Review

The Vasculature in Prediabetes

David H. Wasserman, Thomas J. Wang, Nancy J. Brown
https://doi.org/10.1161/CIRCRESAHA.118.311912
Circulation Research. 2018;122:1135-1150
Originally published April 12, 2018

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Abstract

The frequency of prediabetes is increasing as the prevalence of obesity rises worldwide. In prediabetes, hyperglycemia, insulin resistance, and inflammation and metabolic derangements associated with concomitant obesity cause endothelial vasodilator and fibrinolytic dysfunction, leading to increased risk of cardiovascular and renal disease. Importantly, the microvasculature affects insulin sensitivity by affecting the delivery of insulin and glucose to skeletal muscle; thus, endothelial dysfunction and extracellular matrix remodeling promote the progression from prediabetes to diabetes mellitus. Weight loss is the mainstay of treatment in prediabetes, but therapies that improved endothelial function and vasodilation may not only prevent cardiovascular disease but also slow progression to diabetes mellitus.

Prediabetes is characterized by hyperglycemia that falls below the level used to define diabetes mellitus. As the prevalence of obesity grows worldwide, the prevalence of prediabetes is also increasing. In the United States, >38% of adults have prediabetes.1 In China, the prevalence of prediabetes among adults reaches 50%.2 Without intervention, prediabetes often progresses to diabetes mellitus, and prediabetes is associated with increased risk of cardiovascular disease, cancer, renal disease, and dementia. Although indices of hyperglycemia define clinical criteria for prediabetes, vascular dysfunction results not only from effects of hyperglycemia but also from vascular insulin resistance and from proinflammatory and metabolic consequences of attendant obesity. In insulin resistance, muscle, fat, liver, and vascular cells do not respond normally to insulin. This may result from abnormal insulin signaling, but insulin resistance can also result from vascular endothelial dysfunction which leads to decreased delivery of insulin and glucose to insulin-sensitive tissues, as detailed below. Increased inflammation associated with obesity promotes endothelial dysfunction, ECM (extracellular matrix) formation, and changes in capillary density and glucose uptake, further promoting insulin resistance. Hyperglycemia ensues when insulin -production cannot overcome insulin resistance.

Definition of Prediabetes

The American Diabetes Association (ADA) defines prediabetes based on any one of 3 criteria: fasting plasma glucose of ≥5.6 mmol/L but <7.0 mmol/L (100–125 mg/dL; impaired fasting glucose [IFG]), a 2-hour glucose of ≥7.8 mmol/L but <11.1 mmol/L during a 75 g oral glucose tolerance test (GTT) (140–199 mg/dL; impaired glucose tolerance [IGT]), or a plasma hemoglobin (Hb) A1c of ≥5.7% but <6.5%.3 The World Health Organization uses a higher cutoff for fasting plasma glucose (6.1 mmol/L or 110 mg/dL) and does not include the HbA1c criterion.4 Clinicians do not typically test for insulin resistance, but insulin resistance may be estimated from fasting insulin and glucose, by the homeostasis model assessment of insulin resistance [(insulin × glucose)/22.5].

Heterogeneity of Prediabetes

Based on the classification criteria, prediabetes is a heterogeneous disorder. Hyperglycemia and insulin resistance are the common threads of this condition, however. Glucose clamps and intravenous GTT have been used to elucidate the causes of IFG and insulin resistance in patients and preclinical models. The glucose clamp technique tests β-cell insulin secretory function by clamping at elevated glucose concentrations (≈10 mmol/L) or insulin sensitivity by clamping glucose at fasting levels during an insulin infusion (eg, insulin dose of 40 mU/(m2·min)).5 Glucose is clamped using a glucose infusion, which is varied based on feedback from frequent blood glucose measurements. If insulin is infused, the glucose infusion rate required to maintain euglycemia reflects insulin sensitivity. Subjects who are insulin-resistant require less glucose at a fixed insulin dose than subjects with normal insulin sensitivity,6 and subjects with prediabetes require more glucose than a subject with overt type 2 diabetes mellitus (T2DM).6,7 Stable or radioactive isotopes of glucose can be given during a hyperinsulinemic, glucose clamp to distinguish between insulin’s effect on glucose appearance in the blood (liver effect) and glucose disappearance (primarily muscle).8 The liver responds more rapidly and to lower insulin concentrations than skeletal muscle. The insulin dose during a clamp should target insulin concentrations obtained during a meal high in carbohydrates (≈500 pmol/L). Insulin effects on vascular endothelium, adipocytes, and other tissues can also be examined during an insulin clamp. Intravenous GTT with frequent blood insulin and glucose sampling when combined with the Minimal Model described by Bergman et al9,10 can be used to estimate the roles of the insulin secretory response, insulin-dependent actions, and insulin-independent effects in response. As with any model, results must be considered in light of the assumptions and parsimony of the model. Detailed phenotyping studies using clamps or intravenous GTT suggest that IFG is characterized primarily by impaired hepatic insulin sensitivity and a decrease in the first-phase insulin response, whereas IGT is characterized by impaired muscle insulin sensitivity as well as early- and late-phase insulin responses.11–14 In addition, many patients with prediabetes also have metabolic syndrome, characterized by IFG, hypertension, abdominal obesity, and dyslipidemia (hypertriglyceridemia and low high-density lipoprotein cholesterol).15

Risk of Progression to T2DM

Insulin resistance precedes the development of hyperglycemia and T2DM and results in compensatory hyperinsulinemia. IGT and T2DM ensue when β-cell function fails to compensate.16

