Endothelial dysfunction in (pre)diabetes: Characteristics, causative mechanisms and pathogenic role in type 2 diabetes
Endothelial dysfunction associated with diabetes and cardiovascular disease is characterized by changes in vasoregulation, enhanced generation of reactive oxygen intermediates, inflammatory activation, and altered barrier function. These endothelial alterations contribute to excess cardiovascular disease in diabetes, but may also play a role in the pathogenesis of diabetes, especially type 2. The mechanisms underlying endothelial dysfunction in diabetes differ between type 1 (T1D) and type 2 diabetes (T2D): hyperglycemia contributes to endothelial dysfunction in all individuals with diabetes, whereas the causative mechanisms in T2D also include impaired insulin signaling in endothelial cells, dyslipidemia and altered secretion of bioactive substances (adipokines) by adipose tissue. The close association of so-called perivascular adipose tissue with arteries and arterioles facilitates the exposure of vascular endothelium to adipokines, particularly if inflammation activates the adipose tissue. Glucose and adipokines activate specific intracellular signaling pathways in endothelium, which in concert result in endothelial dysfunction in diabetes. Here, we review the characteristics of endothelial dysfunction in diabetes, the causative mechanisms involved and the role of endothelial dysfunction(s) in the pathogenesis of T2D. Finally, we will discuss the therapeutic potential of endothelial dysfunction in T2D.
KeywordsDiabetes Obesity Insulin Endothelium Intracellular signaling
Diabetes mellitus is a metabolic disease with a high and growing prevalence. Age-standardized prevalence is currently 9.2–9.8 % globally, with an estimated number of ~347 million patients . Type 1 diabetes (T1D) is characterized by an absolute deficiency of insulin attributable to pancreatic insufficiency. Type 2 diabetes (T2D), which accounts for ~90 % of all cases of diabetes, is characterized by insulin resistance, i.e. impairment of insulin-induced whole-body glucose uptake, and a relative insulin deficiency in spite of high plasma levels of insulin . Because of the progressive dysfunction of the pancreatic β-cells, this can eventually lead to an absolute deficiency of insulin for tissues in type 2 diabetes .
Endothelial dysfunction comprises a number of functional alterations in the vascular endothelium, such as impaired regulation of vasodilation and vasoconstriction, impaired or excessive angiogenesis, decreased barrier function and increased inflammatory activation, all of which are associated with cardiovascular disease. In T1D, endothelial dysfunction is predominantly triggered by the metabolic changes related to hyperglycemia. With age, a number of microvascular complications develop in T1D patients, in particular retinopathy, nephropathy, and impaired wound healing . In T2D the relationship between endothelial dysfunction and diabetes is more complex, as endothelial dysfunction starts well before the onset of overt diabetes [4, 5, 6, 7]. Shared mechanisms may underlie endothelial dysfunction and the development of hyperglycemia in T2D, as factors such as dyslipidemia and inflammation of adipose tissue have been linked to both traits [8, 9]. Here, we will review specific aspects and causes of endothelial dysfunction in diabetes. Furthermore, we will discuss the contribution of endothelial dysfunction to the pathogenesis of T2D and its potential as a therapeutic target.
2 Defining diabetes-specific endothelial dysfunction
Endothelial dysfunction can be defined as impairment of one or more endothelial functions. In insulin resistance and diabetes, a variety of endothelial functions is compromised, including regulation of vascular tone [10, 11, 12, 13, 14, 15] and organ perfusion [16, 17], inhibition of inflammation , transendothelial transport of blood solutes , prevention of coagulation  and initiation of angiogenesis and arteriogenesis [20, 21]. In the present review, we will review the specific changes in endothelial function associated with insulin resistance and diabetes and the signaling pathways within endothelial cells that are involved in these alteration, and will discuss the potential of vascular endothelium as a target for prevention of diabetes (type 2) as well as complications of diabetes.
Three facets of the pathogenesis of diabetes can induce specific changes in endothelial signaling and function. These are impairment of insulin signaling, accumulation and inflammation of (ectopic) fat and hyperglycemia. These three factors all directly affect endothelial function, through impairment of insulin-stimulated vasodilatation and effects of adipokines on vascular endothelium and accumulation of glucose and glycated proteins in endothelial cells. We will discuss the relationship of these three facets of diabetes to altered endothelial properties.
