Angiotensin II receptor blockade and insulin sensitivity in overweight and obese adults with elevated blood pressure

Abstract

We tested the hypothesis that olmesartan, an angiotensin II receptor blocker (ARB) devoid of peroxisome proliferator-activated receptor γ agonist activity, would improve whole-body insulin sensitivity in overweight and obese individuals with elevated blood pressure (BP). Sixteen individuals (8 women, 8 men; age=49.5 ± 2.9 years; body mass index=33.0 ± 1.7 kg/m²) were randomly assigned in a crossover manner to control and ARB interventions. Insulin sensitivity was determined from intravenous glucose tolerances tests before and after each 8-week intervention. BP, body weight, body fat, lipid and lipoprotein concentrations, and insulin sensitivity were similar at baseline for both treatments (all p > 0.05). Diastolic BP and triglyceride concentrations were higher (p = 0.007 and 0.042 respectively) at baseline for the ARB compared with the control intervention. Systolic (−11.7 mmHg; p = 0.008) and diastolic (−12.1 mmHg; p = 0.0001) BP decreased, however insulin sensitivity did not change (p > 0.05) following ARB treatment. Furthermore, there were no significant correlates of changes in insulin sensitivity following the ARB intervention. In summary, our findings indicate that short-term ARB treatment did not affect whole-body insulin sensitivity in overweight or obese individuals with elevated BP. Future studies are needed to clarify the effect of individual ARBs on insulin sensitivity in obesity.

Keywords

hypertension insulin sensitivity index olmesartan renin–angiotensin system

Introduction

Obesity is a major risk factor for the development of numerous chronic diseases [Wang et al. 2011]. More than half of overweight and obese individuals develop hypertension [Garrison et al. 1987]. In addition, obese individuals are also insulin resistant and at increased risk of type 2 diabetes [Defronzo and Ferrannini, 1991; Moller and Flier, 1991; Chan et al. 1994].

Overactivation of the renin–angiotensin system (RAS) has been implicated as a mechanism contributing to insulin resistance and type 2 diabetes in overweight and obese individuals with hypertension [Prasad and Quyyumi, 2004; Scheen, 2004a,b]. The primary role of the RAS is to regulate arterial pressure and sodium balance. However, chronic elevations in angiotensin II impair whole-body insulin sensitivity and insulin signaling in skeletal muscle via angiotensin II type 1 receptor activation [Henriksen et al. 2001; Sloniger et al. 2005; Wei et al. 2006, 2008]. In addition, the results of several meta-analyses suggest that the incidence of new-onset diabetes is lower in patients taking ARBs compared with placebo or other antihypertensives including diuretics, β blockers and calcium channel blockers [Scheen, 2004a; Andraws and Brown, 2007; Elliott and Meyer, 2007].

Randomized controlled trials addressing the influence of angiotensin II receptor blockers (ARBs) on insulin sensitivity have been conflicting. Some [Fogari et al. 2005; Vitale et al. 2005; Ichikawa, 2007; Nishimura et al. 2008; Fogari et al. 2009; De Luis et al. 2010; Derosa et al. 2011; Van Der Zijl et al. 2011] but not all studies [Moan et al. 1996; Fogari et al. 1998; Parhofer et al. 2010; Mori et al. 2011; Goossens et al. 2012; Lteif et al. 2012; Perlstein et al. 2012] support an insulin-sensitizing effect of ARBs. ARBs with partial peroxisome proliferator-activated receptor γ (PPARγ) agonist activity, such as telemisartan, appear to consistently improve insulin sensitivity [Vitale et al. 2005; Ichikawa, 2007; Fogari et al. 2009; De Luis et al. 2010]. However, the outcomes of studies involving ARBs other than telemisartan are equivocal [Moan et al. 1996; Fogari et al. 1998, 2005; Vitale et al. 2005; Ichikawa, 2007; Nishimura et al. 2008; De Luis et al. 2010; Parhofer et al. 2010; Derosa et al. 2011; Van Der Zijl et al. 2011; Goossens et al. 2012; Lteif et al. 2012; Perlstein et al. 2012]. In addition, many of these studies have relied on indirect, surrogate measures of insulin sensitivity. Thus, the impact of other ARBs on insulin sensitivity remains unclear. To clarify this issue, we tested the hypothesis that olmesartan, an ARB devoid of the PPARγ agonist activity [Benson et al. 2004; Erbe et al. 2006], would improve insulin sensitivity in middle-aged to older overweight and obese adults with elevated blood pressure (BP). To address this, we conducted a randomized crossover study and assessed insulin sensitivity using the insulin-modified intravenous glucose tolerance test (IVGTT) before and after each treatment period. In addition, skeletal muscle is the primary tissue responsible for insulin-stimulated glucose disposal [Ferrannini et al. 1988] and inflammation and alterations in the extracellular matrix of skeletal muscle have been associated with the development of insulin resistance [Berria et al. 2006; Shoelson et al. 2006]. Therefore, a secondary exploratory aim of the study was to determine whether changes in expression of proinflammatory and extracellular matrix genes predict changes in insulin sensitivity in our sample.