In a meta-analysis of prospective studies examining rates of progression to diabetes mellitus published prior to 2004, the incidence of diabetes mellitus was 4% to 6% in individuals with IGT alone, 6% to 9% in individuals with isolated IFG, and 15% to 19% in individuals with both IGT and IFG.17 In general, HbA1c measurement has less predictive value. In the Diabetes Prevention Program (DPP), the annual incidence of diabetes mellitus in patients with IGT was 11% in the control group.18 In the Multi-Ethnic Study of Atherosclerosis, the incidence of diabetes mellitus was 4% in individuals with IFG.19 In the Toranomon Hospital Health Management Center Study, 7% of individuals who met HbA1c criteria and 9% of individuals with IFG progressed to diabetes mellitus.20 In a population-based Rotterdam Study of adults aged 45 years, 75% of patients with IFG progressed to T2DM over their lifetime.21 In the China Da Qing Diabetes Prevention Study, 90% of participants with IGT developed T2DM over 20 years.22

Risk of Cardiovascular and Renal Disease in Prediabetes

Even before the development of diabetes mellitus, prediabetes is associated with increased risks of macrovascular disease, nephropathy, neuropathy, cancer, and dementia. We focus here on macrovascular complications and later on microvascular disease. In the Emerging Risk Factors Collaboration study, there was a linear relationship between glucose and the hazard ratio for coronary heart disease in nondiabetics with a fasting glucose >5.5 mmol/L (100 mg/dL).23 In a meta-analysis of observational studies, Ford et al24 estimated a relative risk of cardiovascular disease of 1.20 (95% confidence interval, 1.12–1.28) when 6.1 mmol/L (110 mg/dL) was used to define IFG (IFG-World Health Organization) and a relative risk of 1.18 (95% confidence interval, 1.09–1.28) when 5.6 mmol/L (IFG-ADA) was used. The relative risk associated with IGT was similar. In a more recent meta-analysis, Huang et al25 reported a relative risk of cardiovascular disease of 1.13, 1.26, and 1.30 in IFG-ADA, IFG-World Health Organization, and IGT, respectively. The relative risk of all-cause mortality was 1.13, 1.13, and 1.32 in the same three groups. Increases in HbA1c that met the ADA definition of prediabetes were associated with increased risk of cardiovascular disease and coronary heart disease but not with stroke or all-cause mortality. In the ARIC study (Atherosclerosis Risk in Communities), patients with prediabetes (HbA1c 5.7%–6.4%) were 30% more likely to be hospitalized than nondiabetics.26

Among patients with prediabetes, factors associated with insulin resistance including increased oxidative stress, inflammation, and dyslipidemia contribute to microvascular and macrovascular disease. Lowering glucose without addressing the vascular effects of insulin resistance may be insufficient to reduce risk of cardiovascular events.27 Conversely, phenotypes of insulin resistance such as the presence of nonalcoholic fatty liver disease or visceral obesity predict atherosclerosis.28

Endothelial Vasodilator Dysfunction in Prediabetes

The vascular endothelium regulates vascular permeability and tone and protects against intravascular thrombosis. Endothelial dysfunction is characterized by a loss of vasodilation in response to sheer stress induced by release of an occlusive cuff (flow-mediated dilation) or pharmacological stimuli causing nitric oxide (NO) synthase activation such as acetylcholine or bradykinin.29 Methods for measuring endothelial vasodilator function are reviewed elsewhere.29 Endothelial dysfunction occurs early in the pathogenesis of atherosclerosis and predicts future cardiovascular events.30–32 In hyperglycemia, endothelial vasodilator dysfunction precedes the development of T2DM and is seen in both IFG and IGT.33–36

Insulin vasodilates skeletal muscle6,37 and coronary38,39 vasculature. Insulin resistance contributes to endothelial dysfunction in prediabetes (Figure 1). Insulin induces NO-dependent vasodilation in skeletal muscle via stimulation of the insulin receptor, activation of IRS-1 (insulin receptor substrate-1), PI3K (phosphatidylinositol 3 kinase), phosphorylation of Akt, and subsequent phosphorylation of endothelial NO synthase (eNOS).40–44 Counteracting this, insulin stimulates ET-1 (endothelin-1) production via raf-1, MAPK (p38 mitogen-activated protein kinase)/MEK (MAPK/ERK kinase), and ERK1/2 (extracellular signal-regulated kinase 1/2).44–47 Vascular insulin resistance leads to downregulation of IRS-1 and -2 and decreased phosphorylation of Akt and eNOS, whereas the ET-1 pathway remains unaffected.48,49 Insulin also increases adipose tissue blood flow,50 but the mechanism seems to be different than for other insulin-sensitive tissues. Local insulin administration has no effect on adipose tissue blood flow,51 and glucose-stimulated vasodilation is β-adrenergic receptor dependent and independent of eNOS.52

Figure 1.
Figure 1.

Endothelial insulin resistance, hyperglycemia and the formation of advanced glycation products, and increased free fatty acids (FFAs) give rise to oxidative stress, inflammation and endothelial vasodilator, and fibrinolytic dysfunction in prediabetes. PAI-1 indicates plasminogen activator inhibitor-1; RAAS renin–angiotensin–aldosterone system; and VAT, visceral adipose tissue.

Hyperglycemia per se influences endothelial function in prediabetes. Because endothelial cells take up glucose through the insulin-independent carrier GLUT-1 (glucose transporter 1),53 intracellular glucose concentrations reflect plasma glucose concentrations. Excess glucose is metabolized through the polyol pathway to fructose and its metabolites, which are potent glycating agents.54 In glycation, the aldehyde group of reducing sugars bind nonenzymatically to proteins to form a Schiff base which can rearrange into a stable ketoamine or Amadori product.55 Increased glycohemoglobin or HbA1c is one criterion used to define prediabetes by the ADA. Glycation is less in prediabetes than that defining diabetes mellitus. A high hemoglobin glycation index, defined as the measured HbA1c minus a predicted HbA1c calculated from blood glucose, has been associated with cardiovascular disease in treatment-naïve patients with prediabetes and diabetes mellitus.56 This suggests that the negative effects of glycation pertain to prediabetes as well as diabetes mellitus.

