Abstract
Insulin resistance (IR) and cardiovascular disease (CVD) represent two universal public health hazards, especially in today’s Western societies. A causal-effect relationship has been established that links IR with CVD. The mediating mechanisms are perplexing, under ongoing, rigorous investigation and remain to be fully elucidated. IR is a condition encompassing hyperglycemia and compensatory hyperinsulinemia. It occurs when insulin is not capable of exerting its maximum effects on target tissues, including skeletal muscles, liver and adipose tissue. This alteration of insulin signaling pathways results in the development of cardiometabolic disorders, including obesity, dyslipidemia, low-grade inflammation, endothelial dysfunction and hypertension, all of which are predisposing factors for atherosclerosis and CVD. The management of IR can be achieved through dietary modifications, the inclusion of regular exercise routines in everyday life, pharmacological agents and other interventions tailored to each individual patient’s needs. It is important to underline though that, although various antidiabetic drugs that may improve IR are available, no medications are as yet specifically approved for the treatment of IR. This narrative review will focus on the current scientific and clinical evidence pertaining to IR, the mechanisms connecting IR with CVD, as well as plausible strategies for a holistic, personalized approach for IR management.
Keywords
Introduction
Insulin is a hormone involved in the metabolism of carbohydrates, lipids and proteins and is involved in cell growth and differentiation.1,2 Insulin resistance (IR) constitutes a significant health hazard in a global aspect. IR, which is closely related to metabolic syndrome (MetS), has been associated with the so-called Western lifestyle, characterized by high-calorie food consumption, limited physical activity and excessive stress. 3 IR is a clinical condition in which tissues sensitive to insulin, namely skeletal and cardiac muscle, adipose tissue and the liver, demonstrate a diminished ability of glucose uptake due to a reduced biological effect of insulin in comparison with healthy individuals.4,5 The excess glucose in the bloodstream leads to hyperglycemia and indirectly to hyperinsulinemia with subsequent disruption of glucose metabolism.4–7 IR has been extensively linked with chronic low-grade inflammation and production of proinflammatory cytokines, such as tumor necrosis factor α (TNF-α), interleukin (IL)-6, IL-8, plasminogen activator inhibitor-1 (PAI-1) and monocyte chemoattractant protein-1 (MCP-1); their increased production is accompanied by elevated levels of C-reactive protein (CRP), a widely used inflammatory biomarker.8–11 IR can be assessed with various indices, such as fasting insulin levels, homeostasis model assessment-insulin resistance (HOMA-IR), serum-triglyceride-to-serum-high-density-lipoprotein-cholesterol-ratio, as well as by the most recently proposed, clinically valuable IR indices, triglyceride-glucose-neck circumference and triglyceride-glucose-neck circumference to height ratio.11,12 The gold standard for IR measurement is the glucose clamp technique. IR alone has been established as a separate risk factor for cardiovascular events, even in patients without diabetes mellitus.13–15
Cardiovascular disease (CVD) was responsible for 17.9 million lives lost in 2019; by 2030, this number is expected to increase to >22.2 million, 16 making CVD the leading cause of death globally. The vast majority of cardiovascular events are attributed to atherosclerosis, in which lipid plaques form in the vessel walls. 17 CVD has been extensively associated with chronic low-grade inflammation and involvement of both innate and adaptive immunity with macrophages being the protagonists of this process;17,18 thus, it becomes clear that the pathogenesis of CVD has an immunoinflammatory background. During the initial phase of atherosclerosis, endothelial injury triggers the production of proinflammatory cytokines like MCP-1, ILs, TNF-α and adhesion molecules, thus laying the foundation for increased production of CRP. 19 As mentioned earlier, these same events occur in the setting of IR. Impaired insulin cellular signaling in IR alters glucose metabolism and endothelial dysfunction and may contribute to the acceleration of atherosclerosis.19,20 Moreover, numerous studies link IR with other health conditions, including obesity, non-alcoholic fatty liver disease (NAFLD), hypertension, polycystic ovary syndrome (PCOS) and heart failure (HF).21,22 IR and HF form a vicious cycle; IR is an independent risk factor for HF development, while HF may exacerbate whole body IR. 22
This narrative review article shall attempt to present and discuss the current clinical and scientific data illustrating the pathophysiological connection between IR and CVD. In addition, potential therapeutic strategies for the treatment of IR will also be discussed.
