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OBJECTIVE: We investigated whether the antiproteinuric effect of the direct renin inhibitor aliskiren is comparable to that of irbesartan and the effect of the combination. RESEARCH DESIGN AND METHODS: This was a double-blind, randomized, crossover trial. After a 1-month washout period, 26 patients with type 2 diabetes, hypertension, and albuminuria (>100 mg/day) were randomly assigned to four 2-month treatment periods in random order with placebo, 300 mg aliskiren once daily, 300 mg irbesartan once daily, or the combination using identical doses. Patients received furosemide in a stable dose throughout the study. The primary end point was a change in albuminuria. Secondary measures included change in 24-h blood pressure and glomerular filtration rate (GFR). RESULTS: Placebo geometric mean albuminuria was 258 mg/day (range 84-2,361), mean ± SD 24-h blood pressure was 140/73 ± 15/8 mmHg, and GFR was 89 ± 27 ml/min per 1.73 m². Aliskiren treatment reduced albuminuria by 48% (95% CI 27-62) compared with placebo (P < 0.001), not significantly different from the 58% (42-79) reduction with irbesartan treatment (P < 0.001 vs. placebo). Combination treatment reduced albuminuria by 71% (59-79), more than either monotherapy (P < 0.001 and P = 0.028). Fractional clearances of albumin were significantly reduced (46, 56, and 67% reduction vs. placebo). Twenty-four-hour blood pressure was reduced 3/4 mmHg by aliskiren (NS/P = 0.009), 12/5 mmHg by irbesartan (P < 0.001/P = 0.002), and 10/6 mmHg by the combination (P = 0.001/P < 0.001). GFR was significantly reduced 4.6 (95% CI 0.3-8.8) ml/min per 1.73 m² by aliskiren, 8.0 (3.6-12.3) ml/min per 1.73 m² by irbesartan, and 11.7 (7.4-15.9) ml/min per 1.73 m² by the combination. CONCLUSIONS: The combination of aliskiren and irbesartan is more antiproteinuric in type 2 diabetic patients with albuminuria than monotherapy.

Arterial stiffness may contribute to depression via cerebral microvascular damage, but evidence for this is scarce. We therefore investigated whether arterial stiffness is associated with depressive symptoms and whether cerebral small vessel disease contributes to this association. This cross-sectional study included a subset of participants from the AGES-Reykjavik study second examination round, which was conducted from 2007 to 2011. Arterial stiffness (carotid–femoral pulse wave velocity [CFPWV]), depressive symptoms (15-item geriatric depression scale [GDS-15]) and cerebral small vessel disease (MRI) were determined. Manifestations of cerebral small vessel disease included higher white matter hyperintensity volume, subcortical infarcts, cerebral microbleeds, Virchow–Robin spaces and lower total brain parenchyma volume. We included 2058 participants (mean age 79.6 yr; 59.0% women) in our analyses. Higher CFPWV was associated with a higher GDS-15 score, after adjustment for potential confounders (β 0.096, 95% confidence interval [CI] 0.005–0.187). Additional adjustment for white matter hyperintensity volume or subcortical infarcts attenuated the association between CFPWV and the GDS-15 score, which became nonsignificant (p > 0.05). Formal mediation tests showed that the attenuating effects of white matter hyperintensity volume and subcortical infarcts were statistically significant. Virchow–Robin spaces, cerebral microbleeds and cerebral atrophy did not explain the association between CFPWV and depressive symptoms. Our study was limited by its cross-sectional design, which precludes any conclusions about causal mediation. Depressive symptoms were assessed by a self-report questionnaire. Greater arterial stiffness is associated with more depressive symptoms; this association is partly accounted for by white matter hyperintensity volume and subcortical infarcts. This study supports the hypothesis that arterial stiffness leads to depression in part via cerebral small vessel disease.

