OBJECTIVE

To compare serum cystatin C levels, a novel biomarker of renal function, in adolescents with and without type 1 diabetes and to determine what factors affect cystatin C levels.

RESEARCH DESIGN AND METHODS

Cystatin C was measured in youth 12–19 years of age with (n = 259, diabetes duration 9 ± 3 years, HbA1c 8.9 ± 1.6%) and without diabetes (n = 78). Data were compared by diabetes status, and linear regression was used to determine factors affecting cystatin C.

RESULTS

Cystatin C (0.698 ± 0.083 vs. 0.688 ± 0.127 mg/L, P = 0.40) was similar by diabetes status. In multiple linear regression, cystatin C was associated with age and serum creatinine in nondiabetic subjects and sex, age, and serum creatinine in subjects with diabetes (P < 0.05).

CONCLUSIONS

These data suggest sex differences and age-related changes in cystatin C in adolescents with type 1 diabetes. An understanding of these changes is needed to determine the potential role of cystatin C as a marker of renal function in this population.

Aims

Fructose induces metabolic syndrome in rats but studies have been criticized for using high concentrations of fructose that are not physiologic, for using only pure fructose, and for not controlling for energy intake. We tested the hypothesis that a 40% sucrose diet (containing 20% fructose) might induce features of metabolic syndrome in male breeder rats independent of excess energy intake.

Methods

Male Sprague-Dawley breeder rats were pair fed 40% sucrose or isocaloric starch diet for 4 months and evaluated for metabolic syndrome and diabetes. In vitro studies were performed in rat insulinoma cells (RIN-m5F) exposed to uric acid and markers of inflammation were assessed.

Results

Rats fed a 40% sucrose diet developed accelerated features of metabolic syndrome with upregulation of fructose-dependent transporter Glut 5 and fructokinase. Fatty liver and low grade pancreatic inflammation also occurred. Uric acid was found to stimulate inflammatory mediators and oxidative stress in islet cells in vitro.

Conclusions

Sucrose, at concentrations ingested by a subset of Americans, can accelerate metabolic syndrome, fatty liver and type 2 diabetes in male breeder rats, and the effects are independent of excess energy intake.

Despite the advances in the management of patients with diabetes, diabetic nephropathy (DN) remains the most common cause of end stage renal disease (ESRD) in the US and worldwide. Inflammation and endothelial dysfunction appear to play a central role in the onset and the progression of DN. Recent evidence has emerged in the last decade to suggest uric acid is an inflammatory factor and may play a role in endothelial dysfunction. This has lead our group and others to explore the role of uric acid in the onset and progression of DN. In this review, we will highlight some of the animal and human studies that implicate uric acid in DN. Based on the evidence we review, we conclude the need for properly planned randomized controlled studies to lower uric acid levels and assess the impact of such therapy on diabetic kidney disease.

Background

An elevated serum uric acid level is strongly associated with endothelial dysfunction and inflammation, both of which are common in chronic kidney disease (CKD). We hypothesized that endothelial dysfunction in subjects with CKD would correlate with uric acid levels.

Materials and Methods

We evaluated the association between serum uric acid level and ultrasonographic flow-mediated dilatation (FMD) in 263 of 486 patients with recently diagnosed CKD (stage 3–5) (48% male, age 52 ± 12 years). To minimize confounding, 233 patients were excluded because they were diabetic, had established cardiovascular complications or were taking drugs (renin-angiotensin system blockers, statins) interfering with vascular function.

Results

Serum uric acid level was significantly increased in all stages of CKD and strongly correlated with estimated glomerular filtration rate (eGFR-MDRD); FMD was inversely associated with serum uric acid (r = −0.49, p < 0.001). The association of serum uric acid with FMD remained after adjustment for age, gender, smoking, LDL cholesterol, eGFR, high-sensitivity C-reactive protein, systolic blood pressure, proteinuria, and homeostatic model assessment index (β = −0.27, p < 0.001).

Conclusion

Increased serum uric acid is an independent predictor of endothelial dysfunction in subjects with CKD.

OBJECTIVE

To examine uric acid (UA) as a possible predictor of the progression of coronary artery calcification (CAC) using data from the prospective Coronary Artery Calcification in Type 1 Diabetes (CACTI) Study.

RESEARCH DESIGN AND METHODS

CAC was measured by electron beam tomography at the baseline and at a follow-up 6.0 ± 0.5 years later. The study population included 443 participants with type 1 diabetes and 526 control subjects who were free of diagnosed coronary artery disease at baseline. The presence of renal disease was defined by the presence of albuminuria and/or low glomerular filtration rate.

RESULTS

In subjects without renal disease, serum UA predicted CAC progression (odds ratio 1.30 [95% CI 1.07–1.58], P = 0.007) independent of conventional cardiovascular risk factors including diabetes and the presence of metabolic syndrome.

