to underlying obstructive atherosclerotic diseases affecting major arteries. Pathological changes in major blood vessels leading to functional and structural abnormalities in diabetic vessels include endothelial dysfunction, reduced vascular compliance, and atherosclerosis.…”

Regulation and roles of the hyaluronan system in mammalian reproduction

“…Enhanced synthesis of HA by proinflammatory cytokines has been associated with renal and rheumatoid diseases (Dahl et al 1985, Manicourt et al 1993, Feusi et al 1999. Similarly, dysregulation of HA metabolism is a typical feature of diabetes (Nieuwdorp et al 2007) or endometrial cancer (Afify et al 2005, Nykopp et al 2010. HA dysregulation may be associated with unexplained infertility (Altmäe et al 2010), and most relevant here, HA accumulation in the uterus has been linked with early embryo loss including spontaneous abortion (Camenisch et al 2000, Cordo-Russo et al 2009).…”

Effect of anticoagulants on the plasma hyaluronidase activities

“…As physicians/clinicians suggest for evaluating particularly the plasma HAase activity during several pathological conditions, such as diabetes, monoclonal gammapathy, and bladder and prostate tumors (14)(15)(16), prior knowledge of interference by the anticoagulants is very essential. This is in order to avoid misinterpretation of the results obtained.…”

“…In contrast, the enzymes involved in the HA synthesis do not circulate freely (2,13). Moreover, augmented expressions of Hyal-1 mRNA and elevated levels of hHyal-1 are documented in several diseases (14)(15)(16)(17).…”

“…In clinical/pathological conditions, such as diabetes, monoclonal gammapathy, and bladder and prostate tumors, analysis of plasma HAase activity has been widely suggested (14)(15)(16)(17). The preparation of plasma appears to be a critical step as it requires the use of anticoagulants.…”