Materials and methods

Study participants

Sixteen sedentary (moderate to hard activity ≤3 days/week), overweight and obese [body mass index (BMI) >25 kg/m² or body fat ≥20% for men and ≥25% for women] men (n = 8) and women (n = 8) aged 18–75 years served as study participants. All were weight stable ( ± 2.0 kg) for the previous 6 months and not taking any medications known to affect weight or the study outcomes. None of the postmenopausal women were on hormone replacement therapy. All of the study participants had elevated BP (≥120/80 mmHg but <160/100 mmHg), but were free of other overt disease as assessed by medical history, blood chemistry, urinalysis, and physical examination by a physician. Two women discontinued their current BP medication for the duration of the study with their physician’s approval. Their BP was monitored during a 2-week washout period (at least five half lives) before participation in study testing sessions to ensure that their BP remained within the study BP requirements. One smoker was included in the study. The Virginia Polytechnic Institute and State University Institutional Review Board approved the protocol. The nature, purpose, risks, and benefits of the study were explained before obtaining informed consent.

Intervention

Study participants first completed baseline testing sessions within a 2-week period. They were then randomized to one of two treatments olmesartan medoxomil (Benicar, Daiichi Sankyo, Inc., Parsippany, NJ; ARB) or no medication (control) for 8 weeks. The study used a randomized crossover design. When assigned to the olmesartan treatment, participants were provided with daily 20 mg pills for the first 2 weeks. They received additional daily doses of 40 mg olmesartan for the remainder of the study period. The dose remained at 20 mg per day, however, if their BP fell below 110/70 mmHg during the first 2 weeks. They also continued taking the drug during the 2-week follow-up period. There was no drug intervention during the control period. After the first 8-week intervention, study participants participated in post-testing sessions, followed by a 2-week washout period. They then completed the testing sessions again and participated in the opposite intervention. This was followed by post-testing sessions after 8 weeks. During each intervention period and the washout period, BP was measured weekly. Study participants were asked to maintain their current physical activity level, dietary intake and body weight throughout the study.

Measurements

All testing sessions were performed between 7 a.m. and 1 p.m. after a 12-hr fast. Before each testing session, study participants recorded recent infection or illness on an infection/inflammation questionnaire. If an infection/illness was reported, testing was delayed 1–2 weeks for recovery. Study participants refrained from vigorous physical activity for 48 h before testing. They also abstained from ingesting nonsteroidal anti-inflammatory drugs or other medication that may have interfered with study measurements for 72 h prior to the session. BP measurements were documented at each visit.

Resting blood pressure

BP measurements were performed between 7 a.m. and 11 a.m. with serial BP appointments scheduled at the same time for each individual. BP was measured by automated sphygmomanometry (Pilot model 9200, Colin Instruments Corp., San Antonio, TX) in the upright seated posture. Measurements were taken every 3 min after a 5–10 min seated rest and continued until BP stability [± 6 mmHg systolic BP (SBP) and diastolic BP (DBP)] was reached between three consecutive recordings. Baseline BP stability was established after three BP sessions spanning at least 1 week were completed before any testing sessions were performed. For individuals who discontinued their BP medications, six testing sessions over 2 weeks were completed to ensure BP stability.

Body mass and composition

Body weight was measured to the nearest ±0.1 kg on a digital scale (Model 5002, Scale-Tronix, White Plains, NY). Height was measured to the nearest ±0.1 cm using a stadiometer. Body composition (total fat and fat-free mass) was analyzed by dual-energy x-ray absorptiometry (GE Lunar Prodigy Advance, software version 8.10e, Brookfield, WI).

Dietary and physical activity assessment

Before and after each 8-week intervention period, habitual dietary intake was assessed from self-reported 4-day food records. A registered dietitian provided study participants with written and verbal instruction for accurately measuring and recording food intake. The Nutrition Data Systems for Research software (NDS-R 2006, University of Minnesota, Minneapolis, MN, USA) was used to estimate energy and macronutrient content. Habitual physical activity level was measured by an accelerometer (GT1M, Actigraph, Pensacola, FL) worn for 4 consecutive days before and after each intervention.

Plasma lipid and lipoprotein concentrations

Blood samples were drawn with minimal venous stasis. Plasma total cholesterol, high-density and low-density lipoprotein, and triglyceride concentrations were measured by a commercial laboratory (Solstas Lab Partners, Roanoke, VA, USA) using conventional enzymatic methods.