Coronary artery disease (CAD) is the principal cause of death in patients with nonalcoholic fatty liver disease (NAFLD). The aim of the present study was to investigate whether NAFLD is causally involved in the pathogenesis of CAD. For this, previously reported NAFLD susceptibility genes were clustered and tested for an association with CAD in the Coronary Artery Disease Genome‐Wide Replication and Meta‐Analysis plus the Coronary Artery Disease Genetics (CARDIoGRAMplusC4D) Consortium data set. The role of plasma lipids as a potential mediator was explored by using data from the Global Lipids Genetics Consortium. Statistical analyses revealed that the combination of 12 NAFLD genes was not associated with CAD in 60,801 CAD cases and 123,504 controls (odds ratio [OR] per NAFLD risk allele, 1.0; 95% confidence interval [CI], 0.99‐1.00). In a subsequent sensitivity analysis, a positive relationship was observed after exclusion of gene variants that are implicated in NAFLD through impaired very low‐density lipoprotein secretion (i.e., microsomal triglyceride transfer protein [MTTP], patatin‐like phospholipase domain containing 3 [PNPLA3], phosphatidylethanolamine N‐methyltransferase [PEMT], and transmembrane 6 superfamily member 2 [TM6SF2]) (OR, 1.01; 95% CI, 1.00‐1.02). Clustering of the excluded genes showed a significant negative relationship with CAD (OR, 0.97; 95% CI, 0.96‐0.99). A substantial proportion of the observed heterogeneity between the individual NAFLD genes in relation to CAD could be explained by plasma lipids, as reflected by a strong relationship between plasma lipids and CAD risk conferred by the NAFLD susceptibility genes (r = 0.76; P = 0.004 for low‐density lipoprotein cholesterol). Conclusion: NAFLD susceptibility genes do not cause CAD per se. The relationship between these genes and CAD appears to depend to a large extent on plasma lipids. These observations strongly suggest taking plasma lipids into account when designing a new drug to target NAFLD. NAFLD susceptibility genes do not cause coronary artery disease per se. The relationship between these genes and coronary artery disease appears to depend to a large extent on plasma lipids.

Inflammatory Markers, Adiponectin, and Risk of Type 2 Diabetes in the Pima Indian Jonathan Krakoff , MD 1 , Tohru Funahashi , MD, PHD 2 , Coen D.A. Stehouwer , MD 3 , Casper G. Schalkwijk , MD 3 , Sachiyo Tanaka , BS 2 , Yuji Matsuzawa , MD, PHD 2 , Sayuko Kobes , BS 1 , P. Antonio Tataranni , MD 1 , Robert L. Hanson , MD, MPH 1 , William C. Knowler , MD, DRPH 1 and Robert S. Lindsay , MB, PHD 1 1 National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona 2 Department of Internal Medicine and Molecular Science, Osaka University, Osaka, Japan 3 Department of Internal Medicine, University Hospital Vrije Universiteit, Amsterdam, the Netherlands Abstract OBJECTIVE —To examine the association between adiponectin, a known predictor of diabetes in Pima Indians, and markers of inflammation and endothelial function in nondiabetic subjects and to assess whether these markers predict later diabetes in a case-control study within a longitudinal health study in Pima Indians. RESEARCH DESIGN AND METHODS —Participants with normal glucose tolerance at baseline were selected. Case subjects (who later developed type 2 diabetes), and control subjects ( n = 71 pairs) were matched for BMI, age, and sex. Adiponectin, C-reactive protein (CRP), interleukin (IL)-6, tumor necrosis factor-α, phospholipase A2 (sPLA2), soluble E-selectin (SE-selectin), soluble intracellular adhesion molecule-1, soluble vascular adhesion molecule-1, and von Willebrand factor (vWF) were measured in baseline samples. RESULTS —Adiponectin was negatively correlated with CRP ( r = −0.25, P < 0.05), IL-6 ( r = −0.20, P < 0.05), sPLA2 ( r = −0.22, P < 0.05), and SE-selectin ( r = −0.20, P < 0.05). CRP and IL-6 did not predict diabetes. Only vWF predicted the development of diabetes (incidence rate ratio 0.67 for a 1-SD difference, 95% CI 0.41–1.00, P = 0.05), but this was not significant after adjustment for age, glucose, HbA 1c , waist circumference, and fasting insulin (hazard rate ratio 0.73, 95% CI 0.46–1.16, P = 0.18). CONCLUSIONS —Adiponectin is negatively correlated with markers of inflammation in vivo. In case and control subjects matched for BMI, with the exception of vWF, none of the inflammatory markers predicted diabetes. Adiponectin may be the link between adiposity, inflammation, and type 2 diabetes. ARIC, Atherosclerosis Risk in Communities CRP, C-reactive protein ELISA, enzyme-linked immunosorbent assay IL, interleukin IRR, incidence rate ratio OGTT, oral glucose tolerance test SE-selectin, soluble E-selectin sICAM, soluble intracellular adhesion molecule sPLA2, phospholipase A2 sVCAM, soluble vascular adhesion molecule TNF-α, tumor necrosis factor-α vWF, von Willebrand factor WBC, white blood cell count Footnotes Address correspondence and reprint requests to Jonathan Krakoff, MD, Diabetes and Arthritis Epidemiology Section, Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, 1550 East Indian School Rd., Phoenix, AZ 85014. E-mail: jkrakoff{at}mail.nih.gov . Received for publication 18 July 2002 and accepted in revised form 5 March 2003. A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances. DIABETES CARE