Insulin: physiology, signaling and metabolism
In 1921, Frederick Banting and Charles Best made a groundbreaking discovery: a specific substance secreted from the pancreas, later named insulin, lowered blood glucose levels in canines. The first purification of insulin by James Collip and its use for the treatment of the first human patient with diabetes mellitus took place in 1922. 23 The discovery of insulin paved the way for the subsequent effective treatment of type 1 diabetes (T1D), an incurable cause of death at that time, and endless scientific research. Since 1960, studies and experiments have demonstrated that biologically active human insulin is a 51 amino-acid protein composed of two peptide chains, A and B. There are 21 amino acids in chain A and 30 amino acids in chain B. The two chains are interlinked with two disulphide bonds, located in A7-B7 and A20-B19. An additional disulfide bond links amino acids 7 and 11 in chain A. In the presence of zinc, insulin forms hexamers.24,25
Insulin is derived from proinsulin, an inactive protein produced by beta cells in the islets of Langerhans. Its biological activity is precipitated by the cleavage of C-peptide in proinsulin, an event that further allows insulin to connect to the appropriate receptor. 26 Once active, it is stored in granules inside the cells and then released via glucose signaling-induced exocytosis; glucose enters the cell and the pathway of glycolysis produces adenosine triphosphate (ATP) and leads to the closure of ATP-dependent potassium (K+) channels. Membrane depolarization is followed by the opening of voltage-gated calcium (Ca2+) channels, an increase in intracellular Ca2+ concentration and, finally, the exocytosis of insulin-containing granules and the release of insulin in the bloodstream.27,28 Insulin is then released into the portal vein system and enters the hepatocytes. A transmembrane glycoprotein, carcinoembryonic antigen-related cell adhesion molecule 1, is responsible for the clearance of 80% of the secreted insulin; its degradation seems to be reduced in IR, resulting in hyperinsulinemia and suggesting a possible correlation or even causation through desensitization. The remaining insulin molecules are transferred to insulin-sensitive tissues and exert their action via binding to insulin receptors. 29
Insulin is an anabolic hormone with both metabolic and mitogenic effects. It exerts its function during postprandial hyperglycemia, mediates glucose uptake and storage in muscle cells and adipocytes, promotes glycogen synthesis, inhibits lipolysis and decreases gluconeogenesis in hepatocytes.1,6,30 Its function is exerted through binding to insulin receptors. The insulin receptor belongs to the subfamily of tyrosine kinase receptors, similar to the insulin growth factor 1 (IGF-1) receptor, a tetrameric glycosylated protein with two α and two β subunits integrated with the cell membrane.21,24 The receptor is activated when insulin binds to the α subunits, leading to autophosphorylation of tyrosine residues in β subunit domains and subsequent activation of various intracellular kinase cascades, including phosphorylation of phosphatidylinositol 3-kinase (PI3K), Akt-1 and Akt-2, and mammalian target of rapamycin.21,24 This leads to increased transport of glucose transporter 4 (GLUT4) to the surface of the membrane and glucose uptake by skeletal muscle cells and adipocytes. 24 A reference regarding its action on vascular walls ought to be made; insulin can either protect or adversely affect the vessels via different kinase cascades. 6 Its protective action is related to the activation of the PI3K cascade and the production of endothelial nitric oxide synthase (eNOS) and nitric oxide (NO), whereas its detrimental impact pertains to the activation of mitogen-activated protein kinase (MAPK) and vascular smooth muscle cell proliferation, inflammation and atherosclerosis. 6
When insulin signaling malfunctions, as in the case of IR, glucose is not being appropriately used and cellular metabolism shifts to alternative pathways to obtain energy and preserve homeostasis. These alterations may actually represent some of the mechanisms responsible for the development of CVD.