Circulating inflammatory peptides

A Bioplex Pro coupled magnetic bead assay (Bio-rad, Hercules, CA, USA) assessed plasma concentrations of inflammatory markers, tumor necrosis factor α (TNFα), interleukin (IL)-6, IL-10, and monocyte chemoattractant protein 1 (MCP-1). Enzyme-linked immunosorbent assays (ELISAs) were performed to measure total and high-molecular weight adiponectin (ALPCO Diagnostics, Salem, NH, USA).

Estimated insulin sensitivity

Systemic insulin sensitivity was estimated using Bergman’s minimal model (MINMOD Millennium software, version 6.02, Minmod, Inc., Pasadena, CA) during a modified frequently sampled IVGTT [Boston et al. 2003]. An intravenous catheter was inserted in an antecubital vein of each arm for blood collection or glucose and insulin injection. Two baseline plasma blood samples [(t) = −10 and −1 min] were drawn. Glucose (0.3 g/kg; 50% solution) was injected at time 0 and insulin (0.025 U/kg) at (t) = 20 min. Additional blood samples (6 ml) were collected at (t) = 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14, 16, 18, 22, 23, 24, 25, 27, 30, 40, 50, 60, 70, 80, 90, 100, 120, 150, and 180 min during the 3-hr protocol. Glucose concentration (mg/dl) was analyzed immediately using a YSI Glucose Analyzer (Yellow Springs, OH, USA). Insulin (µU/ml) was determined later via ELISA (ALPCO Diagnostics, Salem, NH, USA). Samples were analyzed in duplicate. Thirteen individuals successfully completed all IVGTTs.

Skeletal muscle biopsy

Skeletal muscle samples were taken by needle aspiration from the vastus lateralis. The skin was cleaned with a providone-iodine solution and local anesthetic (50:50 2% xylocaine/0.25% bupivacaine; 10 ml total) was used to numb the skin and tissue. A small (~1/4”) incision was made with a #10 scalpel. Approximately 500 mg of skeletal muscle tissue was collected using suction applied to a 5 mm modified Bergstrom needle. The incision was cleaned with saline and closed with sterile bandage strips. Ice and pressure was applied to minimize discomfort. Tissue samples were immediately washed in 0.9% sterile saline to remove blood and connective tissue. Samples were weighed and immediately flash frozen in liquid nitrogen for future analysis. One study participant declined to have biopsies performed.

Skeletal muscle RNA extraction and quantitative real-time polymerase chain reaction

RNA extraction and quantification were determined using methods previously described by Frisard and colleagues [Frisard et al. 2010]. Briefly, an RNeasy Mini Fibrous Kit and DNase I treatment (Qiagen, Valencia, CA, USA) were used according to the manufacturer’s directions for mRNA extraction. Quantitative real-time polymerase chain reaction (qRT-PCR) measured the expression of nicotinamide adenine dinucleotide phosphate oxidase 4, transforming growth factor β, IL-6, collagen III, and MCP-1 using an ABI PRISM 7900 Sequence Detection System instrument and TaqMan Universal PCR Master Mix according to the manufacturer’s instructions (Applied Biosystems, Foster City, CA, USA). Relative gene expression levels were determined using the number of cycles necessary to reach threshold and results were normalized to cyclophilin B RNA levels.

Statistical analysis

Repeated measures analysis of variance was used to assess the effect of treatment (olmesartan treatment versus control), time, and treatment by time interaction on the dependent variables of interest. Treatment order was used as a covariate in models when its main effect was significant. There was no effect of gender on the study outcomes. Thus, the men and women are presented as a single group. Since we have a small sample, we reran these analyses with standard error estimates based on 1000 bootstrap samples to obtain bias-corrected confidence intervals by repeated re-estimations of the parameter estimates. Paired sample t-tests were used to compare the changes in dependent variables of interest. Pairwise associations among variables were analyzed using Pearson’s product moment correlations. All data are presented as means ± standard error of the mean. Significance level was set a priori at p < 0.05.

Results

A total of 16 out of 20 (80%) randomized study participants completed the interventions. The study medication, olmesartan, was well tolerated and there were no adverse events reported. Seven study participants remained on the 20 mg dose for the duration of the intervention while nine received an increased dose of 40 mg after the initial 2-week period. Adherence during the 8-week olmesartan intervention was 98.4% overall, with no individual missing more than three daily doses in total.

Characteristics of study participants before and after each treatment are depicted in Table 1. There were no significant differences between ARB and control before the treatment period with the exception that DBP and triglycerides were higher in the ARB treatment compared with the control treatment at baseline (p = 0.007 and 0.042 respectively). As expected, there was a significant reduction in both SBP (–11.7 mmHg; –8.3%) and DBP (–12.1 mmHg; –14.2%) with ARB treatment. Body weight, BMI, body fat %, and total body fat mass increased (all p < 0.05) over time but there were no significant differences between treatments. Triglyceride levels remained higher throughout treatment in the ARB compared with the control (p = 0.038). No differences in lipid and lipoprotein or fasting plasma glucose concentrations were observed between treatments (all p > 0.05).