Elevated Plasma Asymmetric Dimethylarginine as a Marker of Cardiovascular Morbidity in Early Diabetic Nephropathy in Type 1 Diabetes Lise Tarnow , MD, DMSC 1 , Peter Hovind , MD 1 , Tom Teerlink , PHD 2 , Coen D.A. Stehouwer , MD, PHD 2 and Hans-Henrik Parving , MD, DMSC 1 3 1 Steno Diabetes Center, Gentofte, Denmark 2 VU University Medical Center, Amsterdam, the Netherlands 3 Faculty of Health Science University of Aarhus, Aarhus, Denmark Address correspondence and reprint requests to Lise Tarnow, MD, DMSc, Steno Diabetes Center, Niels Steensens Vej 2, DK-2820 Gentofte, Denmark. E-mail: ltar{at}steno.dk Abstract OBJECTIVE —Increased plasma concentration of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, has been associated with endothelial dysfunction, insulin resistance, and atherosclerosis in nondiabetic populations. In end-stage renal failure, circulating ADMA is elevated and a strong predictor of cardiovascular outcome. This study investigated the relation between ADMA and diabetic micro- and macrovascular complications in a large cohort of type 1 diabetic patients with and without early diabetic nephropathy. RESEARCH DESIGN AND METHODS —ADMA concentrations in plasma were determined by a high-performance liquid chromatography method in 408 type 1 diabetic patients with overt diabetic nephropathy (252 men; mean age 42.7 years [SD 11.0], mean duration of diabetes 28 years [SD 9], median serum creatinine level 102 μmol/l [range 52–684]). A group of 192 patients with longstanding type 1 diabetes and persistent normoalbuminuria served as control subjects (118 men; mean age 42.6 years [SD 10.2], mean duration of diabetes 27 years [SD 9]). RESULTS —In patients with diabetic nephropathy, mean ± SD plasma ADMA concentration was elevated 0.46 ± 0.08 vs. 0.40 ± 0.08 μmol/l in normoalbuminuric patients ( P < 0.001). An increase in plasma ADMA of 0.1 μmol/l increased the odds ratio of nephropathy to 2.77 (95% CI 1.89–4.05) ( P < 0.001). Circulating ADMA increased in nephropathy patients with declining kidney function, as indicated by elevated values in the lower quartiles of glomerular filtration rate (<76 ml · min –1 · 1.73 m –2 ) ( P < 0.001 ANOVA). Mean ADMA levels were similar in patients with or without diabetic retinopathy ( P > 0.2). However, in 44 patients with nephropathy and history of myocardial infarction and/or stroke, ADMA was significantly elevated at 0.48 ± 0.08 μmol/l compared with 0.46 ± 0.08 μmol/l in patients without major cardiovascular events ( P = 0.05). CONCLUSIONS —Elevated circulating ADMA may contribute to the excess cardiovascular morbidity and mortality in early diabetic nephropathy. ADMA, asymmetric dimethylarginine SDMA, symmetrical dimethylarginine Footnotes Accepted November 20, 2003. Received August 20, 2002. DIABETES CARE

The ongoing worldwide obesity epidemic makes the metabolic syndrome an increasingly important entity. In this review, we provide a short background on the metabolic syndrome, we discuss recent developments in the three main options that have been identified for intervention in the metabolic syndrome, i.e. lifestyle and surgical and pharmacological interventions, and we focus on different views in the literature and also include our own viewpoints on the metabolic syndrome. In addition, we discuss some emerging treatment targets for adipose tissue dysfunction and low-grade inflammation, i.e. activation of the inflammasome and the complement system, and consider some selected opportunities for intervention in these processes.

