Vascular Actions Of Insulin Research Articles

Acute Effects of Insulin Infusion on Kidney Hemodynamic Function in People With Type 2 Diabetes and Normal Kidney Function

Acute Effects of Insulin Infusion on Kidney Hemodynamic Function in People With Type 2 Diabetes and Normal Kidney Function

Obesity-related changes in the vascular actions of insulin

Over the past 2 to 3 decades, research has focused on the changes in the vascular effects of insulin occurring in insulin resistant states like obesity. Consistent evidence indicates that obesity results in reduced endothelial release of nitric oxide in response to insulin, associated with concomitant enhancement in the production of endothelin-1. More recent work has pointed toward reduced vascular permeability and changes in the physical-chemical characteristics of the perivascular extracellular matrix as additional mechanisms of impaired insulin sensitivity in obesity. All these perturbations are important, because they contribute to impaired delivery of insulin itself and metabolic substrates to the target tissues and may play a role in the development of both diabetes and vascular damage. This review will describe the physiological vascular actions of insulin and their changes in obesity, focusing on some established pathophysiological determinants of the derangement of vascular insulin signaling, such as the lipid overflow from expanded fat depots and signals originating from inflamed obese adipose tissue (both distant and perivascular). Also, it will outline novel evidence underscoring the contribution of dysregulated adipokine secretion and changes in intestinal permeability and gut microbiome. Finally, it will touch upon some unresolved issues, such as the potential role of vascular insulin resistance in obesity-driven adipose tissue remodeling, and will discuss perspectives for future studies, regarding in particular possible therapeutic strategies with translational implications for the patients care.

Macrophage Depletion Improves Endothelial Insulin Resistance and Protects against Cardiovascular Injury in Salt-Sensitive Hypertension.

Vascular endothelial insulin signaling is critical for the maintenance of vascular and metabolic homeostasis. We have previously shown that in hypertensive Dahl rats, impaired vascular insulin action is linked to angiotensin II activation of the NFκB inflammatory pathway. Macrophage polarization (M1) has implicated in hypertensive and metabolic diseases. Here, we investigated the effect of macrophage depletion using liposome-encapsulated clodronate (LEC) on endothelial insulin resistance and cardiovascular remodeling in Dahl salt-sensitive (DS) rats. High salt intake (HS) for 5 weeks increased systolic blood pressure (SBP: 192 ± 5 vs. 144 ± 4 mmHg in NS, p < 0.05), aortic and cardiac hypertrophy, cardiac fibrosis, and impaired acetylcholine- and insulin-induced vasorelaxation, accompanied by impaired insulin activation of endothelial nitric oxide synthases (eNOS)/NO signaling. HS rats had a significant increase in CD68 (a monocyte/macrophage marker) expression in the aorta and the heart. LEC reduced SBP (168 ± 5 mmHg, p < 0.05) and cardiovascular injury and improved acetylcholine- and insulin-mediated vasorelaxation and insulin signaling molecules with a reduction in the macrophage infiltration in the aorta and the heart. HS rats also manifested an increase in the aortic expressions of inflammatory cytokines, including the ratio of phosphorylated inhibitory kappa B (Iκb)/Iκb, tumor necrosis factor α, and phosphorylated c-Jun N-terminal kinase (JNK) and oxidative stress, which were reduced in HS/LEC rats. Our results suggest that in salt-sensitive hypertension, macrophage may importantly contribute to endothelial insulin resistance, vascular inflammation, and injury. These findings support the idea that macrophages may be a new target for immunotherapy of vasculopathy in hypertensive and metabolic disorders.