Insulin resistance
Insulin resistance refers to the diminished response of insulin-sensitive tissues to insulin signaling.4,5,7 Insulin cannot exert its full biological activity, which is the facilitation of glucose entrance in cells to be utilized as the primary energy substrate. The excess glucose remains in the blood circulation, a condition named hyperglycemia, and tissues shift their metabolic pathways in response to inadequate energy uptake, underpinning disorders such as impaired adipose tissue function and obesity, inflammation, dyslipidemia, production of reactive oxidative species (ROS), atherosclerosis, endothelial dysfunction and hypertension, all of which are associated with the promotion of CVD.31,32
Obesity and impaired adipose tissue function
White adipose tissue (WAT) was once known to serve the sole purpose of storing energy in the form of lipids. 33 However, over time, this perception has changed radically: adipose tissue is an endocrine tissue as well. 34 WAT is either subcutaneous (SCAT) or visceral (VAT), which vary in distribution, morphology and function. 35 Obesity is defined as a body mass index (BMI) ≥30 kg/m2. 36 In obese individuals, excess fat is stored in the adipocytes of WAT, increasing their size and thus the overall tissue mass. The size of adipocytes is indicative of their function, as large adipocytes tend to be insulin-resistant, hyperlipolytic and resistant to the anti-lipolytic effect of insulin.37,38 Many comorbidities accompany obesity. 39 In particular, IR and impairments in glucose metabolism are associated with increased lipid storage in VAT, although increased SCAT percentage also accounts for IR development. Nonetheless, obesity contributes to low-grade inflammation, activating the immune cells residing in the adipose tissue.40–43
Insulin promotes fatty acid and triacylglycerol synthesis, decreases the rate of lipolysis, increases the uptake of triglycerides from the blood circulation and decreases the rate of fatty acid oxidation in muscle and liver. 44 As previously mentioned, obesity leads to IR and hyperlipolysis in adipocytes. IR activates hormone-sensitive lipase (HSL), 45 leading to an increase of free fatty acids (FFA) plasma levels along with high dietary fat accumulation, namely lipotoxicity. Lipotoxicity is considered a risk factor for IR; high levels of FFA and, in particular, two specific metabolites, ceramide and diacylglycerol (DAG), intervene in proper insulin signaling by generating a negative feedback loop and suppression of insulin receptor substrate-1 (IRS-1). 44 The contribution of elevated FFA plasma levels to IR is also clearly demonstrated in late-term pregnant women, who commonly develop IR in the presence of increased FFA levels. 46 Clearly, IR and lipotoxicity create a vicious cycle and a proatherogenic profile.20,47,48 Mitochondrial dysfunction in obese WAT is also producing lipid metabolites, ultimately contributing to IR. 49
Inflammation
Insulin resistance and an excess lipid pool also trigger inflammatory signaling pathways like c-Jun N-terminal kinase (JNK), IκBα kinase β and nuclear factor KB (NF-kB), resulting in the production of proinflammatory cytokines, such as TNF-α, IL-6, IL-1β, PAI-1, MCP-1, leptin and resistin, and a reduction of adiponectin levels.7,20,47,50 Proinflammatory cytokines shift adipose tissue macrophage polarization, 51 especially in immune cell-rich VAT. Proinflammatory M1 macrophages are abundant in obese mice, while anti-inflammatory M2 are more prominent in lean subjects,52,53 the former further inducing the production of cytokines and thus maintaining the inflammatory state.
