Does interference with the renin–angiotensin system protect against diabetes? Evidence and mechanisms

Abstract

Agents interfering with the renin–angiotensin system (RAS) were consistently shown to lower the incidence of type 2 diabetes mellitus (T2DM), as compared to other antihypertensive drugs, in hypertensive high-risk populations. The mechanisms underlying this protective effect of RAS blockade using angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers on glucose metabolism are not fully understood. In this article, we will review the evidence from randomized controlled trials and discuss the proposed mechanisms as to how RAS interference may delay the onset of T2DM. In particular, as T2DM is characterized by β-cell dysfunction and obesity-related insulin resistance, we address the mechanisms that underlie RAS blockade-induced improvement in β-cell function and insulin sensitivity.

Introduction

Type 2 diabetes mellitus (T2DM) is characterized by impairments in insulin secretion by the β-cells (β-cell dysfunction) and obesity-related disturbances in insulin action in target tissues (insulin resistance) [1]. In susceptible individuals, with increasing body weight and physical inactivity, insulin sensitivity is decreased. This imposes progressive stress on the compromised β-cell. Over time, insulin secretion cannot keep up with the increasing demand and glucose levels start to rise into the prediabetic range leading to impaired fasting glucose and/or impaired glucose tolerance (IGT) [2]. In a population-based study in the Netherlands (the Hoorn-study), the prevalence of impaired glucose metabolism (IGM) in a randomly selected population (age 40–65) was 16% [3]. Similarly, in a European population-based study, the Diabetes Epidemiology: Collaborative Analysis of Diagnostic Criteria in Europe (DECODE study), the prevalence of IGM between the age of 30 and 59 was <15%, increasing to 15–30% above the age of 60 [4]. Although people with IGM were 0.33 [95% confidence interval (CI) 0.23–0.43] times as likely to be normoglycaemic after 1 year compared to people with normal glucose tolerance [5], individuals with IGM had an absolute annual risk of progression to T2DM of approximately 5–10% [5]. As such, identification and treatment of individuals with IGM seems essential in the battle against T2DM. The Finnish Diabetes Prevention Study outlined that lifestyle changes, such as weight reduction via dietary changes and moderate exercise of at least 30 min a day, reduced the incidence of T2DM by 58% in individuals at high risk to develop T2DM [6]. Although lifestyle intervention delayed the onset of T2DM, the Diabetes Prevention Program Outcomes Study showed that after 10 years the cumulative incidence of T2DM was still approximately 40% in the lifestyle intervention group [7].

In as much as lifestyle intervention may postpone the onset of T2DM, once the disease occurs, the currently available pharmacological blood-glucose lowering interventions are not able to delay progressive β-cell dysfunction in patients with T2DM [8]. Recently, the introduction of therapies based on the incretin hormone glucagon-like peptide-1 (GLP-1), which improve islet-cell function in rodents and humans and preserve functional β-cell mass in rodents, has sparked hope for the potential future prevention of β-cell function decline in high-risk individuals [9,10]. Also, in this context, the dramatic effects of bariatric surgical procedures should be mentioned, which were shown to resolve T2DM in morbidly obese patients with T2DM [11,12]. The latter therapies are beyond the scope of this review.

In recent years, the use of pharmacological interventions blocking the renin–angiotensin system (RAS) have been related to delayed onset of T2DM in high-risk populations [13–15]. Evidence mainly derived from rodent and cell experiments suggests that improvements of insulin sensitivity, through improved adipose tissue function and direct effects on insulin signalling in skeletal muscle, and improved β-cell function by ameliorated islet perfusion and anti-fibrotic effects, were among the proposed mechanisms by which RAS blocking agents may reduce T2DM risk [16–19]. Here, we will review the evidence from clinical trials, showing the protective effects of pharmacological RAS blockade, and discuss the underlying mechanisms as showed in preclinical and clinical studies. We focus on blockade of RAS with an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin-receptor blocker (ARB). At the moment, no data are available regarding the effect of the newer drugs directly inhibiting renin on glucose metabolism and the onset of T2DM.