Vascular Action of Insulin in Pregnancy

Physiological insulin resistance associated with pregnancy is attributed to the increase of anti‐insulin hormones such as placental lactogen and p85 (potent negative regulator of PI3K), human growth hormone, TNFα, as well as adipokines. Besides, AT1 receptor for angiotensin II has a clear role in insulin resistance while the role of AT2 receptors is not well understood. On the other hand, it has been described an increased vascular expression of AT2 receptor during pregnancy. On the other hand, insulin has shown a PI3K‐AKT NO mediated vasodilator effect that may contribute to its metabolic actions. Therefore, the aim of this study was to evaluate if pregnancy decrease in the vasodilatory action of insulin and AT2 receptors participation in this change. Using a conventional isolated organ preparation, the vasodilator effect of cumulative concentrations of insulin was evaluated in rat aortic rings pre‐contracted with phenylephrine. Vasorelaxation of aorta rings was compared at day 14 and day 20 (term) of pregnancy in the presence and absence of the AT2 receptor antagonist PD123319. Pregnancy produced resistance to insulin induced vasodilatation in the thoracic aorta while the vasodilator effect increased in the abdominal aorta only in rings with intact endothelium. AT2 receptors participation on the insulin induced vasodilation was more evident on day 14 (half) gestation. These results suggest that the vascular action of insulin is enhanced by the participation of AT2 receptors for angiotensin II. Also, that both insulin action and AT2 receptor participation during pregnancy depend on the vascular territory studied.Support or Funding InformationSIP Instituto Politécnico Nacional, COFFAAThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Puerarin Improves Vascular Insulin Resistance and Cardiovascular Remodeling in Salt-Sensitive Hypertension.

Puerarin is an isoflavonoid isolated from the Chinese herb, Kudzu roots (also known as Gegen), which has been widely used for the treatment of hypertensive diseases and diabetic mellitus in traditional Chinese medicine. Dahl salt-sensitive (DS) rat is a genetic model of salt-sensitive hypertension with cardiovascular injury and vascular insulin resistance. Here, we investigated whether puerarin improved vascular insulin resistance and attenuated cardiac and aortic remodeling in salt-sensitive hypertension. DS rats were given a normal (NS) or high salt diet (HS) for five weeks. An additional group of DS rats was pretreated with puerarin and NS for 10 days, then switched to HS plus puerarin for five weeks. HS for five weeks increased systolic blood pressure (SBP), cardiac hypertrophy and fibrosis, and aortic hypertrophy with increased the expression of phosphor-ERK1/2 in the aorta and heart; puerarin attenuated cardiac and aortic hypertrophy, cardiac fibrosis and phosphor-ERK1/2 with a mild reduction in SBP.Hypertensive rats also manifested impairment of acetylcholine- and insulin-mediated vasorelaxation and insulin-mediated Akt and eNOS phosphorylation associated with the activation of NF[Formula: see text]B/TNF[Formula: see text]/JNK pathway. Puerarin improved acetylcholine- and insulin-mediated vasorelaxation and insulin-stimulated Akt/NO signaling with the inhibition of the NF[Formula: see text]B inflammatory pathway. Our results demonstrated that in salt-sensitive hypertension, puerarin improved vascular insulin action with cardiovascular beneficial effects. Our results found that the underlying mechanisms may involve its inhibition of NF[Formula: see text]B/JNK and ERK1/2 pathway. These results suggest that puerarin could be used as a new antihypertensive agent to expand our armamentarium for the prevention and treatment of end-organ damage in individuals with hypertension and metabolic diseases.

Insulin Downregulates the Transcriptional Coregulator CITED2, an Inhibitor of Proangiogenic Function in Endothelial Cells.

In patients with atherosclerotic complications of diabetes, impaired neovascularization of ischemic tissue in the myocardium and lower limb limits the ability of these tissues to compensate for poor perfusion. We identified 10 novel insulin-regulated genes, among them Adm, Cited2, and Ctgf, which were downregulated in endothelial cells by insulin through FoxO1. CBP/p300-interacting transactivator with ED-rich tail 2 (CITED2), which was downregulated by insulin by up to 54%, is an important negative regulator of hypoxia-inducible factor (HIF) and impaired HIF signaling is a key mechanism underlying the impairment of angiogenesis in diabetes. Consistent with impairment of vascular insulin action, CITED2 was increased in cardiac endothelial cells from mice with diet-induced obesity and from db/db mice and was 3.8-fold higher in arterial tissue from patients with type 2 diabetes than control subjects without diabetes. CITED2 knockdown promoted endothelial tube formation and endothelial cell proliferation, whereas CITED2 overexpression impaired HIF activity in vitro. After femoral artery ligation, induction of an endothelial-specific HIF target gene in hind limb muscle was markedly upregulated in mice with endothelial cell deletion of CITED2, suggesting that CITED2 can limit HIF activity in vivo. We conclude that vascular insulin resistance in type 2 diabetes contributes to the upregulation of CITED2, which impairs HIF signaling and endothelial proangiogenic function.