Table 1.

Study participant characteristics before and after the control and ARB treatment.

Variable	Control		ARB
Variable	Pre	Post	Pre	Post
Body weight, kg	97.2 ± 5.4	98.1 ± 5.5	96.9 ± 5.1	97.5 ± 5.2^$
Body mass index, kg/m²	33.3 ± 1.9	33.6 ± 1.9	33.2 ± 1.8	33.4 ± 1.8^$
Body fat, %	41.8 ± 2.8	42.2 ± 2.9	41.6 ± 2.8	42.1 ± 2.8^$
Total fat mass, kg	39.3 ± 3.7	40.1 ± 3.8	38.9 ± 3.6	39.7 ± 3.8^$
Fat-free mass, kg	56.5 ± 3.4	56.7 ± 3.6	56.3 ± 3.3	56.3 ± 3.3
Systolic BP, mmHg	138.5 ± 4.1	140.7 ± 4.6	140.6 ± 3.2	128.9 ± 2.5^$‡
Diastolic BP, mmHg	79.3 ± 1.7	82.9 ± 2.0	85.5 ± 2.2	73.4 ± 1.6^$‡
Triglycerides, mg/dl	100.6 ± 11.1	104.0 ± 12.6	117.9 ± 15.3	116.0 ± 14.5*
Total cholesterol, mg/dl	196.3 ± 8.0	195.6 ± 8.3	194.3 ± 7.5	190.0 ± 7.7
HDL cholesterol, mg/dl	50.6 ± 5.5	49.0 ± 5.3	48.1 ± 4.5	49.1 ± 4.9
LDL cholesterol, mg/dl	125.6 ± 8.0	125.8 ± 7.9	122.7 ± 7.8	117.7 ± 7.1
Glucose, mg/dl	89.4 ± 2.8	89.8 ± 2.9	91.2 ± 3.3	89.6 ± 3.1
Insulin, µIU/ml	4.3 ± 0.7	6.0 ± 1.2	5.6 ± 1.1	5.7 ± 1.1

All values are expressed as mean ± standard error of the mean. Eight men and eight women were included in the study.

Group effect; ^$time effect; ^‡group × time effect. p < 0.05.

ARB, angiotensin II receptor blocker; BP, blood pressure; HDL, high-density lipoprotein; LDL, low-density lipoprotein.

Habitual physical activity and self-reported dietary intake during ARB and control treatment are shown in Table 2. There were no significant changes in physical activity level or self-reported total calorie or macronutrient intake during either treatment period. The absolute (g) and relative (%) fat intake were lower (p = 0.021 and 0.047 respectively) during the ARB compared with control treatment. The percentage carbohydrate intake was higher (p = 0.012) in the ARB compared with the control treatment. Protein and alcohol intake did not differ during the ARB or control treatment. Cholesterol, saturated fatty acid, fiber, and sodium intake all remained unchanged during the treatments.

Table 2.

Physical activity and dietary intake before and after the control and ARB treatment.

Variable	Control		ARB
Variable	Pre	Post	Pre	Post
Physical activity, counts/day × 10³	236 ± 26	213 ± 30	189 ± 21	210 ± 25
Physical activity, steps/day	5991 ± 573	5168 ± 627	4889 ± 565	5012 ± 550
Kcal, per day	2137 ± 203	1952 ± 148	2070 ± 176	1918 ± 158
Fat, g %	100 ± 11	83 ± 7	87 ± 9	78 ± 8*
	39 ± 1	38 ± 1	37 ± 1	35 ± 2*
Carbohydrates, g %	239 ± 23	225 ± 17	244 ± 19	229 ± 18
	44 ± 1	46 ± 2	47 ± 1	48 ± 2*
Protein, g %	82 ± 8	74 ± 7	77 ± 6	73 ± 6
	16 ± 1	15 ± 1	15 ± 1	15 ± 1
Alcohol, g %	6 ± 3	6 ± 3	5 ± 3	5 ± 2
	2 ± 1	2 ± 1	2 ± 1	2 ± 1
SFA, g	31 ± 3	30 ± 3	30 ± 3	27 ± 3
Cholesterol, mg	270 ± 33	297 ± 43	270 ± 24	259 ± 35
Fiber, g	17 ± 1	18 ± 1	16 ± 1	15 ± 1
Sodium, mg	3596 ± 273	3661 ± 356	3607 ± 346	3408 ± 352

All values are expressed as mean ± standard error of the mean. Eight men and eight women were included in the study.

Group effect. p < 0.05.

ARB, angiotensin II receptor blocker; SFA, saturated fatty acid.