3 Impairment of insulin signaling in vascular endothelium
Vascular insulin resistance, i.e. resistance to insulin-mediated vasodilatation, is characteristic of insulin resistant humans [4, 16, 34] and has been demonstrated in animal models of obesity [15, 35, 36] and hypertension . Insulin resistance and impaired insulin-mediated vasodilatation are associated with hypophosphorylation of Akt and eNOS , whereas insulin’s vasoconstrictor effects are intact in insulin resistance [15, 36, 37, 38]. Altered signaling by the insulin receptor substrates is critical to this impairment. Downregulation of IRS-1 and IRS-2 has been observed in insulin resistance [32, 36] and indeed, deletion of IRS-2 in vascular endothelium results in vascular dysfunction . IRS1-deficient mice have been reported to show impaired endothelium-dependent vasodilatation [39, 40]. Furthermore, we have observed impaired insulin-stimulated activation of eNOS in femoral arteries of IRS1−/− mice (W Bakker, E Eringa et al., unpublished data).
3.1 Intracellular control of endothelial insulin signaling
A number of intracellular mechanisms have been identified that inhibit insulin signaling in vascular endothelium. Inhibition of insulin signaling in endothelial cells can occur at the level of the insulin receptor and the insulin receptor substrates or downstream of the insulin receptor signaling proteins, at the level of Akt, eNOS or through NO scavenging by reactive oxygen species. At the level of the insulin receptor, the receptor for insulin-like growth factor 1 (IGF-1) has been shown to form hybrid receptors with the insulin receptor with a reduced activity [36, 41, 42]. At the level of the IRS proteins, several kinases have been shown to inhibit insulin signaling through phosphorylation of IRS1. They include c-jun N-terminal kinase (JNK) , the protein kinase C isoform theta (PKCθ) [44, 45, 46], p38 mitogen-activated kinase (p38 MAPK) , and IκB kinase (IKK). These kinases target specific serine residues at IRS1, such as Ser 307 (JNK) [43, 49] and Ser 504, 532  and 1101 (PKCθ) .
The PKC isoform PKCβ has previously been linked to vascular dysfunction in diabetes , and inhibition of PKCβ was recently reported to improve insulin signaling in man . In T2D, inhibition of PKCβ was shown to enhance insulin-stimulated eNOS phosphorylation at Ser 1177, which showed a positive correlation with flow-mediated vasodilatation . Interestingly, basal phosphorylation of eNOS was increased in diabetic patients, and this was also reversed after PKCβ inhibition . In another recent study on interaction between PKCβ and insulin in the vessel wall, PKCβ was found to decrease insulin-stimulated eNOS activity by controlling the localization of Akt and eNOS. This change in Akt localization is dependent on inhibition of β-arrestin 2 by G Protein–Coupled Receptor Kinase 2 (GRK2).
Although less intensely investigated, insulin’s vasoconstrictor effects are also regulated by specific intracellular signaling cascades. The multi-domain adaptor protein APPL1 has been shown to inhibit insulin-stimulated ET-1 synthesis by decreasing the phosphorylation of raf-1, which mediates insulin-induced activation of ERK1/2 and ET-1 release from endothelial cells . APPL1 overexpression was also found to restore insulin-mediated vasoreactivity in high fat diet-induced obese mice . In recent research on muscle resistance arteries using the AMPK agonists AICAR and globular adiponectin, we have found that AMPK activation enhances insulin-mediated vasodilatation by inhibiting insulin-mediated activation of ERK1/2 (MP de Boer and EC Eringa, unpublished data). These studies show that regulation of insulin signaling in endothelial cells occurs at multiple levels of signaling from the insulin receptor to eNOS and ERK1/2 (see Fig. 1 for an overview of regulation of insulin signaling in endothelial cells). The balance between the activities of these regulatory pathways ultimately determines the effects of insulin on vascular endothelium.
4 (Perivascular) Adipose tissue control of endothelial signaling and function
Adipose tissue, especially in the abdomen (intra-abdominal adipose tissue, AAT) and around blood vessels (perivascular adipose tissue, PVAT)  has been shown to control insulin sensitivity , endothelial function , especially insulin-mediated vasoreactivity [35, 43, 44, 55, 56]. Adipose tissue secretes a wide variety of bioactive substances (adipokines) that act directly on vascular endothelium , and the list is still growing . Examples of adipokines relevant to endothelial (dys)function are adiponectin [59, 60, 61], leptin , fatty acids [5, 44, 48] and reactive oxygen species [63, 64, 65, 66].