Muscle microvasculature's structural and functional specializations facilitate muscle metabolism.

We review the evolving findings from studies that examine the relationship between the structural and functional properties of skeletal muscle's vasculature and muscle metabolism. Unique aspects of the organization of the muscle microvasculature are highlighted. We discuss the role of vasomotion at the microscopic level and of flowmotion at the tissue level as modulators of perfusion distribution in muscle. We then consider in some detail how insulin and exercise each modulate muscle perfusion at both the microvascular and whole tissue level. The central role of the vascular endothelial cell in modulating both perfusion and transendothelial insulin and nutrient transport is also reviewed. The relationship between muscle metabolic insulin resistance and the vascular action of insulin in muscle continues to indicate an important role for the microvasculature as a target for insulin action and that impairing insulin's microvascular action significantly affects body glucose metabolism.

Role of habitual physical activity in modulating vascular actions of insulin.

What is the topic of this review? This review highlights the importance of increased vascular insulin sensitivity for maintaining glycaemic control and cardiovascular health. What advances does it highlight? We discuss the role of habitual physical activity in modulating vascular actions of insulin. Type 2 diabetes and cardiovascular disease commonly coexist. Current evidence suggests that impaired insulin signalling in the vasculature may be a common link between metabolic and cardiovascular diseases, including glycaemic dysregulation and atherosclerosis. Herein, we highlight the importance of the actions of insulin on the vasculature for glycaemic control and arterial health. In addition, we summarize and discuss findings from our group and others demonstrating that increased physical activity may be an effective approach to enhancing vascular insulin sensitivity. Furthermore, in light of the existing literature, we formulate the hypothesis that increased shear stress may be a prime mechanism through which habitual physical activity improves insulin signalling in the vasculature. Ultimately, we propose that targeting vascular insulin resistance may represent a viable strategy for improving glycaemic control and reducing cardiovascular risk in patients with type 2 diabetes.

Relationship between adiponectin, obesity and insulin resistance.

the conditions of obesity and overweight pose a major risk for a number of comorbidities, including clinical syndromes resulting from atherosclerotic disease. Recent studies strongly indicate that adipose tissue is an active endocrine organ that secretes bioactive factors such as adipokines. Adiponectin appears to have a regulatory role in the mechanism of insulin resistance and in the development of atherosclerosis. This systematic review aims to evaluate the anti-atherogenic effects of adiponectin and its properties to improve and mimic metabolic and vascular actions of insulin and its influence on endothelial function. a qualitative, exploratory and literature review was performed in the PubMed, Portal Capes and Scielo databases using as key-words "adiponectin", "obesity", "insulin resistance", "anti-inflammatory", "therapeutic strategies" and "future prospects". evidence suggests that adiponectin has anti-atherogenic properties with anti-inflammatory effects on the vascular wall. Moreover, it modifies the vascular intracellular signaling and has indirect antioxidant effects on the human myocardium. On the other hand, there are studies suggesting that increased levels of adiponectin are paradoxically associated with a worse prognosis in heart failure syndrome, although the mechanisms are not clear. it is not clear whether adiponectin levels have any clinical significance for risk stratification in cardiovascular disease or if they simply reflect the activation of complex underlying mechanisms. Changes in lifestyle and some drug treatments for hypertension and coronary heart disease have shown significant effect to increase adiponectin levels, and simultaneously decrease in insulin resistance and endothelial dysfunction.

Epoxyeicosatrienoic acids mediate insulin-mediated augmentation in skeletal muscle perfusion and blood volume.