Tumor necrosis factor-α affects the expression of other inflammatory cytokines from adipocytes, such as IL-6, MCP-1 and PAI-1, inhibits peroxisome proliferator-activated receptor-γ2, GLUT4 54 and IRS-1, leading to IR, and increases FFA in the circulation through stimulation of lipolysis and inhibition of triglyceride (TG) synthesis. 55
Interleukin-6 is a pleiotropic cytokine with its levels being elevated in obese individuals. IL-6 increases lipolysis and suppresses the expression of the
Interleukin-1β is secreted by macrophages as the final product of the NLR family pyrin domain-containing 3 (NLRP3) inflammasome activation. This cytokine has been related to type 2 diabetes (T2D) and atherosclerosis. Its deleterious effects on pancreatic β-cells in the islets of Langerhans are notable, along with its action upon endothelial cells, macrophages and smooth muscle cells. The NLRP3 inflammasome possesses a pivotal role in obesity-related insulin resistance. IL-1β is also a mediator for the production of other proinflammatory cytokines.58–60
Plasminogen activator inhibitor-1 is a serine protease inhibitor with pleiotropic functions. It is primarily involved in thrombosis, also mediating a connection between obesity, CVD and IR. The literature pertaining to studies regarding the latter is extensive. The gene that encodes for PAI-1 is upregulated in atherosclerotic plaques. 61 TNF-α, IL-1β, very-low density lipoprotein (VLDL-C) and lipoprotein (a) constitute specific mediators, and PAI-1 itself is an acute phase protein, elevated in inflammatory states. 61 A large cohort study revealed that healthy non-diabetic subjects who developed T2D in a 5-year interval presented significantly elevated PAI-1, fibrinogen and CRP levels compared with those who did not develop T2D. 62 Elevated plasma PAI-1 levels and hypofibrinolysis are interconnected via IR and obesity. 63 All of the aspects of the MetS, namely insulin, glucocorticoids, VLDL, FFA, glucose and angiotensin II, are associated with increased PAI-1 production. VAT secretes PAI-1, thus explaining its connection with obesity-related insulin resistance.64,65 The PAI-1 genotype seems to affect the vascular risk linked to hyperinsulinemia. 66 A previous study also described a causality relationship between elevated PAI-1 plasma levels and coronary artery disease (CAD). 67 Finally, a cross-sectional analysis based on the Framingham Offspring Study showed that elevated fasting insulin levels in impaired glucose tolerance conditions were associated with elevated PAI-1 plasma levels and, subsequently, impaired fibrinolysis. 68
Monocyte chemoattractant protein, or chemokine (CC motif) ligand 2 (CCL2), is a chemokine secreted by skeletal muscle cells, smooth muscle cells, adipocytes and endothelial cells. When bound in its receptor, C-C chemokine receptor type 2, it promotes the recruitment of monocytes and T-lymphocytes in tissues. MCP-1 plays a prominent role in the pathogenesis of atherosclerosis 69 and its high plasma levels have been correlated with plaque vulnerability. Injured endothelium secretes MCP-1 for its renewal, which amongst other effects, facilitates the migration of monocytes to the site of the lesion; these cells later become foam cells. 70 Circulating MCP-1 levels are elevated in subjects with increased adipose tissue mass and T2D, but weight loss, exercise and thiazolidinediones (TZD) lower these levels. 69 CCL2 seems to exert a direct effect on adipocytes, decreasing insulin-regulated glucose uptake and altering the expression of certain adipogenic genes. 71
Leptin is a peptide produced and secreted from WAT and mediates appetite and feeding behavior. Its plasma levels are elevated in obese individuals and patients with CVD. Leptin reduces insulin synthesis, leading to a condition known as leptin resistance, hyperleptinemia and hyperphagia. Leptin increases proinflammatory cytokines’ production from immune cells and stimulates inflammatory pathways, such as MAPK and PI3. These facts confirm a clear correlation between leptin, IR and CVD.72,73
Resistin is another peptide secreted by macrophages, monocytes and bone marrow cells in humans. There is evidence that resistin contributes to IR and inflammation, although the association between resistin levels and IR remains controversial. 72
Adiponectin is the only anti-inflammatory adipokine produced by adipose tissue during inflammation. Overall, it increases insulin sensitivity. Its levels tend to be lower in obese individuals. Inflammation is possibly the main factor suppressing adiponectin levels in IR. The anti-inflammatory effects of adiponectin extend to the cardiovascular system, as adiponectin seems to protect the endothelium and the smooth muscle cells. In a study, male patients with hypoadiponectinemia had a two-fold increased risk of developing CAD. 74 Adiponectin also seems to modify the macrophage phenotype via a plethora of mechanisms.72–75
In addition to the aforementioned mediators, other less familiar yet significant hormones appear to influence IR, some of them acting as potential novel markers of metabolic disturbances.