Early-stage glycation products undergo a series of reactions including oxidation, dehydration, and condensation to form advanced glycation products (AGEs).55 AGEs activate the ERK, JNK (c-Jun N-terminal kinase), p38, and PI3K pathways and promote activation of NF-κB (nuclear factor-κB).57–59 Binding of AGEs to the RAGE (receptor for AGE) enhances the expression of adhesion molecules on endothelial cells to promote the migration and differentiation of monocytes into macrophages.60 AGEs also stimulate monocytes to secrete inflammatory cytokines such as TNF (tumor necrosis factor)-α and IL (interleukin)-6.61 Glycated low-density lipoprotein cholesterol, once oxidized or AGE-modified, is recognized by scavenger receptors on macrophages and leads to the formation of foam cells.62 Glycation of complex III proteins enhances mitochondrial superoxide production.63 In addition, activation of the polyol pathway leads to NADPH depletion and reduced concentration of the antioxidant glutathione.64 Increased intracellular NADH leads to an increase in glycerol-3-phosphate and activation of PKC (protein kinase C).65 Activated PKC in turn promotes oxidative stress by activating NADPH oxidase.66,67 Activated PKC contributes to endothelial dysfunction,68,69 increased endothelial permeability,70 and ECM expansion.71 During hyperglycemia, excess shunting of glucose through the hexosamine pathway results in the O-GlcNAcylation of serine and threonine residues on proteins; O-GlcNAcylation of eNOS at Ser 1177 decreases its activity.72

Increased free fatty acids (FFAs) also contribute to insulin resistance and endothelial dysfunction in obese patients with prediabetes. High fat intake induces endothelial dysfunction in mice,73 and consumption of a meal high in fat acutely decreases brachial artery reactivity in humans.74 FFAs reduce tyrosine phosphorylation of IRS-1/2 and inhibit the PI3K/Akt pathway, leading to decreased glucose transport and decreased phosphorylation of eNOS.75–77 FFAs also reduce ATP-induced mobilization and influx of calcium in endothelial cells.78 FFAs activate NADPH oxidase via PKC to generate reactive oxygen species.66 The generation of reactive oxygen species in turn promotes inflammation by activating NF-κB. FFAs also induce production of HMGB1 (high mobility group box 1), resulting in activation of the NLRP3 (nucleotide-binding domain and leucine-rich repeat-containing [NLR] family and the PYHIN [pyrin and HIN domain]) inflammasome.79 Interestingly, DPP4 (dipeptidyl peptidase-4) inhibition prevents the amino-terminus degradation of HMGB1.80

Inflammation associated with visceral obesity contributes to insulin resistance and endothelial dysfunction in many patients with prediabetes. Visceral adipose tissue has an increased number of adipose resident macrophages.81,82 The total number of T cells, B cells, neutrophils, and mast cells is also increased, whereas the number of Th2 (T-helper) and Treg (regulatory T cells) is unchanged or decreased. Under stimulation by B cells, effector T cells and Th1 cells release cytokines such as interferon-γ to further stimulate activation of macrophages and induce a shift in macrophages from an M2-like phenotype to an M1-like phenotype.83 M1-like macrophages secrete inflammatory cytokines such as TNF-α and IL-6, and studies in M1-like macrophage knockout mice suggest they also promote insulin resistance.84 Although macrophages are distributed throughout lean adipose tissue, lipid-laden macrophages accumulate in crown-like structures around dead adipocytes.85,86 The presence of these crown-like structures is associated with inflammation and insulin resistance.87

Adipose tissue also influences systemic endothelial function through secretion of inflammatory cytokines such as TNF-α, IL-6, leptin, and resistin.88 While leptin suppresses appetite and enhances energy expenditure, it also stimulates proinflammatory immune cells, increases reactive oxygen species production by endothelial cells, and facilitates formation of foam cells.89–91 In humans, resistin concentrations are increased in prediabetes, and elevated resistin concentrations are associated with cardiovascular events.92–94 The best studied anti-inflammatory adipokine is adiponectin. Adiponectin concentrations decrease with increased visceral obesity,95,96 and reduced adiponectin concentrations are associated with increased inflammation and risks of diabetes mellitus and cardiovascular disease.88,97,98 In patients with IGT in the DPP, intensive lifestyle modification increased adiponectin and decreased CRP, IL-6, fibrinogen, and adhesion molecules e-selectin and ICAM-1 (intercellular adhesion molecule-1), as well as insulin resistance.99 Increases in adiponectin were also associated with increases in HDL-cholesterol particle size.99 In the Nurses’ Health Study, increased e-selectin and ICAM-1 concentrations independently predicted incident diabetes mellitus.100

Activation of the renin–angiotensin–aldosterone system in obesity further accentuates vascular insulin resistance. Angiotensin II causes serine (Ser307) phosphorylation and degradation of IRS-1 via the proto-oncogene tyrosine–protein kinase Src.101 Aldosterone induces degradation of IRS-1 in vascular smooth muscle cells via a mineralocorticoid receptor–, reactive oxygen species–, and Src-dependent mechanism.102 Aldosterone also increases IGF (insulin-like growth factor)-1 receptor expression and hybridization, with IRS-1 leading to insulin resistance.103 Aldosterone enhances angiotensin II–stimulated ERK1/2 phosphorylation in vascular smooth muscle cells.104