Skeletal muscle microvascular blood flow (MBF) increases in response to physiological hyperinsulinemia. This vascular action of insulin may facilitate glucose uptake. We hypothesized that epoxyeicosatrienoic acids (EETs), a family of arachadonic, acid-derived, endothelium-derived hyperpolarizing factors, are mediators of insulin's microvascular effects. Contrast-enhanced ultrasound (CEU) was performed to quantify skeletal muscle capillary blood volume (CBV) and MBF in wild-type and obese insulin-resistant (db/db) mice after administration of vehicle or trans-4-[4-(3-adamantan-1-ylureido)cyclohexyloxy]benzoic acid (t-AUCB), an inhibitor of soluble epoxide hydrolase that converts EETs to less active dihydroxyeicosatrienoic acids. Similar studies were performed in rats pretreated with l-NAME. CEU was also performed in rats undergoing a euglycemic hyperinsulinemic clamp, half of which were pretreated with the epoxygenase inhibitor MS-PPOH to inhibit EET synthesis. In both wild-type and db/db mice, intravenous t-AUCB produced an increase in CBV (65-100% increase at 30 min, P < 0.05) and in MBF. In db/db mice, t-AUCB also reduced plasma glucose by ∼15%. In rats pretreated with l-NAME, t-AUCB after produced a significant ≈20% increase in CBV, indicating a component of vascular response independent of nitric oxide (NO) production. Hyperinsulinemic clamp produced a time-dependent increase in MBF (19 ± 36 and 76 ± 49% at 90 min, P = 0.026) that was mediated in part by an increase in CBV. Insulin-mediated changes in both CBV and MBF during the clamp were blocked entirely by MS-PPOH. We conclude that EETs are a mediator of insulin-mediated augmentation in skeletal muscle perfusion and are involved in regulating changes in CBV during hyperinsulinemia.

A vascular mechanism for high-sodium-induced insulin resistance in rats

High sodium (HS) effects on hypertension are well established. Recent evidence implicates a relationship between HS intake and insulin resistance, even in the absence of hypertension. The aim of the current study was to determine whether loss of the vascular actions of insulin may be the driving factor linking HS intake to insulin resistance. Sprague Dawley rats were fed a control (0.31% wt/wt NaCl) or HS (8.00% wt/wt NaCl) diet for 4 weeks and subjected to euglycaemic-hyperinsulinaemic clamp (10 mU min(-1) kg(-1)) or constant-flow pump-perfused hindlimb studies following an overnight fast. A separate group of HS rats was given quinapril during the dietary intervention and subjected to euglycaemic-hyperinsulinaemic clamp as above. HS intake had no effect on body weight or fat mass or on fasting glucose, insulin, endothelin-1 or NEFA concentrations. However, HS impaired whole body and skeletal muscle glucose uptake, in addition to a loss of insulin-stimulated microvascular recruitment. These effects were present despite enhanced insulin signalling (Akt) in both liver and skeletal muscle. Constant-flow pump-perfused hindlimb experiments revealed normal insulin-stimulated myocyte glucose uptake in HS-fed rats. Quinapril treatment restored insulin-mediated microvascular recruitment and muscle glucose uptake in vivo. HS-induced insulin resistance is driven by impaired microvascular responsiveness to insulin, and is not due to metabolic or signalling defects within myocytes or liver. These results imply that reducing sodium intake may be important not only for management of hypertension but also for insulin resistance, and highlight the vasculature as a potential therapeutic target in the prevention of insulin resistance.

Abstract 276: Chemerin Decreases Vascular Insulin Signaling.