Quality control of brain segmentation is a fundamental step to ensure data quality. Manual quality control strategies are the current gold standard, although these may be unfeasible for large neuroimaging samples. Several options for automated quality control have been proposed, providing potential time efficient and reproducible alternatives. However, those have never been compared side to side, which prevents consensus in the appropriate quality control strategy to use. This study aimed to elucidate the changes manual editing of brain segmentations produce in morphological estimates, and to analyze and compare the effects of different quality control strategies on the reduction of the measurement error. Structural brain MRI from 259 participants of The Maastricht Study were used. Morphological estimates were automatically extracted using FreeSurfer 6.0. Segmentations with inaccuracies were manually edited, and morphological estimates were compared before and after editing. In parallel, 12 quality control strategies were applied to the full sample. Those included: two manual strategies, in which images were visually inspected and either excluded or manually edited; five automated strategies, where outliers were excluded based on the tools “MRIQC” and “Qoala-T”, and the metrics “morphological global measures”, “Euler numbers” and “Contrast-to-Noise ratio”; and five semi-automated strategies, where the outliers detected through the mentioned tools and metrics were not excluded, but visually inspected and manually edited. In order to quantify the effects of each quality control strategy, the proportion of unexplained variance relative to the total variance was extracted after the application of each strategy, and the resulting differences compared. Manually editing brain surfaces produced particularly large changes in subcortical brain volumes and moderate changes in cortical surface area, thickness and hippocampal volumes. The performance of the quality control strategies depended on the morphological measure of interest. Overall, manual quality control strategies yielded the largest reduction in relative unexplained variance. The best performing automated alternatives were those based on Euler numbers and MRIQC scores. The exclusion of outliers based on global morphological measures produced an increase of relative unexplained variance. Manual quality control strategies are the most reliable solution for quality control of brain segmentation and parcellation. However, measures must be taken to prevent the subjectivity associated with these strategies. The detection of inaccurate segmentations based on Euler numbers or MRIQC provides a time efficient and reproducible alternative. The exclusion of outliers based on global morphological estimates must be avoided.

Hereditary fructose intolerance (HFI) is a rare inborn disease characterized by a deficiency in aldolase B, which catalyzes the cleavage of fructose 1,6-bisphosphate and fructose 1-phosphate (Fru 1P) to triose molecules. In patients with HFI, ingestion of fructose results in accumulation of Fru 1P and depletion of ATP, which are believed to cause symptoms, such as nausea, vomiting, hypoglycemia, and liver and kidney failure. These sequelae can be prevented by a fructose-restricted diet. Recent studies in aldolase B-deficient mice and HFI patients have provided more insight into the pathogenesis of HFI, in particular the liver phenotype. Both aldolase B-deficient mice (fed a very low fructose diet) and HFI patients (treated with a fructose-restricted diet) displayed greater intrahepatic fat content when compared to controls. The liver phenotype in aldolase B-deficient mice was prevented by reduction in intrahepatic Fru 1P concentrations by crossing these mice with mice deficient for ketohexokinase, the enzyme that catalyzes the synthesis of Fru 1P. These new findings not only provide a potential novel treatment for HFI, but lend insight into the pathogenesis of fructose-induced non-alcoholic fatty liver disease (NAFLD), which has raised to epidemic proportions in Western society. This narrative review summarizes the most recent advances in the pathogenesis of HFI and discusses the implications for the understanding and treatment of fructose-induced NAFLD.