The Renin–Angiotensin System (RAS)

The RAS consists of several key components: the hepatic-derived angiotensinogen (AGT), which is cleaved by the renal-synthesized peptide renin into angiotensin I. Angiotensin I is converted by the lung-derived angiotensin-converting enzyme into angiotensin II (AngII) [20], which mainly exerts its effect via two receptors: the angiotensin type 1 (AT1R) and the angiotensin type 2 (AT2R) receptors. Classically, the RAS is known for its systemic effect on blood pressure, electrolyte and fluid regulation [20]. However, over the past few years, RAS components have been localized in almost any tissue, including heart, blood vessels, kidney, brain, nerve fibres, pancreas, adipose tissue and skeletal muscle [21]. Consequently, RAS components, primarily AngII, not only exert cardiovascular effects but also have multiple autocrine and/or paracrine effects on other tissues resulting in the promotion of inflammation, fibrosis, cell proliferation and apoptosis via the AT1R [21,22] and in anti-inflammatory, and antiproliferatory effects and tissue regeneration mediated by the AT2R (figure 1) [23].

Figure 1. Overview of the mechanisms underlying AngII-induced β-cell dysfunction and impaired insulin sensitivity and the effect of renin–angiotensin system (RAS) blockade in vitro. AngII (solid arrows), in the presence or absence of hyperglycaemia, impairs β-cell function and insulin sensitivity through several pathways, which are detailed in the text. The effect of RAS blockade on glucose metabolism is shown in dashed arrows, and may include improved β-cell function via reduced oxidative stress, inflammation and islet fibrosis; improved adipose tissue function via enhanced adipocyte differentiation with altered adipokine and pro-inflammatory cytokine secretion and increased adipose tissue blood flow; and finally, enhanced insulin signalling and blood flow in the skeletal muscle. CTGF, connective tissue growth factor; GLUT4, glucose transporter type 4; HsCRP, high-sensitive C-reactive protein; IL, interleukin; IRS, insulin receptor substrate; MCP, monocyte chemotactic protein; NADPH, nicotinamide adenine dinucleotide phosphate; PAI, plasminogen activator inhibitor; PI3K, phosphatidylinositol-3-kinase; PPAR, peroxisome proliferator-activated receptor; ROS, reactive oxygen species; TGF, transforming growth factor; TNF, tumour necrosis factor; UCP, uncoupling protein.

The Renin–Angiotensin System and Type 2 Diabetes

RAS activation has been related to both insulin resistance and β-cell dysfunction [24–27]. As such, in rodents, the presence of hyperglycaemia increased expression of RAS components, including AngII, in pancreatic islets, adipose tissue and skeletal muscle [28,29]. Furthermore, AngII diminished insulin secretion in pancreatic β-cells [30] and impaired insulin sensitivity in adipose and skeletal muscle tissue [31–33]. In large clinical trials blockade of RAS with an ACEi or ARB delayed the onset of T2DM in subjects with hypertension [34–36]. On the basis of multiple meta-analyses, it is suggested that treatment with an ACEi or ARB reduces the incidence of T2DM by 22–30% [13,37]. However, in most of the trials investigating the effect of RAS blockade on the incidence of T2DM, the onset of T2DM was not a prespecified endpoint. Recently, two large-scale prospective trials (the Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication, DREAM trial [38] and the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research, NAVIGATOR trial [39]) specifically addressed the potential of the ACEi ramipril and the ARB valsartan, respectively, on incident T2DM in normotensive individuals with IGM. In the DREAM trial, ramipril (15 mg QD), given for 3 years, non-significantly reduced the incidence of T2DM by 9%. At 3 years, individuals treated with ramipril were more likely to revert from impaired to normal glucose metabolism (hazard ratio, 1.16; 95% CI: 1.07–1.27; p = 0.001) and their post-load glucose levels were significantly reduced compared to placebo (7.50 vs. 7.80 mmol/l, ramipril vs. placebo, respectively, p = 0.01) [38]. In the NAVIGATOR trial, valsartan (160 mg QD), given for 5 years, not only reduced fasting and post-load glucose after an oral glucose tolerance test (OGTT), but also reduced the incidence of T2DM by 14% (p < 0.001) [39]. As valsartan was given in addition to lifestyle modification, its true protective potential regarding the incidence of T2DM might be an underestimation. However, the underlying mechanisms are incompletely understood. Here, we discuss the possible effects of RAS blockade on β-cell function and insulin sensitivity. Meta-analyses, including 10 randomized controlled trials, could not establish differences in the beneficial effect of RAS blockade on onset T2DM between ACEi and ARB. Furthermore, as there are no head-to-head comparison studies comparing the effect of ACEi with that of ARB on β-cell function and insulin sensitivity, in this review data from studies investigating the effect of ACEi as well as ARB on glucose metabolism are described.