76
Irisin is a recently discovered myokine, highly expressed in skeletal muscles after exercise. Irisin enters the circulatory system and is able to convert WAT into brown adipose tissue. Other target tissues include skeletal muscles, the pancreas, the liver, the kidneys and the brain, especially the hypothalamus, although most of the mechanisms involved remain unknown. The net effect of irisin in tissues results in normoglycemia and normal lipid levels.
77
Irisin alleviated IR related to FFA and lipotoxicity, ameliorated PI3K/Akt insulin signaling and impeded the Toll-like receptor 4/NF-κB inflammatory pathways in murine models.
78
Another
Apelin is another relatively recently discovered peptide hormone, initially extracted from bovine stomachs. Apelin is an endogenous ligand for the apelin receptor (APJ), a G-coupled protein receptor distributed abundantly in the human body. Apelin is mainly secreted by endothelial cells and adipose tissue and the apelin/APJ system exerts multiple systemic functions. Apelin improves insulin resistance and insulin secretion and diminishes serum glucose, glycosylated hemoglobin (HbA1c) and low-density lipoprotein cholesterol (LDL-C) levels. Apelin and pro-inflammatory factors also participate in an endless regulatory cycle, with apelin downregulating the activity of macrophages and decreasing MCP-1 and other chemotactic proteins and TNF-α, overall improving inflammatory states, although, under certain circumstances, it may potentiate inflammation. 81 Serum apelin levels are found to be elevated in IR states and its direct administration is related to improvements in insulin sensitivity, while its secretion is largely regulated by insulin. Molecular mechanisms involve augmentation of glucose uptake via adenosine monophosphate-activated protein kinase (AMPK) and eNOS and inhibition of lipolysis via phosphorylation of HSL, leading to a decrease of FFA levels and, finally, reduced IR. 82 Further basic and clinical evidence suggest that apelin is an insulin sensitizer and its elevated levels are linked with T2D rather than obesity. 83 Concerning atherosclerosis, a case–control study on 60 Egyptian patients demonstrated a powerful correlation between serum apelin and the degree of carotid intima-media thickness, suggesting a plausible future application for apelin as a clinically useful prognostic biomarker. 84
Visfatin is an insulin-mimetic adipocytokine and its function depends on nicotinamide adenine dinucleotide biosynthesis. Mainly, but not exclusively, produced by visceral fat, visfatin aids in maintaining insulin sensitivity and exerts its actions via phosphorylation of insulin receptors and activation of the PI3K and MAPK signaling pathways. Its levels appear to be elevated in obesity, compensating for abnormal serum glucose levels. Nonetheless, visfatin levels exceeding a certain value may act detrimentally and precipitate development of IR, endothelial dysfunction and inflammation, as it is widely expressed in foam cells.
85
Thus, visfatin presents dose-dependent beneficial or proinflammatory properties.