Impaired endothelium-dependent vasodilation results not only in impaired macrovascular function but also in microvascular dysfunction, as measured by retinal artery vasodilation and heat-induced skin hyperemia.105–107 Insulin-induced capillary recruitment and microvascular dilation, measured by laser Doppler flowmetry during iontophoresis of acetylcholine, correlate with insulin sensitivity and are reduced in obese compared with lean women.108 In the Maastricht Study, microvascular function was impaired in prediabetes, and there was a linear relationship between microvascular dysfunction and HbA1c and fasting glucose.109 In addition, the prevalence of microalbuminuria, a marker of microvascular dysfunction, is increased in prediabetes and predicts cardiovascular morbidity.

Endothelial Fibrinolytic Dysfunction in Prediabetes

Impaired vascular fibrinolytic function contributes to the risk of cardiovascular disease in individuals with insulin resistance and prediabetes. tPA (tissue-type plasminogen activator) is stored in the endothelium and protects against local thrombosis.110,111 PAI-1 (plasminogen activator inhibitor-1) is the primary inhibitor of tPA in vivo.112 Increased circulating PAI-1 activity or antigen is associated with increased risk of thrombotic events including myocardial infarction and stroke.113 PAI-1 levels also predict the development of diabetes mellitus in at-risk patients.114 Glucose increases PAI-1 expression via Sp1 sites.115 Insulin and insulin-like growth factor also increase PAI-1 expression; several forkhead proteins are involved in the regulation of PAI-1 expression by insulin.116–118 Very low–density lipoprotein increases PAI-1 expression via a response element localized from 672 to 657 of the promoter region.119 Thus, PAI-1 concentrations correlate with body mass and markers of insulin resistance. Angiotensin II, aldosterone, and inflammatory cytokines such as IL-6 and TNF-α, all of which are increased in visceral obesity, also stimulate PAI-1 expression.120,121 Conversely, cGMP decreases PAI-1 expression, and impaired endothelial NO production may contribute to impaired fibrinolytic balance in prediabetes.122,123

tPA antigen levels are also associated with increased risk of thrombotic events, but this is largely because 80% of tPA antigen circulates complexed to PAI-1.124 tPA is released both constitutively and in response to receptor stimulation by bradykinin, acetylcholine or methacholine, substance P, and norepinephrine.125–127 Increased shear force also stimulates tPA release. Stimulated tPA release in the human forearm vasculature correlates with tPA release in the coronary vasculature, and diminished forearm endothelial tPA release is associated with an increased risk of cardiovascular events.128,129 Endothelial tPA release is diminished in obesity and in conditions associated with prediabetes, such as hypertension, but the effect of hyperglycemia is not well defined.130,131 Acute glucose and insulin administration decreases tPA activity in the rat.132

MicroRNAs in Insulin Resistance, Prediabetes, and Diabetes Mellitus

The transition from normoglycemia to prediabetes and diabetes mellitus involves changes in the expression of many genes involved in fat and glucose metabolism.133 MicroRNAs are small, noncoding RNAs, 18 to 22 nucleotides in length, that contribute to gene regulation by altering translation or mRNA stability. MicroRNAs can alter the expression of genes in insulin-producing and insulin-sensitive tissues, including the pancreas, liver, and vasculature.134,135

For instance, a variety of microRNAs have been shown to influence pancreatic β cell development and function.136,137 One of the best studied is miR-375, an islet-specific microRNA that regulates both insulin secretion and β cell mass.138,139 Overexpression of miR-375 is associated with reduced insulin secretion, thought to be mediated by inhibition of myotrophin, a protein involved in insulin exocystosis.138 miR-375 also regulates many genes involved in cellular proliferation, which likely underlies its effect on the maintenance of β cell mass.139

The most abundant microRNA in the liver is miR-122.134,140 Inhibition of miR-122 reduces plasma cholesterol and hepatic steatosis, though the specific gene regulatory pathways involved are unclear.140 Another well-studied microRNA is miR-33, which has 2 isoforms, miR-33a and miR-33b. These microRNAs participate in the regulation of cholesterol synthesis, fatty acid metabolism, and insulin signaling.141–143 They are cotranscribed and act in conjunction with their host genes, Srebp1 and Srebp2, to regulate cholesterol synthesis.143

MicroRNAs may also link the metabolic dysregulation seen in prediabetes with vascular dysfunction.135 Hyperglycemia increases the expression of several microRNAs found in the endothelium, including miR-320, miR-221, miR-503, and miR-125b.135,144–147 These microRNAs may promote endothelial dysfunction by inhibiting genes involved in angiogenesis, vascular repair, and inflammatory suppression.

Vasculature in Glucose and Insulin Delivery

Skeletal muscle represents the bulk of insulin-sensitive tissue and is a major determinant of glucose tolerance. The muscle vasculature has, therefore, been the focus of studies on endothelial dysfunction and insulin resistance. Attenuated increases in insulin-stimulated limb blood flow result in decreased limb glucose uptake.6,7 Indeed, rats and mice made insulin-resistant by high fat intake have such severe impairment of microvascular blood flow that the delivery of glucose to skeletal muscle limits insulin-stimulated glucose uptake during an insulin clamp.148–150 Impaired adipose tissue blood flow does not contribute substantially to glucose disposal in prediabetes but may contribute to impaired lipid storage in adipocytes and increased ectopic lipid stores.151

Several lines of evidence suggest that microvascular function (determined by capillary blood flow, the number of perfused capillaries, and capillary insulin permeability) is key to skeletal muscle insulin action in health and prediabetes. First, the gradient in insulin concentration from plasma to interstitial fluid is increased in humans with prediabetes and in mouse models of prediabetes during an insulin clamp,152–154 suggesting impaired microvascular insulin delivery. The effect of the impairment in skeletal muscle access is illustrated in Figure 2.

