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

Abstract

BackgroundBlockade 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).Methodology/Principal FindingsWe 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 (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.Conclusions/Significance26-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.Trial RegistrationTrialregister.nl NTR721 (ISRCTN Registry: ISRCTN42786336)

The Effects of Long-Term Valsartan Treatment on Skeletal Muscle Fatty Acid Handling in Humans With Impaired Glucose Metabolism

“…The VAL-induced decrease in Ra FFA , indicating a higher suppression of adipose tissue lipolysis, supports the notion of improved adipose tissue lipid buffering capacity. Notably, we have recently shown that VAL treatment markedly reduced adipocyte size, which may underlie the enhanced lipid storage capacity (14).…”

The Renin-Angiotensin System in the Pathophysiology of Type 2 Diabetes

“…Conversely, RAS blockade has been found to reduce adipocyte size [97,98,99,100,101]. In line, we have recently shown that long-term ARB treatment markedly decreased abdominal subcutaneous adipocyte size, with a shift towards a higher frequency of small adipocytes, compared with placebo in subjects with impaired glucose metabolism [102]. Interestingly, it has been demonstrated that some ARBs show partial peroxisome proliferator-activated receptor-gamma (PPARγ) agonistic activity in vitro, which may contribute to increased adipocyte differentiation [103,104].…”

“…As mentioned above, we have recently found that treatment with the ARB valsartan for 26 weeks reduced abdominal subcutaneous adipocyte size compared with placebo in subjects with impaired glucose metabolism [102]. This may lead to beneficial alterations in AT gene expression and secretion of inflammatory cell markers.…”

“…This may lead to beneficial alterations in AT gene expression and secretion of inflammatory cell markers. Indeed, we have recently demonstrated that the valsartan-induced decrease in adipocyte size was associated with reduced expression of macrophage infiltration markers in human AT [102]. The reduction in AT gene expression of inflammatory cell markers after RAS blockade may in turn translate into alterations in circulating adipokines.…”

Macrophages Switch: The Fate of Adipose Tissue in Obesity

“…In a randomized open labeled study on 13 women, it was suggested that Phosphatidylcholine and deoxycholate injection increases the presence of crown like structures and degree of macrophage infiltration in subcutaneous abdominal fat, and thereby reduces abdominal fat volume and thickness by inducing adipocyte necrosis [16]. A randomized, double-blind, placebo-controlled parallel-group study on 38 subjects demonstrated that valsartan, a renin-angiotensin system inhibitor, decreases adipocyte size and is associated with reduced degree of macrophage infiltration [17]. Injection of lipostabil, a phosphatidylcholine containing substance, results in a distinct inflammatory reaction as demonstrated by the formation of macrophages and foam cells in the affected fat tissue [18].…”