85
An
Fetuin-A is a hepatokine, which has been demonstrated to affect MetS and atherosclerosis and may act as either a positive or a negative acute phase protein. In patients with MetS, where the SCAT percentage is increased, an overproduction of fetuin-A occurs. This protein possibly contributes to adipose tissue inflammation acting as a chemoattractant and macrophage-polarizing agent. Concerning CVD, from a clinical perspective, decreased fetuin-A levels are associated with subclinical as well as with clinical CAD. On the other hand, fetuin-A levels have been shown to be significantly lower in the setting of ischemic cardiomyopathy, as compared with that of dilated cardiomyopathy, potentially providing fetuin-A with a discriminative power between these different types of HF. 88 Results of different studies regarding fetuin-A confirm its contribution to the pathogenesis of IR; it seemingly impedes the maturation of β cells in the pancreatic islets, 89 enhances apoptosis and damages pancreatic β cells when oversecreted, 90 and is overexpressed at the initiation of a high-fat diet, concurrent with IR, in murine models. 91 Additionally, fetuin-A along with a Western lifestyle are held accountable for the development of IR, vascular inflammation and atherosclerosis, 92 as well as for the development of T2D in people of Pakistani origin. 93 In addition, a previous study suggested that a pro-inflammatory diet might aide IR and T2D development via fetuin-A. 94 Moreover, a thorough meta-analysis comprising more than 110 00 participants concluded that increased circulating levels of fetuin-A were linked to an elevated risk of T2D. 95 Serum fetuin-A levels have been proposed to be used as a potential biomarker regarding IR and PCOS. 96 Elevated serum levels of fetuin-B, a second member of the fetuin family in mammals, are also linked to impaired glucose metabolism, inducing IR and chronic inflammation, with hepatic steatosis apparently being the common denominator.97–100 Its expression is modified via upregulation of the leptin-STAT3 signaling cascade. 101 Along with fetuin-A, it can also be a potentially useful biomarker in PCOS. 102 Interestingly, other studies suggest that fetuin-A and fetuin-B may alter glucose metabolism in a different manner, 103 or may present inconsistent findings regarding their metabolic effects. 104 There is also some evidence suggesting a non-causal relationship between fetuin-B and IR. 105
Adropin is a peptide with pleiotropic functions. Interest has been focused on glucose metabolism, as literature reports evidence of a reduction of hepatic gluconeogenesis, activation of the GLUT4 receptor, stimulation of insulin sensitizing cascades, such as Akt, improvement of lipid profile and most importantly, inhibition of inflammation. TNF-α and IL-6 are reduced and the endothelium is protected via effects exerted on eNOS. 106 With regard to liver glucose synthesis, researchers demonstrated that adropin sensitizes the AMPK pathway by acting on protein phosphatase 2 (PP2A). 107 A few studies also demonstrated the association between elevated plasma adropin levels and glucose and lipid homeostasis and insulin sensitivity, whereas its absence predisposes to obesity and IR.108–110
Sodium-glucose cotransporter 2 inhibitors (SGLT2-i), which will be discussed later, are instrumental in regulating atherosclerosis-related inflammation. Their mechanism of action includes attenuation of M1 macrophages and foam cell formation, enhancement of anti-inflammatory M2 macrophages and peroxisome proliferator-activated receptor-gamma (PPAR-γ) signaling, reduced oxidation of LDL-C and reduced production of pro-inflammatory cytokines, tipping the balance in favor of an anti-inflammatory state and regression of atherosclerotic plaque formation. 111
Dyslipidemia
Type 2 diabetes mellitus and IR are associated with dyslipidemia; the combination of these entities may further increase the risk for CVD. For example, the Framingham Heart Study (FHS) and later associated studies have demonstrated a correlation between abnormal circulating cholesterol levels and CVD for more than half a century;112,113 setting the foundation for determining certain risk profiles and scores, including the well-known Framingham Risk Score for coronary heart disease (CHD). 114 Total cholesterol and high-density lipoprotein cholesterol (HDL-C) plasma levels are among the score parameters. On the other hand, the ARIC study has also demonstrated an increased relative risk of CHD, and therefore CVD, with increased LDL-C and especially small dense LDL-C (sdLDL-C) levels. 