The Renin–Angiotensin System and β-Cell Function

In the development of T2DM, β-cell failure is a prerequisite and deterioration of β-cell function as well as loss of functional β-cell mass are important determinants of the development and the progressive course of the disease. In addition to the vascular distribution of AT1R in the pancreas, the involvement of RAS in insulin synthesis/release was suggested by the presence of AT1R on pancreatic β-cells [28,40]. In rodents, hyperglycaemia induced an upregulation of RAS components in pancreatic islets [28] and AngII diminished islet blood flow and impaired insulin secretion [24,30]. Furthermore, RAS blockade with an ACEi or ARB counteracted these effects and increased insulin secretion and glucose tolerance [16,19,30,41]. Together, these data indicate that the pancreatic islet RAS is not only involved in islet blood flow but may also be directly involved in insulin secretion. Molecular mechanisms explaining these observations have been addressed in vitro and in vivo in animal models of T2DM, and may include increased oxidative stress, inflammation and islet fibrosis.

Oxidative Stress and Inflammation. The disproportionate activation of RAS as seen in animal models of T2DM, is associated with increased activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, which is a major source of reactive oxygen species (ROS) [42,43]. As β cells have low levels of endogenous antioxidants, they are susceptible to ROS-induced damage [44], and consequently RAS-mediated ROS production may alter β-cell structure, impair function and contribute to the development of T2DM [45–48]. Furthermore, ROS activates uncoupling protein-2 (UCP-2), which uncouples the electrochemical gradient produced by the respiratory chain from ATP synthesis [49,50]. Enhanced UCP-2 expression can be protective against oxidative damage, but, however, ATP synthesis is essential for insulin secretion. Therefore, upregulated UCP-2 expression may contribute to the deleterious effects of ROS on β-cell function. In vivo in db/db mice, RAS blockade with an ARB selectively inhibited oxidative stress via down regulation of NADPH oxidase [28,51,52] and suppression of UCP-2 [52,53] with improved mitochondrial function [16,51,53]. Together, this increased the insulin secretion and diminished apoptosis. Finally, the AngII-induced oxidative stress may trigger inflammatory processes, resulting in an upregulation of inflammatory mediators, such as interleukin (IL)-1, tumour necrosis factor (TNF)-α and monocyte chemoattractant protein (MCP)-1 [54]. Inflammation in pancreatic islets has been related to the progression of β-cell dysfunction and apoptosis in T2DM [55]. Blockade of RAS with an ARB ameliorated the inflammatory profile and improved β-cell function in male Wistar rats that were fed a high-fat diet [53].

Islet Fibrosis. An intact pancreatic islet structure is required for normal islet function [56]. However, because of hyperglycaemia and the formation of hyperglycaemia and hyperlipidaemia-related toxic intermediates, T2DM is associated with prominent fibrosis within the islet interstitium [19]. Owing to islet fibrosis, cell-to-cell contact and communication is impaired and this reduces the secretory function of the β cells. In different tissues, including the pancreas, an upregulation of RAS has been related to increased fibrosis [57]. Via the AT1R, AngII induced apoptosis and upregulation of the cytokine transforming growth factor (TGF)-β and connective tissue growth factor (CTGF). Together, an upregulation of TGF-β and CTGF results in matrix accumulation and fibrosis [19,58]. In rodents, RAS blockade downregulated TGF-β and CTGF, thereby decreasing islet fibrosis [19,51,58]. In addition to the anti-inflammatory effects of RAS blockade, these alterations resulted in improved islet structure, mass and function with increased insulin secretion [19,51,52,58].