The IVGTT variables before and after each treatment period are depicted in Figure 1. There were no significant differences for any of the IVGTT variables at baseline between the ARB and control treatments. Insulin sensitivity index (SI) and glucose effectiveness (Sg) did not change throughout the study. A significant effect of time was detected for acute insulin response to glucose (AIRg) and disposition index (DI) (p = 0.026 and 0.045 respectively) during the treatment periods (Figure 2). However, neither AIRg nor DI changed significantly during ARB or control treatment. There was no significant effect of olmesartan dose on the IVGTT-related outcomes. In addition, the removal of smoker status from the analysis did not change the primary findings except that the time effect for AIRg was no longer significant (p = 0.072). The bootstrapping procedure did not change the results of the IVGTT outcomes described above.

Figure 1.

Absolute values of insulin sensitivity index (SI) (a) and glucose effectiveness (Sg) (b) before and after the control and angiotensin II receptor blocker (ARB) treatment. Values are mean ± standard error of the mean. n =12 study participants.

Figure 2.

Absolute values of the acute insulin response to glucose (AIRg) (a) and disposition index (b) before and after the control and angiotensin II receptor blocker (ARB) treatment. Time effect (†), p < 0.05. Values are mean ± standard error of the mean. n = 12 study participants.

Circulating cytokine and adiponectin concentrations are presented in Table 3. Baseline concentrations of all circulating inflammatory markers were not different between the treatment periods (p > 0.05). There was a trend (treatment effect, p = 0.065) for a higher MCP-1 concentration in the ARB compared with the control treatment. There were no significant changes in IL-6, IL-10, or TNFα with ARB treatment. Similarly, there were no significant changes in circulating total or high-molecular weight adiponectin concentrations in the ARB or control treatment.

Table 3.

Circulating plasma cytokine and adiponectin levels before and after the control and ARB treatment.

Variable	Control		ARB
Variable	Pre	Post	Pre	Post
IL-6, pg/ml	23.5 ± 6.7	20.0 ± 3.6	21.5 ± 5.2	26.2 ± 7.4
TNFα, pg/ml	8.1 ± 1.3	6.6 ± 0.7	5.7 ± 0.3	9.3 ± 2.5
IL-10, pg/ml	23.7 ± 2.0	22.8 ± 2.2	22.2 ± 1.0	24.9 ± 1.4
MCP-1, pg/ml	190 ± 20	177 ± 14	217 ± 21	197 ± 21
Total adiponectin, ng/ml	3702 ± 455	3820 ± 560	3632 ± 521	3824 ± 575
HMW adiponectin, ng/ml	3299 ± 441	3275 ± 453	3360 ± 389	3357 ± 512

All values are expressed as mean ± standard error of the mean. Eight men and eight women were included in the study.

ARB, angiotensin II receptor blocker; HMW, high molecular weight; IL, interleukin; MCP-1, monocyte chemoattractant protein 1; TNFα, tumor necrosis factor α.

Muscle mRNA expression levels are presented only for the ARB treatment due to insufficient RNA yield for the majority of participants during the control treatment (Table 4). There were no significant changes in mRNA expression levels of any of the target genes from pre- to post-ARB treatment.

Table 4.

Skeletal muscle mRNA before and after ARB treatment.

Variable (AU)	ARB
Variable (AU)	Pre	Post
NOX4 (n = 12)	1.1 ± 0.2	1.4 ± 0.2
TGFβ (n = 10)	28.8 ± 3.4	29.8 ± 1.9
IL-6 (n = 8)	23.0 ± 6.2	25.3 ± 10.0
COL3 (n = 7)	1491 ± 510	774 ± 271
MCP-1 (n = 7)	4.7 ± 1.1	5.0 ± 1.4

All values are expressed as mean ± standard error of the mean.

ARB, angiotensin II receptor blocker; COL3, collagen III; IL, interleukin; MCP-1, monocyte chemoattractant protein 1; NOX4, nicotinamide adenine dinucleotide phosphate oxidase 4; TGFβ, transforming growth factor β.

There were no baseline characteristics or IVGTT-related variables that were correlated with changes in SI, Sg, or DI (all p > 0.05). The change in fasting insulin was associated with the change in AIRg (p = 0.011). However, there were no other changes in variables that correlated with SI, Sg, or DI (all p > 0.05).

Discussion

The results of our randomized crossover trial demonstrate that an 8-week period of olmesartan treatment does not affect insulin sensitivity in overweight and obese people with elevated BP. We did not observe significant changes in circulating inflammatory markers or skeletal muscle inflammatory or collagen gene expression following olmesartan treatment. In addition, there were no significant correlates of changes in insulin sensitivity in response to olmesartan treatment.

Meta-analyses of large clinical trials of antihypertensive therapy have suggested that the incidence of new-onset diabetes is lower in patients taking ARBs compared with placebo or other antihypertensives such as diuretics, β blockers, and calcium channel blockers [Scheen, 2004a; Elliott and Meyer, 2007]. In addition, numerous studies in nondiabetic hypertensive or diabetic animal models have demonstrated improvements in whole-body insulin sensitivity after ARB therapy [Sasaki et al. 1999; Henriksen et al. 2001; Furuhashi et al. 2004; Shiuchi et al. 2004].