Figure 2.
Figure 2.

The microcirculation is a barrier to skeletal muscle insulin access which is delayed in obesity. Interstitial insulin concentrations rise more slowly than arterial insulin concentrations because of capillary insulin egress. This time is prolonged in obesity. Data derived from Sjöstrand et al.152

Insulin-induced blood flow increases its own tissue delivery, as well as the delivery of nutrient substrates.155 Access to perfused tissues requires not only increased blood flow but also capillary egress. Glucose can easily traverse narrow paracellular gaps. The endothelium poses a major barrier for insulin as the diameter of insulin approaches the size of the paracellular space. Insulin movement across the muscle capillary endothelium has been postulated to be regulated and rate-limiting.156,157 Still, little is known about mechanism(s) underlying this process.

Direct visualization of fluorescent insulin across the endothelium of capillaries perfusing mouse muscle using confocal microscopy shows that insulin moves across the capillary endothelium by a mechanism that is unsaturable, insulin receptor–independent, and conforms to the properties of fluid-phase transport.158 Fluid-phase transport is determined by the balance between hydrostatic and oncotic pressures. An increase in microvascular blood flow could facilitate insulin efflux should it result in increased capillary hydrostatic pressure. Fluid-phase transport can occur through paracellular junctions or by transcytosis through vesicles formed in endothelial cells. Insulin access to skeletal muscle is illustrated in Figure 3.

Figure 3.
Figure 3.

Insulin access is determined by (1) vascular reactivity; (2) microcirculatory hemodynamics; and (3) capillary insulin permeability (determined by vesicular or paracellular fluid phase transport). Vascular reactivity and microcirculatory hemodynamics are determined by endocrine factors, paracrine factors, cytokines, and microcirculatory architecture. Capillary insulin efflux is determined by the balance between hydrostatic and oncotic pressures.

Impaired Microvascular Blood Flow in the Progression of Prediabetes to Diabetes Mellitus

The contribution of impaired blood flow to the progression of prediabetes to diabetes is evidenced by the demonstration that vasodilators can partially prevent159,160 or reverse161 diet-induced insulin resistance in rodents. Administration of the phosphodiesterase inhibitor sildenafil to obese mice prevents inflammation162 and insulin resistance.159 Liraglutide treatment increases NO, decreases ET-1, normalizes endothelial function, and increases microvasculature blood flow and glucose disposal in obese rats.160

Relaxin acts on RXFP1 receptors expressed on vascular endothelial and smooth muscle cells. Activation of these receptors leads to vasodilation because of actions on both endothelium163 and smooth muscle.164 Relaxin administration caused endothelial relaxation and reversed insulin resistance in obese mice.161 Relaxin did not improve insulin action in isolated muscle, demonstrating the reliance on the microvascular for its insulin-sensitizing effect.

If increased microvascular blood flow improves insulin action in prediabetes, a decrease in microvascular function could create insulin resistance in healthy mice. This hypothesis was tested in mice in which skeletal and cardiac muscle VEGF (vascular endothelial growth factor)-A was deleted and tissue capillarity was reduced by ≈50%.165 Capillary skeletal and cardiac muscle rarefaction resulted in glucose intolerance and impairments in skeletal and cardiac muscle insulin-stimulated glucose uptake in vivo.165 There was no impairment in insulin action in muscle isolated from lean VEGF-A knockout mice, demonstrating the requirement for intact microvasculature for this effect.

ECM and Vascular Glucose and Insulin Delivery

The ECM is a dynamic structure comprised of proteins and proteoglycans that remodels in responses to injury and inflammation.166 Changes in ECM may affect insulin and glucose delivery either by causing capillary regression or neovascular growth (Figure 4). Increased recruitment of proinflammatory macrophages to muscle168 and adipose81 results in TGF-β (transforming growth factor-β)-mediated fibrosis.169 Increased PAI-1 in prediabetes contributes to fibrosis, as does elevated concentrations of the adipokine thrombospondin-1.170 Thrombospondin-1 contributes to the skeletal muscle meta-fibrosis and insulin resistance in high fat–fed mice.171

Figure 4.
Figure 4.

The extracellular matrix (ECM) in the sequelae of prediabetes. Inflammation results in ECM remodeling which creates endothelial dysfunction, capillary regression, spatial barriers, and increased ECM component interaction with cell surface receptors, including the integrin receptor family. These result in a decrease in tissue insulin access and, consequently, insulin action. PAI-1 indicates plasminogen activator inhibitor-1; and TGF-β, transforming growth factor-β. Adapted from Williams et al167 with permission. Copyright ©2015, Elsevier.

The proinflammatory prediabetic state results in an increase in skeletal muscle collagens and other ECM proteins162,172 and ECM remodeling.173 The glycosaminoglycan hyaluronan is increased in tissues of prediabetic animals,174,175 and serum hyaluronan is increased in T2DM.176 Hyaluronan is a major component of the glycocalyx of capillary lumens, where it may affect the access of insulin to tissues. A reduction of hyaluronan using PEGylated hyaluronidase in high fat–fed mice improves insulin action.174 CD44, the main hyaluronan cell surface receptor, is associated with T2DM, as shown by expression-based genome-wide association studies.177 Anti-CD44 antibody treatment reduces inflammation and improves insulin sensitivity in obese mice.178

ECM remodeling171,173,174,179 causes changes in signaling via cell surface receptors that sense the extracellular microenvironment.162,180–182 ECM remodeling is necessary for increased capillary growth and proliferation.165 Treatments that improve insulin action in rodent models of prediabetes normalize collagen levels and increase muscle capillaries.161,162,174,180 Expansion of the muscle ECM and decreased muscle capillaries are associated with insulin resistance.179 Collectively, these data suggest that endothelial dysfunction and capillary rarefaction are mechanisms by which ECM remodeling may mediate muscle insulin resistance.

