Valsartan Improves Adipose Tissue Function in Humans with Impaired Glucose Metabolism: A Randomized Placebo-Controlled Double-Blind Trial

<div><h3>Background</h3><p>Blockade of the renin-angiotensin system (RAS) reduces the incidence of type 2 diabetes mellitus. In rodents, it has been demonstrated that RAS blockade improved adipose tissue (AT) function and glucose homeostasis. However, the effects of long-term RAS blockade on AT function have not been investigated in humans. Therefore, we examined whether 26-wks treatment with the angiotensin II type 1 receptor blocker valsartan affects AT function in humans with impaired glucose metabolism (IGM).</p> <h3>Methodology/Principal Findings</h3><p>We performed a randomized, double-blind, placebo-controlled parallel-group study, in which 38 subjects with IGM were treated with valsartan (VAL, 320 mg/d) or placebo (PLB) for 26 weeks. Before and after treatment, an abdominal subcutaneous AT biopsy was collected for measurement of adipocyte size and AT gene/protein expression of angiogenesis/capillarization, adipogenesis, lipolytic and inflammatory cell markers. Furthermore, we evaluated fasting and postprandial AT blood flow (ATBF) (¹³³Xe wash-out), systemic inflammation and insulin sensitivity (hyperinsulinemic-euglycemic clamp). VAL treatment markedly reduced adipocyte size (<em>P</em><0.001), with a shift toward a higher proportion of small adipocytes. In addition, fasting (<em>P</em> = 0.043) and postprandial ATBF (<em>P</em> = 0.049) were increased, whereas gene expression of angiogenesis/capillarization, adipogenesis and macrophage infiltration markers in AT was significantly decreased after VAL compared with PLB treatment. Interestingly, the change in adipocyte size was associated with alterations in insulin sensitivity and reduced AT gene expression of macrophage infiltration markers. VAL did not alter plasma monocyte-chemoattractant protein (MCP)-1, TNF-α, adiponectin and leptin concentrations.</p> <h3>Conclusions/Significance</h3><p>26-wks VAL treatment markedly reduced abdominal subcutaneous adipocyte size and AT macrophage infiltration markers, and increased ATBF in IGM subjects. The VAL-induced decrease in adipocyte size was associated with reduced expression of macrophage infiltration markers in AT. Our findings suggest that interventions targeting the RAS may improve AT function, thereby contributing to a reduced risk of developing cardiovascular disease and type 2 diabetes.</p> <h3>Trial Registration</h3><p>Trialregister.nl NTR721 (ISRCTN Registry: ISRCTN<a href="http://www.controlled-trials.com/isrctn/pf/42786336">42786336</a>)</p> </div

Altered Skeletal Muscle Fatty Acid Handling in Subjects with Impaired Glucose Tolerance as Compared to Impaired Fasting Glucose

Altered skeletal muscle fatty acid (FA) metabolism contributes to insulin resistance. Here, we compared skeletal muscle FA handling between subjects with impaired fasting glucose (IFG; n = 12 (7 males)) and impaired glucose tolerance (IGT; n = 14 (7 males)) by measuring arterio-venous concentration differences across forearm muscle. [2H2]-palmitate was infused intravenously, labeling circulating endogenous triacylglycerol (TAG) and free fatty acids (FFA), whereas [U-13C]-palmitate was incorporated in a high-fat mixed-meal, labeling chylomicron-TAG. Skeletal muscle biopsies were taken to determine muscle TAG, diacylglycerol (DAG), FFA, and phospholipid content, their fractional synthetic rate (FSR) and degree of saturation, and gene expression. Insulin sensitivity was assessed using a hyperinsulinemic-euglycemic clamp. Net skeletal muscle glucose uptake was lower (p = 0.018) and peripheral insulin sensitivity tended to be reduced (p = 0.064) in IGT as compared to IFG subjects. Furthermore, IGT showed higher skeletal muscle extraction of VLDL-TAG (p = 0.043), higher muscle TAG content (p = 0.025), higher saturation of FFA (p = 0.004), lower saturation of TAG (p = 0.017) and a tendency towards a lower TAG FSR (p = 0.073) and a lower saturation of DAG (p = 0.059) versus IFG individuals. Muscle oxidative gene expression was lower in IGT subjects. In conclusion, increased liver-derived TAG extraction and reduced lipid turnover of saturated FA, rather than DAG content, in skeletal muscle accompany the more pronounced insulin resistance in IGT versus IFG subjects

Enrollment flow chart.

<p>Enrollment flow chart.</p

Correlation between the change in adipocyte diameter and insulin sensitivity after 26-wks VAL or PLB treatment (<i>n</i> = 30)

<p>The decrease in adipocyte size was significantly associated with alterations in insulin sensitivity after VAL (n = 14, closed circles) and PLB (n = 16, open circles) treatment (<i>r</i> = −0.452, <i>P</i> = 0.012).</p

Abdominal subcutaneous AT gene expression before and after 26-wks treatment with VAL or PLB.

<p>PPARγ, peroxisome proliferator-activated receptor γ; aP2, adipocyte fatty acid binding protein; C/EBPα, CCAAT/enhancer binding protein α; VEGF, vascular endothelial growth factor; ANG, angiogenin; CTSS, cathepsin S; ATGL, adipose triglyceride lipase; CGI-58, comparative gene indentification 58; G0S2, G0/G1 switch gene 2; HSL, hormone-sensitive lipase. ^*VAL <i>vs.</i> PLB treatment assessed by repeated-measures ANOVA. Values are medians (interquartile range).</p

Subject characteristics before and after 26-wks treatment with VAL or PLB.

<p>BMI, body mass index; HbA1C, glycated haemoglobin; NEFA, non-esterified fatty acid; SBP, systolic blood pressure; DBP, diastolic blood pressure; TAG, triacylglycerol; WHR, waist-to-hip ratio; <i>N.S.</i>, not significant. ^*VAL <i>vs.</i> PLB treatment assessed by repeated-measures ANOVA. ^#<i>P</i><0.05 <i>vs</i>. PLB. Values are means±SEM.</p

Fasting and postprandial ATBF

<p>VAL treatment (<i>n</i> = 16) significantly increased both (<b>A</b>) fasting ATBF and (<b>B</b>) postprandial ATBF (<i>P</i> = 0.049) compared with PLB (<i>n</i> = 14). A high-fat mixed-meal (containing 2.6 MJ, consisting of 61E% fat (35.5E% saturated fatty acids (FAs), 18.8E% monounsaturated FAs and 1.7E% polyunsaturated FAs), 33E% carbohydrate and 6E% protein) was ingested at t0 min. Values are means±SEM. *<i>P</i><0.05 VAL vs. PLB. ATBF, adipose tissue blood flow.</p