Evidence in Humans. Notwithstanding the extensive data derived from rodent studies, evidence from human investigations is limited and less conclusive. In human pancreatic β cells, the presence of a local RAS has been identified and hyperglycaemia was found to increase the expression of RAS components [40,59–61]. Similar to rodent models, hyperglycaemia impaired insulin secretion and induced activation of NADPH oxidase in pancreatic islets from individuals without T2DM in vitro, resulting in increased ROS production [59]. Treatment with an ACEi protected these human pancreatic islets from the functional damage induced by hyperglycaemia [59]. However, the profibrotic effect of pancreatic RAS activation in the development of T2DM has not yet been established in human pancreatic islets.

In vivo, short-term (6-weeks) RAS blockade with the ARB valsartan (80 mg twice daily) did not affect β-cell function, assessed with a hyperglycaemic clamp, in subjects with IGT [62]. In contrast, 3-months treatment with the ARB candesartan (8 mg QD) increased first-phase insulin secretion following an OGTT in subjects with IGT and hypertension [63]. A similar effect was measured after treatment with the ACEi captopril for 4 months (mean dose 81 ± 12 mg/day) in patients with essential hypertension, who showed an increase in early-phase insulin secretion in response to intravenous glucose administration compared to placebo [64]. Recently, in a randomized placebo-controlled trial we investigated the effect of 26-weeks high-dose valsartan (320 mg QD) on multiple aspects of β-cell function using the gold-standard hyperglycaemic clamp method and a frequently sampled OGTT. We found an increase in clamp-measured glucose-stimulated insulin secretion [65] and, in line with the findings of Suzuki et al. [63], an increase in first-phase insulin secretion during an OGTT. The discrepant findings between the results from both Suzuki et al. [63] and our group and the study of Bokhari et al. [62] who did not find an effect on clamp-measured β-cell function, may be explained by differences in the compound used, the exposure-time, methodology, dosage and study population. As stated above, the processes underlying RAS blockade-induced improvements in β-cell function are based on rodent data and should, as much as possible, be established in humans.

The Renin–Angiotensin System and Insulin Sensitivity at a Multi-Organ Level

As stated above, components of the RAS have been identified in many different organs, most notably in those playing a significant role in metabolism and insulin sensitivity, including the liver, skeletal muscle and adipose tissue. In this review, we focus on the effects of disproportionate RAS activation and RAS blockade on insulin sensitivity in skeletal muscle and adipose tissue.

The Renin–Angiotensin System and Skeletal Muscle

As the major tissue for insulin-mediated glucose disposal, skeletal muscle is crucial in the development of insulin resistance. The skeletal muscle expresses and secretes many components of the RAS, including AGT [66], AngII and AT1R [67]. Local RAS components may affect insulin sensitivity not only via changes in muscle blood flow but also directly via interference with insulin signalling and mitochondrial function.

Muscle Blood Flow. A reduction in muscle blood flow reduces nutrient, hormone and oxygen delivery, including glucose and insulin, and may contribute to insulin resistance [68]. The well-known vasoconstrictive effect of AngII was present in the gastrocnemius and forearm, as AngII decreased blood flow in healthy normal-weight and obese male individuals [69,70]. In accordance, in both rodents and humans, RAS blockade resulted in an increase in forearm blood flow [68,71], thereby increasing glucose and insulin delivery to skeletal muscle, which in turn may lead to increased glucose utilization. Similarly, in rodents, AngII was shown to impair microvascular skeletal muscle blood flow and glucose uptake [43]. Furthermore, ARB treatment prevented or improved microvascular dysfunction in spontaneously hypertensive and Spraque–Dawley rats [72–74]. However, limited data are available regarding the effect of RAS blockade on the microcirculation in humans. Previously, our group did not find an effect of 26-weeks valsartan treatment on skin microvascular function and structure in individuals with IGM [75]. Importantly, the effect of RAS blockade on microvascular structure and function might be more pronounced in other populations, such as (untreated) hypertensive patients, or after longer treatment duration. These possibilities should be addressed in future studies.