The expanded ECM in prediabetes produces a distinct signal that alters activation of integrin and other cell surface receptors. The integrin α2 subunit is highly expressed in endothelial cells, fibroblasts, and other cell types. The α2β1 integrin receptor regulates cell migration, proliferation, and survival.183 Genetic deletion of the α2 subunit has no effect on insulin action in lean mice but increases capillaries and insulin action in obese mice.

Studies in mice with a muscle-specific deletion of the integrin downstream protein, the ILK (integrin-linked kinase), support the importance of muscle ECM in insulin action. Skeletal muscle ILK knockout has no effect on insulin action in lean mice but increases capillaries and insulin action in obese mice.180 The downstream integrin signaling molecule, FAK (focal adhesion kinase), has also been implicated in the regulation of insulin action in the muscle.184,185 FAK phosphorylation is decreased in muscle from obese rats,184 and siRNA knockdown of FAK impairs glucose tolerance and insulin action in lean mice.185

ECM expansion occurs in adipose tissue of obese subjects and limits adipocyte fat storage,186 leading to ectopic fat stores in liver and skeletal muscle, lipotoxicity, oxidative stress, and inflammation.167

Treatment of Prediabetes: Weight Loss and Lifestyle Modification

Weight loss is the mainstay of reducing the risk of progression to diabetes mellitus in patients with prediabetes. In addition to reducing hyperglycemia, weight loss leads to significant improvements in other cardiovascular risk factors, including blood pressure, lipids, and biomarkers of inflammation.

In patients with IGT followed for 6 years in the Da Qing Study, diet, exercise, and combined diet and exercise reduced incident T2DM by 31%, 46%, and 42% respectively, compared with control.187 In the Finnish DPP, weight loss counseling targeted to 5% total body weight, decreased total and saturated fat consumption, increased fiber consumption, and increased activity to 30 minutes/day resulted in a 58% reduction in incident T2DM in individuals with IGT and BMI >25 kg/m2.188

In the DPP study of 3234 patients with IGT and BMI ≥24 kg/m2 (≥22 kg/m2 for Asian Americans), intensive lifestyle modification led to a loss of 5.6 kg over an average follow-up of 2.8 years, and this was associated with a 58% reduction in incident diabetes mellitus.189 At 10 years, the sustain risk reduction was 34% in the lifestyle arm compared with placebo even though weights were no longer different between groups.18 Regression to normal glucose tolerance results in an ≈6% reduction in 10-year risk of cardiovascular risk by Framingham criteria.190

Similar effects of diet and exercise were seen in men in the Japanese IGT study and in the Indian DPP in patients with IGT.20,191 The reduction of incident diabetes mellitus seems to be proportionate to the amount of weight loss, but plateaus at a loss of 10% of body mass.

Long-term follow-up of participants in lifestyle intervention trials demonstrate that weight loss is difficult to maintain. Pharmacological weight loss therapy also reduces the risk of progression to diabetes mellitus. In the XENDOS study (Xenical in the Prevention of Diabetes in Obese Subjects), orlistat therapy resulted in a 5.8 kg weight loss and reduced the progression of IGT to T2DM by 37%.192 Phentermine/topiramate ER reduced incident T2DM in patients with prediabetes or metabolic syndrome by 79%.193

Bariatric surgery reduces incident diabetes mellitus not only through weight loss but through effects on incretin hormones, bile acids, or gut microflora. In the SOS (Swedish Obese Subjects), a prospective, nonrandomized study of bariatric surgery (gastric banding, vertical-banded gastroplasty, and Roux-en-Y gastric bypass) patients and obese controls, among patients without diabetes mellitus at baseline, incident diabetes mellitus was reduced by 76%.194 Retrospective and cohort studies have showed similar reductions in T2DM in patients with IFG or obesity.195

Treatment of Prediabetes With Anti-Diabetic Agents

In the DPP, treatment with metformin 850 mg twice a day reduced incident diabetes mellitus by 31% compared with placebo in patients with IGT over 2.8 years of follow-up.189 The effect was greater in more obese patients and those with a higher fasting glucose. The DPP Outcomes Study followed participants for up to 15 years and found a persistent reduction in incident diabetes mellitus of 18%.196 Weight loss explained 64% of the beneficial effect. Despite an initial effect on lipoprotein subfractions, C-reactive protein, and tPA, with long-term follow-up, there was no effect of metformin on cardiovascular risk factors. Coronary artery calcification was decreased in men but not in women. There was no effect of metformin on microvascular complications independent of effects of diabetes mellitus. In the Indian DPP, metformin 250 mg twice a day reduced incident diabetes mellitus by 28% in IGT.191 There was no added benefit of combined metformin and lifestyle modification. Despite the lack of persistent effect of metformin on cardiovascular risk factors such as lipids and inflammation in the DPP Outcomes Study, metformin may improve insulin sensitivity through effects on endothelial function. Metformin improves endothelial function in insulin-resistant rodents.197 In humans, the effect of metformin on endothelial function has been studied most in patients with T2DM or polycystic ovarian syndrome,198 but metformin improves endothelial function in patients with metabolic syndrome, and improvement in flow-mediated dilation correlates with improvement in insulin resistance.199