Previous trials on the effects of ARB on insulin sensitivity in humans have been conflicting. The results of some randomized controlled trials have suggested improvements in insulin sensitivity with ARB treatment compared with other antihypertensive medications [Paolisso et al. 1997; Fogari et al. 2005, 2009; Vitale et al. 2005; Ichikawa, 2007; Nishimura et al. 2008; De Luis et al. 2010; Derosa et al. 2011; Van Der Zijl et al. 2011]. However, many of these studies relied on imprecise measures of insulin sensitivity (e.g. Homeostasis Model of Assessment-Insulin Resistance) [Fogari et al. 2005; Vitale et al. 2005; Ichikawa, 2007; Nishimura et al. 2008; De Luis et al. 2010]. Van der Zijl and colleagues reported a significant improvement in insulin sensitivity in people treated with valsartan compared with those on placebo [Van Der Zijl et al. 2011]. However, the small treatment effect and relatively larger reduction in insulin sensitivity in the placebo-treated individuals makes interpretation of this study difficult. Our present study and others [Laakso et al. 1996; Moan et al. 1996; Fogari et al. 1998; Parhofer et al. 2010; Goossens et al. 2012; Lteif et al. 2012; Perlstein et al. 2012] suggest no improvement in whole-body insulin sensitivity following ARB treatment. The reasons for this apparent discrepancy are unclear but do not appear to be related to the duration of treatment, method used to assess insulin sensitivity, or study population. Rather, the partial PPARγ agonist activity of the particular ARB studied may be important.

Some ARBs, such as telmisartan, exhibit partial PPARγ agonist activity [Benson et al. 2004; Schupp et al. 2004; Kurtz, 2005, 2006]. PPARγ activation enhances insulin’s effectiveness to promote glucose uptake in peripheral metabolic tissues [Picard and Auwerx, 2002]. Thus, some ARBs can influence insulin action via pathways independent of angiotensin II signaling [Schupp et al. 2004; Kurtz, 2005, 2006]. This observation may contribute, at least in part, to the different outcomes observed in previous studies on this issue [Vitale et al. 2005; Benndorf et al. 2006; Ichikawa, 2007; Fogari et al. 2009; De Luis et al. 2010]. We used olmesartan in the present study because it is devoid of partial PPARγ agonist activity [Benson et al. 2004; Erbe et al. 2006]. Therefore, future studies are necessary to clarify whether the ability of ARBs to improve insulin sensitivity depend on intrinsic PPARγ agonist activity.

There are some limitations of our study that should be considered. The sample size was small and the majority of study participants were white. In addition, our sample was limited to overweight and obese individuals with high normal or stage 1 hypertension. Furthermore, it is possible that the ability of ARB treatment to improve insulin sensitivity may depend on baseline insulin resistance. Although overweight and obese individuals tend to be insulin resistant as a population, baseline insulin sensitivity was not correlated with the change in insulin sensitivity with ARB treatment. Future studies will be necessary to more comprehensively address this issue. Finally, the statistical analysis of the inflammatory and collagen gene targets by qRT-PCR was limited by the extraction of sufficient mRNA from the samples collected during each biopsy.

In conclusion, our findings suggest that ARB treatment with olmesartan for 8 weeks does not improve insulin sensitivity in overweight and obese individuals with elevated BP. Furthermore, there were no significant changes in inflammatory and collagen mRNA expression in skeletal muscle following ARB treatment. Taken together, the results of our study suggest that an improvement in insulin sensitivity is not among the additional benefits of olmesartan that extend beyond its BP-lowering capability [Benson et al. 2004]. Further research is needed to delineate which RAS antagonists improve whole-body insulin sensitivity during RAS inhibition and, if so, what populations are most likely to benefit.

Footnotes

Acknowledgements

We would like to thank the participants for their time and commitment to the study.

Funding

This study was supported by a National Institutes of Health HL092572 grant (to KPD).

Conflict of interest statement

The authors declare no conflicts of interest in preparing this article.

References

Andraws

Brown

(2007) Effect of inhibition of the renin–angiotensin system on development of type 2 diabetes mellitus (meta-analysis of randomized trials). Am J Cardiol 99: 1006–1012.

Benndorf

Rudolph

Appel

Schwedhelm

Maas

Schulze

. (2006) Telmisartan improves insulin sensitivity in nondiabetic patients with essential hypertension. Metabolism 55: 1159–1164.

Benson

Pershadsingh

Chittiboyina

Desai

Pravenec

. (2004) Identification of telmisartan as a unique angiotensin II receptor antagonist with selective PPARgamma-modulating activity. Hypertension 43: 993–1002.