Proinflammatory adipokines are key mediators of insulin resistance. The adipokine chemerin influences major aspects of the metabolic syndrome, including adipogenesis and glucose homeostasis in adipocytes and skeletal muscle cells. Amongst its many actions insulin also influences vascular function. Considering that chemerin impairs vascular reactivity, and that its effects in the vascular actions of insulin have not been investigated, we postulate that chemerin decreases vascular responses to insulin by reducing PI3K/Akt signaling. Isometric force was recorded in mesenteric arteries from C57Bl6 mice, incubated with chemerin (0.5 ng/mL, 1 h) or vehicle (veh). Chemerin decreased relaxation responses to insulin (0.1 - 3000 ng/mL, pD2: chemerin: 94.5±0.1 vs. veh: 23.6±0,1) and to ACh (pD2: 5.2±0.1 vs. veh 6.6±0.1). Chemerin effects on insulin-induced vasodilatation were reverted by the PI3K activator YS-49 (pD2: veh= 23.0±0.1; chem= 108.5±0.1, YS-49+chem= 28.5±0.1) and by inhibitors of p38 (pD2: veh= 23.0±0.1; chem= 108.5±0.1, SB203580+chem= 27.1±0.1) and ERK1/2 (pD2: veh= 24.6±0.1; chem= 112.0±0.1, PD98059+chem= 25.4±0.1). Chemerin also decreased PI3K [arbitrary units (a.u.): 0.8±0.1 vs. veh 1.1±0.1) and Akt (a.u.: 0.8±0.1 vs. veh 1.2±0.1) phosphorylation in cultured vascular smooth muscle cells (VSMCs). Furthermore, chemerin inhibited insulin-stimulated glucose uptake by VSMCs ([3H] 2-deoxy-glucose (2DG) uptake, counts per minute: 5668±729.0 vs. veh 9923±662.7). In conclusion, chemerin decreases insulin vascular responses by reducing PI3K/Akt signaling and by activating the MAPK pathway. These results suggest that chemerin may be involved in the pathogenesis of vascular insulin resistance. Our study may contribute to a better understanding of the role of factors released by the adipose tissue on insulin vascular responsiveness and, consequently, on the vascular dysfunction in obesity and obesity-associated diseases. Financial Support: FAPESP.

Insulin and insulin-like growth factor-1 inhibit release of endothelin-1 from mouse micro-vascular endothelial cells

Objectives: Type 2 diabetes mellitus (T2DM) is caused by abnormalities of insulin function and Beta-cell failure. T2DM also include aspects of endothelial dysfunction and in human subjects, insulin has been shown to increase leg blood flow through vasodilation with reduced effects in diabetic individuals. Vasodilation by insulin is dependent on the endothelium and dependent on the production of nitric oxide, and recently, a complete signalling pathway in the endothelium linking the insulin receptor (IR) to activation of endothelial nitric oxide synthase (eNOS) through the AKT pathway has been revealed. Insulin has also been suggested through activation of the MAPK pathway to cause vasoconstriction by release of the vasoconstrictor Endothelin-1. The vascular actions of insulin might therefore be a balance of activation of these two pathways AKT and MAPK causing either dilation or constriction, respectively.

Blueberry Tea Enhances Insulin Sensitivity by Augmenting Insulin-Mediated Metabolic and Microvascular Responses in Skeletal Muscle of High Fat Fed Rats

Background: The aim of the current study was to determine whether a unique blueberry tea (BT) ameliorates insulin resistance by improving metabolic and vascular actions of insulin in skeletal muscle. Methods: Male Sprague Dawley rats were fed normal (4.8% fat wt/wt, ND) or high (22.6% fat wt/wt, HFD) fat diets for 4 weeks. A second group of HFD rats was provided BT (4.0% wt/vol) in the drinking water during the final 2 weeks. Animals were subjected to an intraperi toneal glucose tolerance test (1g glucose/kg IPGTT) or euglycaemic hyperinsulinaemic clamp (10mU/min/kg x 2hr). Results: HFD rats displayed significantly (p<0.05) higher plasma glucose levels at 15 and 30 mins following the IPGTT compared to ND, and this increase was completely abolished by BT treatment. Glucose infusion rate, muscle glucose uptake, and microvascular perfusion in muscle were significantly (p<0.05) impaired during clamps in HFD and all markedly improved (p<0.05) with BT treatment. Insulin-mediated changes in femoral artery blood flow were unaffected by HFD or BT treatment. Conclusions: We conclude that BT treatment ameliorates glucose intolerance and insulin resistance by restoring both metabolic and microvascular insulin sensitivity in high fat-fed rats. Therefore, BT consumption may have therapeutic implications for insulin resistance and type 2 diabetes.