With regard to endothelial function, PVAT is increasingly recognized as a critical fat depot that regulates local vascular tone  and inflammation [67, 68]. We and others have shown that PVAT stimulates endothelium-dependent vasodilatation, and that this function of PVAT is impaired in obesity and T2D [61, 69, 70]. PVAT consists of adipocytes, fibroblasts, stem cells , inflammatory cells [72, 73] and nerves . In obesity PVAT expands, in parallel to growth of intra-abdominal adipose tissue [74, 75]. The mechanisms involved in the expansion of perivascular adipose tissue involve differentiation of resident mesenchymal stem cells/preadipocytes as well as infiltration and differentiation of stem cells from bone marrow. The conversion of stem cells/preadipocytes to adipocytes can be triggered by activation of PPARγ , and can be inhibited by the Wnt signaling pathway and preadipocyte factor 1 (pref-1) .
In obesity and atherosclerosis, infiltration of PVAT by immune cells such as macrophages and T lymphocytes has been shown in the aorta [78, 79, 80], and this inflammation is a critical determinant of vasodilator properties of PVAT [61, 69, 70]. Accumulation of T lymphocytes may trigger expansion of perivascular adipose tissue as T cells stimulate adipogenesis by production of the natural PPARγ activator 15d-PGJ2 . In addition to T lymphocytes, mast cells have also been shown to control adipose tissue expansion and insulin sensitivity . The pro-adipogenic effect of mast cells may also be mediated by PPARγ, as mast cells secrete 15d-PGJ2 . Macrophages do not affect the quantity of PAT, but produce cytokines that alter the secretion of adipokines by PVAT . Interestingly, endothelium-specific inhibition of NFκB signaling improves muscle blood flow, insulin sensitivity and life span in mice , further substantiating the role of inflammation in the control of muscle perfusion and insulin sensitivity.
We have recently shown that PVAT controls insulin-stimulated vasodilation in muscle resistance arteries through two antagonistic signaling pathways: a vasodilator pathway mediated by adiponectin and 5′AMP-activated protein kinase (AMPK) and an inflammatory pathway mediated by c-jun N-terminal kinase (JNK) . Remarkably, acute inhibition of JNK activity using a cell-permeable peptide fully restored insulin-mediated vasodilatation in the presence of PVAT of type 2 diabetic db/db mice. This indicates that inflammation of PVAT is an important step in determining endothelium-dependent vasodilatation in obesity and T2D.
It should be noted that adipose tissue inflammation may not only contribute to endothelial dysfunction, but hypoperfusion of adipose tissue and the resulting hypoxia may also trigger inflammation and alter adipokine secretion [61, 84, 85]. Indeed, impaired perfusion of adipose tissue is statistically related to insulin resistance in man . As such, adipose tissue inflammation and endothelial dysfunction may form a positive feedback loop in obesity-related insulin resistance.
5 Exercise-like signaling in vascular endothelium: 5′AMP-activated protein kinase
Aside from its role in PVAT signaling, the “exercise kinase” AMPK  can be activated by a variety of stimuli including metformin  and shear stress , and has been shown to control several endothelial functions. These include NO-dependent vasodilatation and muscle perfusion [90, 91], angiogenesis  and inflammation . AMPK regulates eNOS activity by phosphorylation at two serine residues, Ser 633  and Ser 1177 [90, 95], and by stimulating the association of eNOS with heat-shock protein 90 . Mice deficient in one of the kinase subunits of AMPK, AMPKα2, display enhanced vascular inflammation and accelerated atherosclerosis . Moreover, the AMPK agonist and exercise mimetic 5-Aminoimidazole-4-Carboxamide 1-β-D-Ribofuranoside (AICAR) , enhances NO production, perfusion [90, 96] and insulin sensitivity  in muscle. To what extent the microvascular effects of AICAR contribute to its metabolic effects remains to be assessed. In conclusion, AMPK carries significant potential as a part of exercise-mimicking therapies, but its role in the pathogenesis of endothelial dysfunction in human diabetes has not been fully elucidated.
6 Effects of hyperglycemia and advanced glycation endproducts on endothelial function
Hyperglycemia is a well-known cause of endothelial dysfunction in diabetes, and overproduction of reactive oxygen species (ROS) is critical to effects of hyperglycemia on vascular endothelium [98, 99]. For an overview of hyperglycemia-induced endothelial dysfunction, the reader is referred to an excellent review by Giacco and Brownlee . Earlier, Michael Brownlee brought several pathways that were activated by hyperglycemia together in one mechanism, in which enhanced generation of superoxide causes sequentially PARP activation, inhibition of GAPDH and accumulation of glycolysis intermediates. In the rodents subsequent studies showed that interference of superoxide generation or reduction of these glycolysis intermediates by activation of the pentose phosphate shunt improved endothelial microvasular function [100, 101]. One of the major mechanisms underlying hyperglycemia-induced endothelial dysfunction is formation of advanced glycation endproducts (AGEs), which have been demonstrated to trigger proinflammatory changes and decrease NO activity through peroxynitrite formation from NO and ROS . Aside from formation of AGEs in the circulation, intracellular accumulation of the AGE intermediate methylglyoxal (MGO) is critical to impairment of endothelium-dependent vasorelaxation by hyperglycemia . Overexpression of glyoxalase-1 (GLO-1), the enzyme that degrades MGO, rescued relaxation to acetylcholine in diabetic rats [99, 103] and prevented vascular degeneration in the retina .
