Journal Article

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

Alili, Rohia, Essers, Yvonne, Jocken, Johan W. E., Cleutjens, Jack P., Clément, Karine, Venteclef, Nicolas, Diamant, Michaela, Blaak, Ellen E., Goossens, Gijs H., Moors, Chantalle C. M., van der Zijl, Nynke J.

2012

Overview

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). 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) ((133)Xe wash-out), systemic inflammation and insulin sensitivity (hyperinsulinemic-euglycemic clamp). VAL treatment markedly reduced adipocyte size (P<0.001), with a shift toward a higher proportion of small adipocytes. In addition, fasting (P = 0.043) and postprandial ATBF (P = 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. 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. Trialregister.nl NTR721 (ISRCTN Registry: ISRCTN42786336).

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adipocytes / Adipocytes - drug effects / Adipocytes - metabolism / Adipocytes - pathology / Adipogenesis / Adiponectin / Adipose tissue / Adipose Tissue - blood supply / Adipose Tissue - drug effects / Adipose Tissue - pathology / Adipose Tissue - physiopathology / Angiogenesis / Angiotensin / Angiotensin II / Angiotensins / Antihypertensive Agents - pharmacology / Biology / Biomarkers / Biomarkers - blood / Biomarkers - metabolism / Biopsy / Blood flow / Blood Pressure - drug effects / Body fat / Capillaries - drug effects / Capillaries - pathology / Cardiovascular diseases / Cell Hypoxia - drug effects / Cell Size - drug effects / Chemotactic Factors - pharmacology / Clinical trials / Diabetes / Diabetes mellitus / Double-Blind Method / Double-blind studies / Fasting / Fasting - blood / Fatty acids / Female / Gene expression / Gene Expression Regulation - drug effects / Glucose / Glucose - metabolism / Health risks / Homeostasis / Humans / Hypertension / Immunoglobulin M / Infiltration / Inflammation / Inflammation - metabolism / Inflammation - pathology / Insulin / Insulin - pharmacology / Insulin resistance / Internal medicine / Leptin / Lipids / Lipolysis - drug effects / Macrophages / Macrophages - drug effects / Macrophages - metabolism / Macrophages - pathology / Male / Markers / Medicine / Metabolism / Middle Aged / Nutrition research / Physiological aspects / Placebos / Postprandial Period / Proteins / Randomization / Renin / Risk management / Risk reduction / Rodents / Sensitivity / Studies / Tetrazoles - pharmacology / Toxicology / Tumor necrosis factor-α / Type 2 diabetes / Valine - analogs & derivatives / Valine - pharmacology / Valsartan / Xenon 133