Berria

Wang

Richardson

Finlayson

Belfort

Pratipanawatr

. (2006) Increased collagen content in insulin-resistant skeletal muscle. Am J Physiol Endocrinol Metab 290: E560–E565.

Boston

Stefanovski

Moate

Sumner

Watanabe

Bergman

(2003) MINMOD millennium: a computer program to calculate glucose effectiveness and insulin sensitivity from the frequently sampled intravenous glucose tolerance test. Diabetes Technol Ther 5: 1003–1015.

Chan

Rimm

Colditz

Stampfer

Willett

(1994) Obesity, fat distribution, and weight gain as risk factors for clinical diabetes in men. Diabetes Care 17: 961–969.

Defronzo

Ferrannini

(1991) Insulin resistance a multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care 14: 173–194.

De Luis

Conde

Gonzalez-Sagrado

Aller

Izaola

Duenas

. (2010) Effects of telmisartan vs olmesartan on metabolic parameters, insulin resistance and adipocytokines in hypertensive obese patients. Nutr Hosp 25: 275–279.

Derosa

Maffioli

Ferrari

Palumbo

Randazzo

Fogari

. (2011) Different actions of losartan and ramipril on adipose tissue activity and vascular remodeling biomarkers in hypertensive patients. Hypertens Res 34: 145–151.

10.

Elliott

Meyer

(2007) Incident diabetes in clinical trials of antihypertensive drugs: a network meta-analysis. Lancet 369: 201–207.

11.

Erbe

Gartrell

Zhang

Suri

Kirincich

Will

. (2006) Molecular activation of PPARgamma by angiotensin II type 1-receptor antagonists. Vascul Pharmacol 45: 154–162.

12.

Ferrannini

Simonson

Katz

Reichard

Jr Bevilacqua

Barrett

. (1988) The disposal of an oral glucose load in patients with non-insulin-dependent diabetes. Metabolism 37: 79–85.

13.

Fogari

Derosa

Zoppi

Rinaldi

Lazzari

Fogari

. (2005) Comparison of the effects of valsartan and felodipine on plasma leptin and insulin sensitivity in hypertensive obese patients. Hypertens Res 28: 209–214.

14.

Fogari

Zoppi

Corradi

Lazzari

Mugellini

Lusardi

(1998) Comparative effects of lisinopril and losartan on insulin sensitivity in the treatment of non diabetic hypertensive patients. Br J Clin Pharmacol 46: 467–471.

15.

Fogari

Zoppi

Ferrari

Mugellini

Preti

Lazzari

. (2009) Comparative effects of telmisartan and eprosartan on insulin sensitivity in the treatment of overweight hypertensive patients. Horm Metab Res 41: 893–898.

16.

Frisard

McMillan

Marchand

Wahlberg

Voelker

. (2010) Toll-like receptor 4 modulates skeletal muscle substrate metabolism. Am J Physiol Endocrinol Metab 298: E988–E998.

17.

Furuhashi

Ura

Takizawa

Yoshida

Moniwa

Murakami

. (2004) Blockade of the renin–angiotensin system decreases adipocyte size with improvement in insulin sensitivity. J Hypertens 22: 1977–1982.

18.

Garrison

Kannel

Stokes

3rd Castelli

(1987) Incidence and precursors of hypertension in young adults: the Framingham Offspring Study. Prev Med 16: 235–251.

19.

Goossens

Moors

Van Der Zijl

Venteclef

Alili

Jocken

. (2012) Valsartan improves adipose tissue function in humans with impaired glucose metabolism: a randomized placebo-controlled double-blind trial. PLoS One 7: e39930.

20.

Henriksen

Jacob

Kinnick

Teachey

Krekler

(2001) Selective angiotensin II receptor antagonism reduces insulin resistance in obese Zucker rats. Hypertension 38: 884–890.

21.

Ichikawa

(2007) Comparative effects of telmisartan and valsartan on insulin resistance in hypertensive patients with metabolic syndrome. Intern Med 46: 1331–1336.

22.

Kurtz

(2005) Treating the metabolic syndrome: telmisartan as a peroxisome proliferator-activated receptor-gamma activator. Acta Diabetol 42(Suppl. 1): S9–S16.

23.

Kurtz

(2006) New treatment strategies for patients with hypertension and insulin resistance. Am J Med 119: S24–S30.

24.

Laakso

Karjalainen

Lempiainen-Kuosa

(1996) Effects of losartan on insulin sensitivity in hypertensive subjects. Hypertension 28: 392–396.

25.

Lteif

Chisholm

Gilbert

Considine

Mather

(2012) Effects of losartan on whole body, skeletal muscle and vascular insulin responses in obesity/insulin resistance without hypertension. Diabetes Obes Metab 14: 254–261.

26.