Protein Kinase C θ Activation Induces Insulin-Mediated Constriction of Muscle Resistance Arteries Wineke Bakker 1 , Pieter Sipkema 1 , Coen D.A. Stehouwer 2 , Erik H. Serne 3 , Yvo M. Smulders 3 , Victor W.M. van Hinsbergh 1 and Etto C. Eringa 1 1 Laboratory for Physiology, Institute for Cardiovascular Research, Vrije Universiteit Medical Center, Amsterdam, the Netherlands 2 Department of Internal Medicine, Academic Hospital Maastricht, the Netherlands 3 Department of Internal Medicine, Vrije Universiteit Medical Center, Amsterdam, the Netherlands Address correspondence and reprint requests to Etto C. Eringa, PhD, Laboratory of Physiology, Institute for Cardiovascular Research, Vrije Universiteit Medical Center, van der Boechorststraat 7, 1081BT Amsterdam, Netherlands. E-mail: e.eringa{at}vumc.nl Abstract OBJECTIVE— Protein kinase C (PKC) θ activation is associated with insulin resistance and obesity, but the underlying mechanisms have not been fully elucidated. Impairment of insulin-mediated vasoreactivity in muscle contributes to insulin resistance, but it is unknown whether PKCθ is involved. In this study, we investigated whether PKCθ activation impairs insulin-mediated vasoreactivity and insulin signaling in muscle resistance arteries. RESEARCH DESIGN AND METHODS— Vasoreactivity of isolated resistance arteries of mouse gracilis muscles to insulin (0.02–20 nmol/l) was studied in a pressure myograph with or without PKCθ activation by palmitic acid (PA) (100 μmol/l). RESULTS— In the absence of PKCθ activation, insulin did not alter arterial diameter, which was caused by a balance of nitric oxide–dependent vasodilator and endothelin-dependent vasoconstrictor effects. Using three-dimensional microscopy and Western blotting of muscle resistance arteries, we found that PKCθ is abundantly expressed in endothelium of muscle resistance arteries of both mice and humans and is activated by pathophysiological levels of PA, as indicated by phosphorylation at Thr 538 in mouse resistance arteries. In the presence of PA, insulin induced vasoconstriction (21 ± 6% at 2 nmol/l insulin), which was abolished by pharmacological or genetic inactivation of PKCθ. Analysis of intracellular signaling in muscle resistance arteries showed that PKCθ activation reduced insulin-mediated Akt phosphorylation (Ser 473 ) and increased extracellular signal–related kinase (ERK) 1/2 phosphorylation. Inhibition of PKCθ restored insulin-mediated vasoreactivity and insulin-mediated activation of Akt and ERK1/2 in the presence of PA. CONCLUSIONS— PKCθ activation induces insulin-mediated vasoconstriction by inhibition of Akt and stimulation of ERK1/2 in muscle resistance arteries. This provides a new mechanism linking PKCθ activation to insulin resistance. ACh, acetylcholine ERK, extracellular signal–related kinase ET-1, endothelin-1 IRS, insulin receptor substrate l -NA, N -nitro- l -arginine PA, palmitic acid PKC, protein kinase C Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on DOI: 10.2337/db07-0792. Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db07-0792 . The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Received June 11, 2007. Accepted December 4, 2007. DIABETES

To examine the effects of baseline and incident diabetes on change in cognitive function over 12 years. A sample of 1,290 individuals aged ≥ 40 years at baseline, participating in the Maastricht Aging Study, were cognitively tested at baseline, after 6 years, and after 12 years. Of these, 68 participants had type 2 diabetes at baseline, and 54 and 57 had incident diabetes at the 6- and 12-year follow-up, respectively. Changes in performance on tests of information-processing speed, executive function, and verbal memory from baseline to 6- and 12-year follow-up were compared between groups using linear mixed models. Effects of diabetes on cognitive decline were adjusted for demographic variables, history of smoking, alcohol intake, and comorbid conditions, including hypertension, cardiovascular disease, BMI, and depression. Participants with baseline diabetes showed larger decline in information-processing speed (estimate -7.64; P < 0.01), executive function (21.82; P < 0.01), and delayed word recall (-1.35; P < 0.05) over the 12-year follow-up compared with control subjects. No significant difference in decline was observed for immediate word recall. Compared with control subjects, participants with incident diabetes showed subtle early decline in information-processing speed only. Interestingly, they did not show larger decline in any other cognitive domain. Individuals with baseline type 2 diabetes show accelerated cognitive decline, particularly in information-processing speed and executive function, compared with individuals without diabetes. In incident diabetes, decline in speed becomes detectable first, and cognitive decline seems to increase with increasing exposure time.