Alpha-glucosidase inhibitors have also been studied in prediabetes. In the STOP-NIDDM trial (Study to Prevent Noninsulin-Dependent Diabetes), acarbose reduced the incidence of diabetes mellitus by 25% in individuals with IGT and a fasting plasma glucose from 5.6 to 7.7 mmol/L.200 Despite a 25% dropout rate, acarbose treatment reduced cardiovascular events by 49%.201 Voglibose (0.2 mg tid) treatment reduced incident diabetes mellitus 41% compared with placebo in a trial in Japan.202

Thiazolidinediones prevent the development of diabetes mellitus in individuals with IFG or IGT. In ACT NOW (Actos Now for Prevention of Diabetes), treatment with pioglitazone 45 mg per day reduced incident diabetes mellitus 72% over 2.4 years in patients with IGT and at least one other risk factor for T2DM and BMI ≥25 kg/m2.203 Pioglitazone also reduced PAI-1 and slowed the rate of progression of carotid intima–media thickening.204 In the DREAM trial (Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication), rosiglitazone 8 mg/day reduced incident diabetes mellitus 60% in patients with IFG or IGT >29 years.205 In the CANOE trial (Canadian Normoglycemia Outcomes Evaluation), treatment with rosiglitazone 2 mg per day and metformin 500 mg twice a day combined reduced incident diabetes mellitus 66%, an effect size larger than that observed in trials of metformin alone; however, there was no single-drug comparator arm.206 The thiazolidinediones increase the risk of heart failure in patients with diabetes mellitus.207

Treatment with the GLP-1 (glucagon-like peptide 1) receptor agonist, liraglutide, also reduces incident diabetes mellitus in obese patients with prediabetes.208 In the SCALE Obesity and Prediabetes study, patients with prediabetes with BMI ≥30 kg/m2 or a BMI ≥27 kg/m2 and hyperlipidemia or hypertension were randomized to liraglutide 3.0 mg or placebo. Patients randomized to liraglutide lost more weight (6.5±8.1 kg versus 2.0±7.3 kg) and were less likely to progress to T2DM (2% versus 6%) over 3 years. Whether the effect of GLP-1 receptor antagonism exceeds the effect of equivalent weight loss is not known.

Importantly, long-acting GLP-1 agonists reduce mortality in patients with T2DM. In the LEADER trial (Liraglutide Effect and Action in Diabetes of Cardiovascular Outcomes Results), liraglutide 1.8 mg/day reduced the primary composite outcome of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke in patients with T2DM and high cardiovascular risk compared with placebo (from 14.9% to 13%; hazard ratio 0.87; 95% confidence interval, 0.78–0.97; P=0.01).209 Patients in the liraglutide group lost 2.3 kg more than the placebo treatment group. Systolic blood pressure was also significantly lower in the liraglutide group. Semaglutide (0.5 or 1 mg/week) reduced the primary composite end point of first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke in patients with T2DM and a HbA1c ≥7% compared with placebo (hazard ratio, 0.74; 95% confidence interval, 0.58–0.94; P<0.001).210 Body weight decreased 3.6 and 4.9 kg in the 0.5 and 1.0 mg groups. Again, whether the effect of GLP-1 receptor antagonism exceeds the effect of equivalent weight loss on cardiovascular risk is not known. In mice, GLP-1 causes vasodilation through both GLP-1 receptor–dependent and –independent mechanisms.211 The latter requires degradation of GLP-1 to GLP-1 (9–36) by DPP-4 and involves NO. Human studies provide conflicting information about the effect of GLP-1 or stable analogues on endothelial function.212–217

Effect of Drugs That Improve Vascular (Endothelial) Function on Insulin Resistance

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers improve endothelium-dependent vasodilation and reduce morbidity and mortality in heart failure and nephropathy, including diabetic nephropathy.218–221 ACE inhibitors also improve endothelial fibrinolytic function and reduce the risk of thrombotic events, such as myocardial infarction.222–226 Given the aforementioned evidence that angiotensin II and aldosterone alter insulin sensitivity, there has been significant interest in the possibility that treatment with an ACE inhibitor or angiotensin receptor blockers could prevent progression of prediabetes to diabetes mellitus while reducing cardiovascular risk. In the DREAM study, ramipril did not reduce incident diabetes mellitus in patients with IFG.227 A greater proportion of patients treated with ramipril regressed to fasting normoglycemia compared with placebo-treated patients (42.5% versus 38.2%; P<0.001), however. The median 2-hour glucose after oral GTT was also lower in the ramipril group. In the NAVIGATOR study (Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research), treatment with valsartan reduced the risk of incident diabetes mellitus compared with placebo (31% versus 33%; P<0.001) in patients with IGT and cardiovascular risk factors, although there was no effect on cardiovascular mortality.228 In a meta-analysis of randomized, placebo-controlled clinical trials of ACE inhibitors or angiotensin receptor blockers in patients without heart failure (ie, not specifically prediabetes), ACE inhibitors reduced the risk of incident diabetes mellitus 13.7% (P=0.02) and angiotensin receptor blockers reduced the risk of incident diabetes mellitus by 10% (P<0.001).229