7 Roles of endothelial dysfunction in the pathogenesis of type 2 diabetes
Aside from its role in cardiovascular complications in diabetes, altered functioning of vascular endothelium has been implicated in a number of aspects of the pathogenesis of diabetes. These include insulin resistance, lipotoxicity, and impaired insulin secretion.
7.1 Endothelial insulin signaling, insulin transport across vascular endothelium and insulin resistance
Insulin action in endothelial cells is thought to determine the net transport of insulin from the blood across vascular endothelium to the muscle interstitium and ultimately, the myocytes [105, 106]. Proof for this concept has been obtained in a series of elegant studies by the groups of Barrett, Clark and Bergman [107, 108, 109]. Two endothelial effects of insulin are relevant to this process: regulation of the endothelial surface area and transendothelial insulin transport .
In spite of the demonstration that insulin access to myocytes determines insulin sensitivity, the quantitative contribution of these effects of insulin to insulin resistance has been uncertain until recently. Therefore, several models of impaired endothelial insulin signaling have been used: mice lacking insulin receptors in vascular endothelium and mice lacking IRS1 and/or IRS2 in vascular endothelium. Surprisingly, these models have yielded somewhat divergent results regarding insulin sensitivity. Vascular endothelium-specific insulin receptor knockout (VENIRKO) mice as well as mice with expressing a dominant-negative mutant insulin receptor (ESMIRO mice) are not insulin resistant [110, 111], despite a 30–60 % decrease in eNOS expression. In contrast, endothelium-specific deletion of IRS2 in endothelium results in a ~50 % decrease in insulin sensitivity . Interestingly, endothelium-specific deletion of IRS1 did not decrease insulin sensitivity in that study. A satisfactory explanation for the discrepancy between the effects of endothelium-specific deletion of the insulin receptor and IRS2 on insulin sensitivity is not yet available, but two things should be considered. First, IRS proteins are activated by factors other than insulin, such as IGF1  and leptin . Therefore, the physiological effects of IRS deletion may be stronger than that of IR deletion. Second, deletion of the insulin receptor in vascular endothelium not only reduces expression of eNOS, but also reduces expression of the potent vasoconstrictor ET-1 by ~40 % . Therefore, a decrease in insulin sensitivity resulting from impaired eNOS activity  may be masked by impairment of insulin’s vasoconstrictor effects in endothelium-specific IR knockout mice. In support, ET-1 has been shown to reduce insulin sensitivity in man  and reducing ET-1 activity increases insulin sensitivity in obese subjects [116, 117].
7.2 Endothelial lipid transport as a determinant of lipotoxicity-induced insulin resistance and type 2 diabetes
Accumulation of lipid in skeletal muscle, the myocardium and the liver are important causes of impaired insulin-stimulated glucose uptake in these tissues . Two recent studies have demonstrated that vascular endothelial growth factor B (VEGF-B) and regulation of lipid transport across vascular endothelium are critical determinants of lipid accumulation in muscle, heart and even liver, a tissue with a relatively permeable endothelial barrier [119, 120]. Moreover, inhibiting VEGF-B expression was sufficient to prevent T2D, restore insulin sensitivity and preserve beta cell morphology in db/db mice and mice fed a high-fat diet. These fascinating data show that lipid transport across vascular endothelium determines susceptibility to ectopic lipid accumulation and the associated progression of T2D.
7.3 Endothelial dysfunction as a determinant of insulin secretion
A relative insufficiency of pancreatic insulin secretion is the hallmark of T2D . It has long been assumed that insulin secretion by the pancreas was only determined by metabolic regulation of the beta cells. Nevertheless, vascular endothelium has recently been shown to play an important additional regulatory role in pancreatic insulin secretion. First, decreased islet vascularization was shown to precede reduced insulin secretion by the pancreas in a rat model of T2D . Second, in the studies on VEGF-B controlled lipid transport across vascular endothelium mentioned above, inhibition of VEGF-B by a monoclonal antibody increased insulin secretion in the pancreas by limiting lipid accumulation in beta cells . Finally, expression of the glycoprotein thrombospondin-1 by endothelial cells in the pancreas is necessary for normal glucose-stimulated insulin secretion . This regulatory role of thrombospondin-1 is mediated by transforming growth factor beta (TGFβ), as overexpression of TGFβ restored insulin secretion in TSP-1−/− deficient mice. Taken together, these data suggest that the vascular endothelium regulates insulin secretion by controlling lipid access to beta cells, maintaining adequate blood supply and stimulating local TGFβ activity. The contribution of these processes to insulin secretion in man has yet to be determined.