Differential vasomotor effects of insulin on gastrocnemius and soleus feed arteries in the OLETF rat model: role of endothelin‐1

The vascular actions of insulin are complex, because it can stimulate both nitric oxide-mediated dilatation and endothelin (ET)-1-mediated constriction. We examined vasoreactivity to insulin in isolated feed arteries of the gastrocnemius (GFA) and soleus muscles (SFA) of 32-week-old Long-Evans Tokushima Otsuka (LETO) and Otsuka Long-Evans Tokushima fatty (OLETF) rats, a hyperphagic rodent model of obesity and insulin resistance. The insulin-induced vasoreactivity of SFA and GFA was similar in LETO (healthy) and OLETF (obese/insulin-resistant) rats. However, examination of between-vessel effects revealed a number of novel insights into the heterogeneous vascular effects of insulin. Soleus feed arteries dilated more than GFA in LETO at 100 and 1000 μIU ml(-1) insulin (23 versus 6 and 28 versus 0%, respectively; P < 0.05 for between-vessel differences). Likewise, in OLETF rats there was significantly greater dilatation in SFA than GFA at 10, 100 and 1000 μIU ml(-1) insulin (28 versus 3, 30 versus 0 and 34 versus 0%, respectively; all P < 0.05). In the presence of 3 μm tezosentan, a non-specific endothelin-1 receptor blocker, insulin-induced dilatation of the GFA was enhanced such that differences between vessels were largely abolished in both groups. Furthermore, acetylecholine-induced dilatation was significantly greater in SFA than GFA within each group, whereas sodium nitroprusside-induced dilatory responses were greater in the GFA compared with the SFA. Overall, our findings indicate that the insulin/endothelin-1 vasoconstrictor pathway is more active in GFA than in SFA, independent of obesity in the OLETF rat model.

Local NOS inhibition impairs vascular and metabolic actions of insulin in rat hindleg muscle in vivo

Insulin stimulates microvascular recruitment in skeletal muscle, and this vascular action augments muscle glucose disposal by ∼40%. The aim of the current study was to determine the contribution of local nitric oxide synthase (NOS) to the vascular actions of insulin in muscle. Hooded Wistar rats were infused with the NOS inhibitor N(ω)-nitro-L-arginine methylester (L-NAME, 10 μM) retrogradely via the epigastric artery in one leg during a systemic hyperinsulinemic-euglycemic clamp (3 mU·min(-1)·kg(-1) × 60 min) or saline infusion. Femoral artery blood flow, microvascular blood flow (assessed from 1-methylxanthine metabolism), and muscle glucose uptake (2-deoxyglucose uptake) were measured in both legs. Local L-NAME infusion did not have any systemic actions on blood pressure or heart rate. Local L-NAME blocked insulin-stimulated changes in femoral artery blood flow (84%, P < 0.05) and microvascular recruitment (98%, P < 0.05), and partially blocked insulin-mediated glucose uptake in muscle (reduced by 34%, P < 0.05). L-NAME alone did not have any metabolic effects in the hindleg. We conclude that insulin-mediated microvascular recruitment is dependent on local activation of NOS in muscle and that this action is important for insulin's metabolic actions.

Distinct Mechanisms for Globular Adiponectin That Integrate Vascular and Metabolic Actions of Insulin to Help Maintain Coordinated Cardiovascular and Glucose Homeostasis

In the current issue of Circulation Research , Zhao et al1 present interesting and important studies describing mechanisms by which insulin and adiponectin interact to integrate cardiovascular and metabolic physiology. The mechanism revealed by these studies uses both parallel and distinct pathways that may have important implications for the pathophysiology of diabetes mellitus, obesity, and their cardiovascular complications, as well as for the development of novel effective therapies in the future. Article, see p 1263 The molecular signaling pathways in skeletal muscle and adipose tissue responsible for direct actions of insulin to enhance glucose uptake and disposal involve activation of the insulin receptor, which then initiates a signaling cascade, involving IRS-1/PI3K/PDK-1/Akt and PKC-ζ, that culminates further downstream in the translocation of insulin response glucose transporters (GLUT4) from intracellular compartments to the cell surface, where GLUT4 acts as a facilitative transporter to drive glucose down its concentration gradient.2,3 Strikingly similar insulin signaling pathways in vascular endothelium involving insulin receptor/IRS-1/PI3K/PDK-1/Akt/eNOS promote increased production of the potent vasodilator nitric oxide that increases blood flow and capillary recruitment leading to increased delivery of the substrate (glucose) and the hormone (insulin) to metabolic targets, including skeletal muscle.4,5 These vascular actions of insulin represent a secondary mechanism for insulin to promote glucose uptake and disposal. Indeed, ≈40% of insulin-stimulated glucose uptake in skeletal muscle may be attributed to vascular actions of insulin in conduit arteries and recruitment of nutritive capillaries.6,7 In addition, the transendothelial transport of insulin has recently been identified as a potential rate-limiting step in metabolic actions of insulin.8–10 Taken together, it is apparent that reciprocal relationships between insulin resistance and endothelial dysfunction help tie together metabolic diseases with their …