Studies in obese, insulin-resistant rodents indicate that ACE inhibitors improve insulin sensitivity through bradykinin B2 receptor– and NOS-dependent effects, and NO contributes to bradykinin-stimulated muscle glucose uptake in humans.230,231 An alternative pharmacological strategy for increasing vascular cGMP without increasing NO include increasing the production of cGMP by soluble guanylate cyclase or decreasing the degradation of cGMP via phosphodiesterase. As noted earlier, administration of sildenafil prevents insulin resistance in high fat–fed mice.159 In a proof-of-concept study, 3-week treatment tadalafil improved β-cell function measured using the frequently sampled intravenous GTT in individuals with metabolic syndrome and reduced disposition index (a composite measure of insulin sensitivity and secretion) in the women studied.232 Ho et al233 reported that 12-week treatment with tadalafil improved disposition index and oral disposition index and tended to improve insulinogenic index in insulin-resistant subjects undergoing oral GTT; tadalafil also improved insulin sensitivity among severely obese participants. Ramirez et al234 reported that 3-month treatment with sildenafil increased the insulin sensitivity index calculated from hyperglycemic clamps in individuals with prediabetes without affecting early or late insulin secretion. Sildenafil reduced urine microalbuminuria, a marker of endothelial function that predicts adverse cardiovascular outcomes. Sildenafil treatment also improved fibrinolytic balance, decreasing PAI-1 concentrations without altering tPA concentrations. Several studies have reported that phosphodiesterase inhibition reduces the urine albumin-to-creatinine ratio and HbA1c in patients with T2DM and microalbuminuria.235,236

Summary and Future Directions

Prediabetes is defined clinically by hyperglycemia. Pathophysiologic features include vascular insulin resistance, oxidative stress, and inflammation, which collectively promote endothelial vasodilator and fibrinolytic dysfunction. Concomitant obesity increases inflammation and FFAs to exacerbate these processes. Weight loss is the most effective treatment of prediabetes accompanied by obesity as it interrupts these pathophysiological processes.

Considering the challenges of sustained weight loss, identification of pharmaceutical targets is needed. Preclinical studies demonstrate that the inflammatory response of prediabetes and obesity leads to ECM expansion, which accompanies endothelial dysfunction. ECM deposition is associated with capillary rarefaction, decreased insulin delivery, and insulin resistance in liver and muscle. It is increasingly apparent that microcirculatory events are closely intertwined with insulin action. Therapies that improve endothelial function, such as metformin, also reduce risk of incident diabetes mellitus and cardiovascular events. Moreover, vasodilatory agents prevent or reverse insulin resistance in preclinical models.

Future studies are needed to elucidate the mechanism of the beneficial effect of GLP-1 analogues on cardiovascular mortality, to determine whether weight loss is requisite, and to develop more convenient and less-expensive GLP-1 delivery methods. Based on preclinical and mechanistic human studies, trials of phosphodiesterase inhibitors and other drugs that increase cGMP, such as guanylate cyclase activators, on endothelial function and insulin sensitivity in prediabetes are warranted. Although the role of microRNAs in the pathogenesis of prediabetes has not been fully elucidated, promising preclinical data suggest that these should be explored as therapeutic targets.

Sources of Funding

We are funded by grants HL125426, DK054902, DK050277, DK059637, DK108159, HL128983, HL132320, DK081572 from the National Institutes of Health and by 17SFRN33520059 from the American Heart Association.

Disclosures

N.J. Brown is a member of the Scientific Advisory Board for Alnylam Pharmaceuticals and serves as a consultant for Novartis Pharmaceuticals, Shire Pharmaceuticals, and Viamet Pharmaceuticals. N.J. Brown receives research support from Novo Nordisk. T.J. Wang has served as a consultant to Takeda Pharmaceuticals and Ultragenyx and has received research support from Diasorin. The other author reports no conflicts.

Footnotes

  • Nonstandard Abbreviations and Acronyms
    ACE
    angiotensin-converting enzyme
    ADA
    American Diabetes Association
    AGE
    advanced glycation products
    ARIC
    Atherosclerosis Risk in Communities
    DPP
    Diabetes Prevention Program
    DPP4
    dipeptidyl peptidase-4
    ECM
    extracellular matrix
    eNOS
    nitric oxide synthase
    ERK1/2
    extracellular signal-regulated kinase 1/2
    ET-1
    endothelin-1
    FAK
    focal adhesion kinase
    FFA
    free fatty acid
    GLP-1
    glucagon-like peptide 1
    GTT
    glucose tolerance test
    Hb
    hemoglobin
    HMGB1
    high mobility group box 1
    ICAM-1
    intercellular adhesion molecule-1
    IFG
    impaired fasting glucose
    IGF
    insulin-like growth factor
    IGT
    impaired glucose tolerance
    IL
    interleukin
    ILK
    integrin-linked kinase
    IRS-1
    insulin receptor substrate-1
    JNK
    c-Jun N-terminal kinase
    MAPK
    p38 mitogen activated protein kinase
    MEK
    MAPK/ERK kinase
    NF-κB
    nuclear factor-κB
    NLR
    nucleotide-binding domain and leucine-rich repeat-containing
    NLRP3
    NLR family and the PYHIN
    NO
    nitric oxide
    PAI-1
    plasminogen activator inhibitor-1
    PKC
    protein kinase C
    PI3K
    phosphatidylinositol 3 kinase
    PYHIN
    pyrin and HIN domain
    RAGE
    receptor for AGE
    T2DM
    type 2 diabetes mellitus
    Th2
    T-helper
    TGF-β
    transforming growth factor-β
    TNF
    tumor necrosis factor
    tPA
    tissue-type plasminogen activator
    Treg
    regulatory T cells

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  • The Vasculature in Prediabetes
    David H. Wasserman, Thomas J. Wang and Nancy J. Brown
    Circulation Research. 2018;122:1135-1150, originally published April 12, 2018
    https://doi.org/10.1161/CIRCRESAHA.118.311912
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