8 Impaired endothelial insulin signaling and atherosclerosis
Impairment of intracellular insulin signaling is a hallmark of insulin resistance and T2D, and is associated with accelerated atherosclerosis. Downregulation of IRS-1 and IRS-2, critical mediators of insulin signaling in endothelium [31, 32] has been observed in insulin resistance [32, 36]. In genome-wide association studies genetic variation in the IRS1 promoter has been linked to both T2D and risk of early myocardial infarction [123, 124, 125], suggesting a causal link between insulin signaling defects and cardiovascular disease. To provide a mechanistic explanation for this association, a recent study in ApoE−/− mice, a mouse model of atherosclerosis, showed that genetic deletion of insulin receptors in vascular endothelium induced a >2-fold increase in atherosclerotic lesion size. This effect of vascular insulin resistance was associated with reduced Ser 1177 phosphorylation of eNOS and enhanced vascular inflammation. Taken together, these data strongly suggest that impairment of vascular effects of insulin is a useful target for prevention of cardiovascular complications in T2D.
9 The vascular endothelium as a therapeutic target in diabetes
Effects of interventions in endothelium-dependent signaling and their effect on insulin sensitivity and fasting glucose. PDE5, phosphodiesterase 5; ETR, endothelin receptor
Increasing NO bioactivity can be achieved by inhibiting phosphodiesterase 5 (PDE5-) activity , increasing dietary intake of nitrate  or overexpression of eNOS . As a proof of concept, the PDE5 inhibitor sildenafil has been shown to improve insulin sensitivity in diet-induced insulin-resistant mice [131, 134]. Dietary supplementation of nitrate can also increase NO bioavailability, and has been found to improve insulin sensitivity in eNOS-deficient mice . Interesting, overexpression of eNOS in mice potently induced weight loss, but did not improve insulin sensitivity and even increased fasting glucose .
Decreasing ET-1 activity using endothelin receptor blockers (ETRBs) has been shown to improve endothelium-dependent vasodilatation, muscle blood flow and insulin sensitivity in human insulin resistance and T2D [115, 117].
Exercise, one of the best known and effective strategies for preventing T2D and cardiovascular disease , also antagonizes ET-1-induced decreases in leg blood flow, providing a physiological way to decrease endothelin activity [136, 137]. As mentioned above, effects of exercise may be mimicked by AMPK agonists such as AICAR.
Vascular insulin signaling can be improved using inhibitors of protein kinase C (PKC), such as ruboxistaurin . Especially PKCβ has emerged as a promising target, and PKC inhibition has been shown in multiple studies in mice and humans to improve endothelial insulin signaling, nitric oxide synthesis and barrier function in diabetes [51, 138, 139]. In addition, PKCθ has been shown to impair endothelial insulin signaling and may be an additionally relevant PKC isoform for improving endothelial function [44, 46], but evidence in humans has yet to be obtained.
As argued above, inhibiting endothelial lipid transport is a promising goal for diabetes prevention and management. The beneficial effect of VEGF-B inhibition on lipid accumulation in muscle, liver and the pancreas has been described in mice, and awaits proof-of-concept studies in man. These data further support the potential of improving endothelial barrier function for treating T2D and it cardiovascular complications.
Finally, while cardiovascular disease and diabetes are consensus clinical end points, strategies aimed at increasing insulin resistance should be carefully designed. Insulin resistance is a common occurrence in the general population and in patients and may be beneficial in conditions of metabolic stress such as fasting, growth and trauma . Therefore, the chance of harmful side effects of increasing insulin sensitivity should be considered when devising new therapies for diabetes prevention.
In conclusion, altered functioning of the vascular endothelium, characterized by altered regulation of vascular tone and tissue perfusion, altered barrier function and increased activity of inflammatory signaling, is a highly relevant mechanism linking the pathogeneses of diabetes and cardiovascular disease. Obesity, insulin resistance and diabetes are characterized by specific impairments in endothelial cell signaling and function, which provide promising targets for prevention of both diabetes and its cardiovascular complications.
ECE is sponsored by the Netherlands Organization for Scientific Research (Grant 916.76.179) and EHS is supported by the Netherlands Heart Foundation (Grant 2009B098).
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