Moan

Hoieggen

Seljeflot

Risanger

Arnesen

Kjeldsen

(1996) The effect of angiotensin II receptor antagonism with losartan on glucose metabolism and insulin sensitivity. J Hypertens 14: 1093–1097.

27.

Moller

Flier

(1991) Insulin resistance – mechanisms, syndromes, and implications. N Engl J Med 325: 938–948.

28.

Mori

Tanaka

Matsuura

Yokoyama

Utsunomiya

(2011) Influence of telmisartan on insulin response after glucose loading in obese patients with hypertension: ARB Trial of Hypertension in Obese Patients with Hyperinsulinemia Assessed by Oral Glucose Tolerance Test (ATHLETE). Adv Ther 28: 698–706.

29.

Nishimura

Sanaka

Tanihata

Naito

Higuchi

Otsuka

(2008) Losartan elevates the serum high-molecular weight-adiponectin isoform and concurrently improves insulin sensitivity in patients with impaired glucose metabolism. Hypertens Res 31: 1611–1618.

30.

Paolisso

Tagliamonte

Gambardella

Manzella

Gualdiero

Varricchio

. (1997) Losartan mediated improvement in insulin action is mainly due to an increase in non-oxidative glucose metabolism and blood flow in insulin-resistant hypertensive patients. J Hum Hypertens 11: 307–312.

31.

Parhofer

Birkeland

Defronzo

Del Prato

Bhaumik

Ptaszynska

(2010) Irbesartan has no short-term effect on insulin resistance in hypertensive patients with additional cardiometabolic risk factors (i-RESPOND). Int J Clin Pract 64: 160–168.

32.

Perlstein

Henry

Mather

Rickels

Abate

Grundy

. (2012) Effect of angiotensin receptor blockade on insulin sensitivity and endothelial function in abdominally obese hypertensive patients with impaired fasting glucose. Clin Sci (Lond) 122: 193–202.

33.

Picard

Auwerx

(2002) PPAR(gamma) and glucose homeostasis. Annu Rev Nutr 22: 167–197.

34.

Prasad

Quyyumi

(2004) Renin–angiotensin system and angiotensin receptor blockers in the metabolic syndrome. Circulation 110: 1507–1512.

35.

Sasaki

Kushiro

Nakagawa

Kanmatsuse

(1999) [Effects of angiotensin II receptor antagonist on insulin sensitivity and sympathetic activity in spontaneously hypertensive rats]. Nihon Jinzo Gakkai Shi 41: 692–696.

36.

Scheen

(2004a) Renin–angiotensin system inhibition prevents type 2 diabetes mellitus. Part 1. A meta-analysis of randomised clinical trials. Diabetes Metab 30: 487–496.

37.

Scheen

(2004b) Renin–angiotensin system inhibition prevents type 2 diabetes mellitus. Part 2. Overview of physiological and biochemical mechanisms. Diabetes Metab 30: 498–505.

38.

Schupp

Janke

Clasen

Unger

Kintscher

(2004) Angiotensin type 1 receptor blockers induce peroxisome proliferator-activated receptor-gamma activity. Circulation 109: 2054–2057.

39.

Shiuchi

Iwai

Min

. (2004) Angiotensin II type-1 receptor blocker valsartan enhances insulin sensitivity in skeletal muscles of diabetic mice. Hypertension 43: 1003–1010.

40.

Shoelson

Lee

Goldfine

(2006) Inflammation and insulin resistance. J Clin Invest 116: 1793–1801.

41.

Sloniger

Saengsirisuwan

Diehl

Dokken

Lailerd

Lemieux

. (2005) Defective insulin signaling in skeletal muscle of the hypertensive TG(mREN2)27 Rat. Am J Physiol Endocrinol Metab 288: E1074–E1081.

42.

Van Der Zijl

Moors

Goossens

Hermans

Blaak

Diamant

(2011) Valsartan improves {beta}-cell function and insulin sensitivity in subjects with impaired glucose metabolism: a randomized controlled trial. Diabetes Care 34: 845–851.

43.

Vitale

Mercuro

Castiglioni

Cornoldi

Tulli

Fini

. (2005) Metabolic effect of telmisartan and losartan in hypertensive patients with metabolic syndrome. Cardiovasc Diabetol 4: 6.

44.

Wang

McPherson

Marsh

Gortmaker

Brown

(2011) Health and economic burden of the projected obesity trends in the USA and the UK. Lancet 378: 815–825.

45.

Wei

Sowers

Clark

Ferrario

Stump

(2008) Angiotensin II-induced skeletal muscle insulin resistance mediated by NF-kappaB activation via NADPH oxidase. Am J Physiol Endocrinol Metab 294: E345–E351.

46.

Wei

Sowers

Nistala

Gong

Uptergrove

Clark

. (2006) Angiotensin II-induced NADPH oxidase activation impairs insulin signaling in skeletal muscle cells. J Biol Chem 281: 35137–35146.