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.

The postprandial lipoprotein metabolism is important since it determines the circulation of potentially atherogenic particles and influences the metabolism of high-density lipoproteins (HDL) in a complex manner that is at present not completely understood. Therefore, the short-term (24-h) changes in postprandial lipoprotein metabolism, including retinyl palmitate (RP), apolipoprotein A-I (apo A-I), and apolipoprotein B, were studied in relation to postheparin lipolytic activities in six healthy normolipidemic men after an oral RP fat tolerance test. The fat load (98 g) was cleared in 7 h, because the triglyceride (TG) concentrations had returned to initial values (0.72 +/- 0.31 mmol/l) at that time. RP showed a peak in plasma at 4 and 5 h but remained present in chylomicron (remnants) in low concentrations after 8 and 24 h. After the fat load, HDL cholesterol and HDL-associated apo A-I showed a significant decrease in concentration of 35 and 29%, respectively. The decrease coincided with the increase in chylomicron remnants and the transient appearance of TG-enriched HDL. Hepatic lipase was correlated to both the initial HDL cholesterol concentration as well as the peak concentration of TG in chylomicron remnants, suggesting that it could be one of the regulating common physiological pathways in postprandial HDL and TG metabolism. In the subjects studied, the atherogenic potential of plasma increased in response to an oral fat load, characterized by a decrease in HDL cholesterol and HDL-associated apo A-I.

The postprandial lipoprotein metabolism of two orally administered vitamin A-fat loads consisting of either 20% (wt:vol) soybean oil or 17% olive oil plus 3% soybean oil was studied in six normolipidemic young men according to a randomized crossover design. Mean (+/- SEM) retinyl palmitate concentrations (area under the 24-h curve) were higher in olive oil chylomicrons (97.3 +/- 5.5 mmol.L-1 x h-1), than in soybean-oil chylomicrons (84.0 +/- 10.5 mmol.L-1 x h-1; P < 0.02). Apolipoprotein B-48 concentrations were higher in the olive oil chylomicron remnants with densities (d) of 1.006-1.019 compared with soybean-oil remnants. The slower removal of olive oil chylomicron remnants was correlated to hepatic lipase activity (r = 0.84, P < 0.02). The initial HDL-cholesterol concentration (0.87 +/- 0.17 mmol/L--relatively low but within the normal range for young Dutch men) decreased significantly after ingestion of soybean oil to 0.66 +/- 0.10 mmol/L after 5 and 7 h, but no significant decrease was observed after olive oil ingestion. Soybean oil induced decreases in HDLs correlated inversely with hepatic lipase (r = -0.88, P < 0.02). The results suggested that competition between olive oil chylomicron remnants and HDL for hepatic lipase may have been the underlying mechanism that prevented the postprandial decrease in HDL cholesterol.

OBJECTIVE -In patients with type 2 diabetes, microalbuminuria is associated with an increase in predominantly cardiovascular mortality. Considerable interindividual variability in the rate of progression of microalbuminuria exists. The prognostic significance of rate of progression of microalbuminuria with regard to cardiovascular and renal clinical end points is, however, unknown. The purpose of this study was to determine the prognostic significance of rate of progression of microalbuminuria for cardiovascular end points and renal function.RESEARCH DESIGN AND METHODS -In a previous prospective cohort study, progression of microalbuminuria (expressed as mean yearly change in albumin-to-creatinine ratio) was assessed in 58 patients with type 2 diabetes. During a median follow-up of 7 years after progression of microalbuminuria was determined, we registered all-cause mortality and coronary heart disease mortality as primary end points and coronary heart disease (fatal or nonfatal), peripheral vascular disease, ischemic stroke, retinopathy, macroalbuminuria, and change in serum creatinine as secondary end points.RESULTS -Seven subjects died during the study; five of these subjects died of coronary heart disease. Cox's regression analysis identified progression of microalbuminuria as a significant predictor of all-cause mortality (hazard ratio 1.46 per point increase in albumin-to-creatinine ratio per year, P Ͻ 0.001), coronary heart disease mortality (hazard ratio 2.32, P ϭ 0.006), and macroalbuminuria (hazard ratio 1.79, P Ͻ 0.001). Adjustment for multiple cardiovascular risk factors did not affect these results. Identical analyses for baseline level of microalbuminuria instead of progression rate of microalbuminuria did not show significant hazard ratios. In addition, progression of microalbuminuria significantly predicted an increase in serum creatinine (r ϭ 0.29, P ϭ 0.04).CONCLUSIONS -In patients with type 2 diabetes and microalbuminuria, the rate of progression of albumin excretion seems to be a powerful independent predictor of mortality caused mainly by coronary heart disease.

The R194W mutation in PPARG disrupts its DNA binding activity and through haploinsufficiency leads to clinical manifestation of FPLD3 and the associated metabolic disturbances.