Skeletal Muscle Insulin Signalling and Mitochondrial Function. Insulin resistant states are characterized by reduced insulin-stimulated tyrosine phosphorylation of the insulin receptor (IR) and IR substrate (IRS)-1 and reduced activation of phosphatidylinositol-3-kinase (PI3K)/Akt pathway [76–78]. This leads to defects in glucose transporter type 4 (GLUT4) translocation [79] from the intracellular space to the plasma membrane, resulting in impaired glucose uptake in the myocyte. On the basis of rodent data, it has been proposed that increased expression of RAS components, as seen in the TG(mREN2)27 rat, directly interferes with insulin signalling in skeletal muscle and, consequently, contributes to insulin resistance [32,80]. Similar results were obtained with AngII infusion studies [27,33]. As such, in different rodent models and cell lines, acute infusion with AngII-induced tyrosine phosphorylation of IRS-1 and -2 and inhibited basal and insulin-stimulated PI3K [27,33,81]. In contrast, chronic infusion of AngII enhanced insulin-induced tyrosine phosphorylation of the IR and IRS-1 and -2 and activated the PI3K/Akt pathway [82]. In the latter study, however, AngII induced the insulin resistance via impaired GLUT4 translocation.

The relation between disproportionate RAS activation and skeletal muscle insulin resistance was established in multiple rodent studies investigating the effect of RAS blockade with an ACEi or ARB on insulin signalling. However, conflicting results have been reported whether RAS blockade improves insulin sensitivity via increased insulin-induced phosphorylation of IRS-1 and PI3K activity [18,33,72,83] or whether the effect is because of reduced oxidative stress, which improves GLUT4 translocation and insulin sensitivity via effects downstream of PI3K [82]. The relation between AngII-induced oxidative stress and insulin resistance in skeletal muscle has been confirmed by several studies [80,83,84]. AngII increased ROS generation via NADPH oxidase activity in skeletal muscle. Interestingly, this not solely impaired GLUT4 translocation to the plasma membrane [84], but also impaired insulin-induced IRS-1 tyrosine phosphorylation and Akt activation. On the basis of these data, it is probable that RAS components affect skeletal muscle insulin signalling at multiple levels with an eminent role for AngII-induced oxidative stress and impaired GLUT4 translocation. Currently, there are no human data available regarding the direct effects of AngII and RAS blockade on skeletal muscle insulin signalling. Consequently, the hypothesis that RAS blockade-induced improvement in insulin sensitivity is because of improvements in insulin signalling in skeletal muscle remains speculative and should be investigated in future studies.

Recently, Mitsuishi et al. [85] assessed the effect of AngII and RAS blockade on skeletal muscle mitochondrial function. In this study, AngII reduced mitochondrial content in both cultured myotubular cells and skeletal muscle of mice. Furthermore, AngII infusion decreased fat oxidation in mice, which was associated with an increase in intramuscular triglyceride content and IGT [85]. These recent findings should be confirmed in future studies.

The Renin–Angiotensin System and Adipose Tissue

One of the physiological functions of adipose tissue is to buffer the daily influx of dietary fat entering the circulation by suppressing the release of non-esterified fatty acids (NEFA) into the circulation and increasing the clearance of triacylglycerol. However, in obese insulin-resistant individuals the capacity of the adipose tissue to take up and store dietary lipids is insufficient, leading to lipid overflow in the circulation which may increase fat storage in non-adipose tissues such as skeletal muscle, liver and pancreatic islets [86]. These ectopic lipids have been related to hepatic and skeletal muscle insulin resistance [87–89]. Furthermore, the adipose tissue of obese individuals is characterized by increased expression and/or secretion of adipokines and pro-inflammatory cytokines, including TNF-α, IL-6, MCP-1 and leptin, and decreased expression/secretion of the insulin-sensitizing hormone adiponectin [86], which leads to systemic inflammation. These alterations contribute to insulin resistance, presumably via both local (autocrine/paracrine) as well as systemic (endocrine) effects (as reviewed in Ref. [86]).

Rodent as well as human adipose tissue expresses many components of the RAS [90]. In obese and insulin-resistant humans, this local adipose tissue RAS is upregulated and may contribute to adipose tissue dysfunction and obesity-related complications, such as hypertension [29,66,91]. Ang II was shown to impair adipocyte differentiation, leading to large insulin-resistant adipocytes [90]. Together with RAS-induced impairments in adipose tissue blood flow and altered adipokines and pro-inflammatory cytokine secretion, this may lead to impaired lipid handling and contribute to an increased lipid supply to non-adipose tissues [92]. The underlying processes that contribute to insulin resistance, including the effect of RAS blockade, will be described below.