Toll-like receptor 2 mediates high-fat diet-induced impairment of vasodilator actions of insulin

Obesity is characterized by a chronic proinflammatory state that leads to endothelial dysfunction. Saturated fatty acids (SFA) stimulate Toll-like receptors (TLR) that promote metabolic insulin resistance. However, it is not known whether TLR2 mediates impairment of vascular actions of insulin in response to high-fat diet (HFD) to cause endothelial dysfunction. siRNA knockdown of TLR2 in primary endothelial cells opposed palmitate-stimulated expression of proinflammatory cytokines and splicing of X box protein 1 (XBP-1). Inhibition of unfolding protein response (UPR) reduced SFA-stimulated expression of TNFα. Thus, SFA stimulates UPR and proinflammatory response through activation of TLR2 in endothelial cells. Knockdown of TLR2 also opposed impairment of insulin-stimulated phosphorylation of eNOS and subsequent production of NO. Importantly, insulin-stimulated vasorelaxation of mesenteric arteries from TLR2 knockout mice was preserved even on HFD (in contrast with results from arteries examined in wild-type mice on HFD). We conclude that TLR2 in vascular endothelium mediates HFD-stimulated proinflammatory responses and UPR that accompany impairment of vasodilator actions of insulin, leading to endothelial dysfunction. These results are relevant to understanding the pathophysiology of the cardiovascular complications of diabetes and obesity.

The vascular endothelium in diabetes—a therapeutic target?

Insulin resistance affects the vascular endothelium, and contributes to systemic insulin resistance by directly impairing the actions of insulin to redistribute blood flow as part of its normal actions driving muscle glucose uptake. Impaired vascular function is a component of the insulin resistance syndrome, and is a feature of type 2 diabetes. On this basis, the vascular endothelium has emerged as a therapeutic target where the intent is to improve systemic metabolic state by improving vascular function. We review the available literature presenting studies in humans, evaluating the effects of metabolically targeted and vascular targeted therapies on insulin action and systemic metabolism. Therapies that improve systemic insulin resistance exert strong concurrent effects to improve vascular function and vascular insulin action. RAS-acting agents and statins have widely recognized beneficial effects on vascular function but have not uniformly produced the hoped-for metabolic benefits. These observations support the notion that systemic metabolic benefits can arise from therapies targeted at the endothelium, but improving vascular insulin action does not result from all treatments that improve endothelium-dependent vasodilation. A better understanding of the mechanisms of insulin's actions in the vascular wall will advance our understanding of the specificity of these responses, and allow us to better target the vasculature for metabolic benefits.

Role of insulin resistance in endothelial dysfunction

Insulin resistance is frequently associated with endothelial dysfunction and has been proposed to play a major role in cardiovascular diseases. Insulin exerts pro- and anti-atherogenic actions on the vasculature. The balance between nitric oxide (NO)-dependent vasodilator actions and endothelin-1- dependent vasoconstrictor actions of insulin is regulated by phosphatidylinositol 3-kinase-dependent (PI3K) - and mitogen-activated protein kinase (MAPK)-dependent signaling in vascular endothelium, respectively. During insulin-resistant conditions, pathway-specific impairment in PI3K-dependent signaling may cause imbalance between production of NO and secretion of endothelin-1 and lead to endothelial dysfunction. Insulin sensitizers that target pathway-selective impairment in insulin signaling are known to improve endothelial dysfunction. In this review, we discuss the cellular mechanisms in the endothelium underlying vascular actions of insulin, the role of insulin resistance in mediating endothelial dysfunction, and the effect of insulin sensitizers in restoring the balance in pro- and anti-atherogenic actions of insulin.