CONCLUSIONS

Serum UA levels predict the progression of coronary atherosclerosis and may be useful in identifying who is at risk for vascular disease in the absence of significant chronic kidney disease.

Background. Recent studies suggest that uric acid is a mediator of diabetic nephropathy. We hypothesized that elevated serum uric acid levels are a strong predictor of albuminuria in patients with type 1 diabetes.

Methods. We analyzed data from the Coronary Artery Calcification in Type 1 Diabetes study, a prospective observational study. A stepwise logistic regression model was applied to predict the development of micro- or macroalbuminuria after 6 years of follow-up in 324 participants who had no evidence of micro- or macroalbuminuria at baseline. A P-value <0.1 was used as the criteria for entry into and removal from the model.

Results. The following factors were selected in the stepwise multivariate model as predictors of micro- or macroalbuminuria at the 6-year follow-up visit: baseline serum uric acid levels, HbA1c and pre-albuminuria. For every 1-mg/dl increase in serum uric acid levels at baseline, there was an 80% increased risk of developing micro- or macroalbuminuria at 6 years (odds ratio 1.8; 95% confidence interval 1.2, 2.8; P = 0.005). Additional covariates considered in the stepwise model were sex, age, duration of diabetes, angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker treatment, waist circumference, waist/hip ratio, body mass index, systolic and diastolic blood pressure, smoking, serum creatinine, cystatin C, high-density lipoprotein cholesterol and triglycerides.

Conclusion. Elevated serum uric acid levels are a strong predictor of the development of albuminuria in patients with type 1 diabetes.

Aldosterone is a major regulator of epithelial Na+ absorption. One of its principal targets is the epithelial Na+ channel α-subunit (ENaCα), principally expressed in the kidney collecting duct, lung, and colon. Models of aldosterone-mediated trans-activation of the ENaCα gene have focused primarily on interactions of liganded nuclear receptors with the ENaCα gene promoter. Herein, we demonstrate that the murine histone H3 lysine-79 methyltransferase, murine disruptor of telomeric silencing alternative splice variant “a” (mDot1a), is a novel component in the aldosterone signaling network controlling transcription of the ENaCα gene. Aldosterone downregulated mDot1a mRNA levels in murine inner medullary collecting ducts cells, which was associated with histone H3 K79 hypomethylation in bulk histones and at specific sites in the ENaCα 5′-flanking region, and trans-activation of ENaCα. Knockdown of mDot1a by RNA interference increased activity of a stably integrated ENaCα promoter-luciferase construct and expression of endogenous ENaCα mRNA. Conversely, overexpression of EGFP-tagged mDot1a resulted in hypermethylation of histone H3 K79 at the endogenous ENaCα promoter, repression of endogenous ENaCα mRNA expression, and decreased activity of the ENaCα promoter-luciferase construct. mDot1a-mediated histone H3 K79 hypermethylation and repression of ENaCα promoter activity was abolished by mDot1a mutations that eliminate its methyltransferase activity. Collectively, our data identify mDot1a as a novel aldosterone-regulated histone modification enzyme, and, through binding the ENaCα promoter and hypermethylating histone H3 K79 associated with the ENaCα promoter, a negative regulator of ENaCα transcription.

Background

Some experimental evidence suggests that uric acid impairs endothelial function. It is controversial if high uric acid levels and impaired endothelial function are related in healthy adults. In addition, the effect of uric acid on endothelial cells (ECs) of humans is unexplored.

Methods

Data of 107 healthy adult volunteers were analyzed. The association between serum uric acid and endothelial-dependant dilation (EDD) and endothelial-independent dilation (EID) was evaluated by linear regression models. We also examined the relations between uric acid and systemic and cellular markers of inflammation and oxidative stress in all or subsets of participants.

Results

Uric acid levels and EDD were not related in unadjusted or adjusted models. There was a significant negative correlation between uric acid and EID in the pooled sample (r = −0.34, P = 0.005). This correlation remained significant after adjusting for demographics (P = 0.04) and was attenuated after adjusting for other cardiac risk factors (P = 0.12). Higher serum uric acid levels were found to correlate significantly with C-reactive protein (CRP) (r = 0.31, P = 0.002). Serum uric acid levels were not associated with brachial artery EC nuclear factor-κB (NF-κB) p65 or NADPH oxidase p47phox expression or with nitrotyrosine staining, but were inversely associated with EC manganese superoxide dismutase (MnSOD) expression (r = −0.5, P = 0.01, n = 25).

Conclusion

Elevated serum uric acid is not associated with endothelial dysfunction among healthy adults, but is inversely related to EID and EC MnSOD, and positively related to systemic inflammation. These findings may have implications for cardiovascular risk in healthy adults.