Adipocyte Growth and Differentiation. One of the main features of adipose tissue dysfunction is enlargement of adipocytes. In humans, enlarged adipocytes are directly related to insulin resistance (assessed with a hyperinsulinaemic–euglycaemic clamp) and the development of T2DM [93–95]. An important feature of adipose tissue RAS could be its role in adipocyte differentiation. Data from rodents outline an inhibitory effect of AngII in pre-adipocyte differentiation, which results in enlarged adipocytes [96,97]. In line, RAS blockade promoted the recruitment and differentiation of (pre)adipocytes, resulting in an increased number of small insulin-sensitive adipocytes in different rodent populations [17,97,98], and improved insulin sensitivity [17]. In vitro studies in human adipocyte cell lines showed similar inhibitory effects of AngII [99,100], whereas others found a stimulatory effect of AngII on the proliferation of human visceral mature adipocytes as well as in vitro-differentiated pre-adipocytes [101]. These discrepant findings might be due to the fact that human mesenchymal stem cells and adipocytes from rodents express both AT1R as well as AT2R, whereas human adipocytes predominantly express AT1R [102]. Activation of the AT2R may counteract the differentiating effect of AngII, which is mainly mediated by the AT1R [102]. Furthermore, in differentiated murine 3T3-L1 preadipocytes and human adipocytes, AngII stimulation resulted in hypertrophic cells with elevated triglyceride content and increased expression of the lipogenic enzymes glycerol-3-phosphate dehydrogenase and fatty acid synthase [103]. ARB treatment attenuated these lipogenic effects of AngII [103]. In vivo, long-term treatment with the ARB valsartan in individuals with IGM significantly reduced adipocyte size, which may contribute to increased insulin sensitivity [104].

One of the processes that could underlie the observed effects of RAS blockade on adipocyte size is the activation of peroxisome proliferator-activated receptor (PPAR)-γ[105]. PPAR-γ plays a role in regulating glucose and lipid metabolism and PPAR-γ agonists improve insulin sensitivity [106]. Although ACEi have been shown to have PPAR-γ-agonistic effects, more pronounced effects have been reported for ARB [107,108]. However, ARB-induced PPAR-γ activation might differ among the various compounds [89]. As such, consistent data exist regarding the PPAR-γ-agonistic effect of telmisartan [105,108], while this is less conclusive with respect to valsartan [108,109] and olmesartan [89]. However, this difference in PPAR-γ activation does not lead to a more pronounced protective effect of telmisartan compared to other ARB (or ACEi).

Adipose Tissue Blood Flow and Lipolysis. The positive effect of ARB treatment on human adipose tissue lipid handling may include an increase of adipose tissue blood flow. Normal adipose tissue blood flow is a prerequisite for normal adipose tissue function. Interestingly, an impaired adipose tissue blood flow is associated with obesity [110–112] and OGTT-derived insulin resistance [112]. Impaired adipose tissue blood flow reduces triglyceride clearance and may contribute to increased circulating triglycerides, which may lead to ectopic fat deposition [86]. Furthermore, it may contribute to increased re-esterification of NEFA in adipose tissue [113]. Previously, it was shown that acute infusion with AngII dose-dependently reduced local blood flow in both normal weight and obese male subjects [69,114,115], whereas local administration of an ARB into abdominal subcutaneous adipose tissue restored adipose tissue blood flow [114]. In addition, AngII has been shown to exert modest inhibitory effects on adipose tissue lipolysis [69,115]. Together this might contribute to enlarged adipocytes and aggravate insulin resistance. To date, no studies have been performed investigating the effect of prolonged RAS blockade on adipose tissue blood flow. Preliminary data from our group indicate an improvement in adipose tissue blood flow after 26-weeks treatment with the ARB valsartan in individuals with IGM [104].

Circulating Adipokines and Pro-Inflammatory Cytokines. Adipose tissue is not only involved in energy storage but also has emerged as a highly active endocrine tissue secreting a variety of proteins, including TNF-α, IL-6, MCP-1, leptin, resistin and adiponectin [116]. Impaired adipose tissue function leads to alterations in adipokine secretion, with increased expression of pro-inflammatory cytokines and decreased adiponectin. As described previously, AngII may impair adipose tissue function, via impaired adipocyte differentiation and the reduction of adipose tissue blood flow. Consequently, an upregulation of RAS has frequently been related to altered expression of circulating adipokines and pro-inflammatory cytokines [103,117,118].

The effect of RAS blockade is mainly derived from rodent data. In rodents, the detrimental effects induced by AngII were counteracted by ARB treatment, resulting in suppressed AngII-induced oxidative stress, plasminogen activator inhibitor-1, TNF-αand MCP-1 levels and increased adiponectin levels [97,119,120]. Similarly, in western diet-fed mice, valsartan improved the inflammatory profile of adipose tissue and improved insulin sensitivity [16]. The underlying mechanisms may include a reduction in adipocyte size via increased adipocyte differentiation [17,120,121] and reduced oxidative stress [119]. Furthermore, PPAR-γ-agonists, such as thiazolidinediones, have been shown to improve adipokine dysregulation [122]. As several ARBs have PPAR-γ agonistic effects, it has been suggested that ARB treatment may improve adipokine secretion directly via PPAR-γ activation, although not all studies found altered PPAR-γ expression [122].

In humans, consistent findings have been reported regarding the positive effect of RAS blockade on adiponectin in insulin-resistant individuals with or without hypertension [123–127]. However, limited data are available with respect to the effect of RAS blockade on other adipokines. Low-dose valsartan for 3 months reduced serum TNF-α and IL-6, without changes in C-reactive protein (CRP) in patients with essential hypertension [128]. In addition to the extensive data in rodents, future studies should clarify the role of RAS blockade on adipokines and pro-inflammatory cytokines in humans.

In summary, AngII may play an important role in adipose tissue dysfunction, which is reflected by enlargement of adipocyte size. This results in altered adipokine and pro-inflammatory cytokine secretion, lipid overflow and excessive fat storage in non-adipose tissue, which together may contribute to insulin resistance. Consequently, pharmacological treatment with an ARB or ACEi may improve adipose tissue function, thereby contributing to improvements in insulin sensitivity after RAS blockade.

Conclusion

Blockade of the RAS is associated with delayed onset of T2DM and the underlying mechanisms include both improvements in β-cell function as well as insulin sensitivity. The underlying mechanisms of improved β-cell function and insulin sensitivity after RAS blockade are multifactorial and may include alterations in adipose tissue function, such as reduction in adipocyte size, improvements in the pro-inflammatory phenotype of adipocytes and increased adipose tissue blood flow, which in turn may contribute to reduced ectopic fat deposition and improved insulin sensitivity. Furthermore, RAS blockade may directly affect skeletal muscle insulin signalling and may possibly reduce ectopic fat accumulation through effects on mitochondrial function and fat oxidation. Although in this review the effects of RAS blockade on the pancreas, skeletal muscle and adipose tissue are described separately, they are interrelated. As such, adipose tissue dysfunction might impair lipid storage capacity of adipose tissue, which may lead to accumulation of lipids in skeletal muscle and the pancreas. As stated, these ectopic lipids may interfere with normal pancreatic function and insulin signalling in skeletal muscle. Consequently, the effects of RAS blockade on insulin secretion and sensitivity are the result of RAS blockade-induced effects on multiple tissues. Finally, it should be mentioned that the data described in this review reflect the effect of RAS blockade on glucose metabolism on treatment and does not give information regarding sustainable effects after treatment discontinuation.

Individuals with IGM often display concurrent cardiometabolic abnormalities, including hypertension. Accordingly, antihypertensive drugs with neutral or positive side effects on glucose and lipid metabolism are of clinical importance. Physicians prescribing blood pressure lowering therapy in individuals with hypertension and concurrent glucometabolic derangements should consider ARB or ACEi as first-choice therapy, provided that there are no specific indications to use β-blockers or diuretics. Furthermore, in addition to lifestyle intervention and classical anti-diabetic pharmacological therapies, ARB or ACEi may be considered in patients without hypertension, who are at high risk to develop T2DM, as their beneficial metabolic actions may help to delay the onset of T2DM.

Conflict of Interest

N. J. van der Z. and C. C. M. M. wrote the manuscript. G. H. G., E. E. B. and M. D. reviewed the manuscript.

No author has competing interest.