115 IR is the culprit behind diabetic dyslipidemia and is characterized by decreased levels of HDL-C and increased levels of sdLDL-C, both metabolically linked to each other through hypertriglyceridemia or elevated VLDL-C plasma levels. 116 Approximately 75% of T2D patients present with dyslipidemia; 117 it precedes T2D and constitutes an early event in the pathogenesis of atherosclerotic CVD. 118 In the Look AHEAD study, a higher risk of adverse CVD outcomes was found in overweight and obese patients with T2D and dyslipidemia. 119 Studies suggest causality between hypertriglyceridemia and CVD;120–122 TG levels >500 mg/dl (>5.7 mmol/l) are associated with increased CVD risk and mortality. 123 Another study demonstrated a strong correlation between hypertriglyceridemia and sdLDL-C with myocardial infarction (MI) and peripheral atherosclerosis. 124
In the IR state, insulin, despite its already high levels, cannot exert its inhibitory effects toward VLDL-C secretion from the hepatocytes or degradation of apolipoprotein B (apoB), leading to the elevation of triglycerides in the circulation; these levels are also sustained at a high value due to the concurrent release of FFA, as part of IR-related adipose tissue dysfunction. Lipoprotein lipase (LPL) activity is also affected and the clearance of VLDL-C is impaired. Hypertriglyceridemia ultimately leads to the generation of the highly atherogenic sdLDL-C, although the total LDL-C levels appear to increase only mildly, and also leads to lower quality and quantity of HDL-C. The role of cholesteryl ester transfer protein is crucial in enriching LDL-C and HDL-C with TG, further inducing their lipolysis by hepatic lipase. As a result, sdLDL-C plasma levels increase, whereas HDL-C plasma levels and apolipoprotein A-I diminish. 125 In fact, TG to HDL-C ratio is a widely used index indicative of IR development, 126 although it may not necessarily represent an independent prognostic factor for CVD development after taking into account the already established traditional risk factors, as demonstrated by a cohort study conducted on postmenopausal women. 11 The sdLDL-C particles are particularly proatherogenic for various reasons: their smaller size facilitates their entrance into the vessel walls; they have impaired affinity with the LDL-C receptor; a longer half-life and lower resistance to oxidation.127,128
Oxidative stress
A contemporary definition of oxidative stress focuses on the incapability of endogenous cellular mechanisms to maintain redox homeostasis, mainly because of the disruption of redox signaling. Abundant reactive oxygen species (ROS) and nitrogen species, either radical or non-radical, and deficiency of antioxidant mechanisms are the main components of oxidative stress. Focusing on ROS, inflammation majorly contributes to their genesis, enhanced by the accumulation of polymorphonuclear cells and macrophages. 129 Odd electrons derived from cellular respiration and other metabolic processes generate superoxide and hydrogen peroxide, the primary oxidants that cause cellular and molecular damage, also giving rise to reactive species like peroxynitrite, singlet oxygen and hypochlorous acid. 129 Oxidative stress has a detrimental impact on DNA, proteins and lipids and participates in the formation of advanced glycation end-products (AGEs) in hyperglycemic conditions, while being also an essential contributing factor to the formation of atherosclerotic plaques. 130
Oxidized LDL-C (oxLDL-C) is produced when ROS indirectly oxidize apoB-100 and modify the original LDL-C, rendering it a crucial factor in atherogenesis. Smoking also directly oxidizes LDL-C. OxLDL-C is capable of binding to specific receptors on endothelial cells, known as lectin-like oxidized LDL receptors-1. The uptake of oxLDL-C by endothelial cells promotes matrix metalloproteinase (MMP) production, downregulates eNOS, thus impairing vasodilation ability, induces leukocyte adhesion to the endothelium and renders the endothelium prothrombotic. OxLDL-C also binds to scavenger receptors (SR) on macrophages, yielding lipid-rich foam cells, a core element of plaques. Excess ROS are additionally held accountable for stimulating smooth muscle cell migration and SR expression, as well as collagen deposition to the injured endothelial site, acting as a link between innate and adaptive immunity and inducing the release of MMPs, which ultimately lead to rupture of the plaques’ fibrous caps.131,132 They also lead to dismantled insulin function and adipokine dysregulation. 31 ROS are generated by various systems, namely nicotinamide adenine dinucleotide phosphate oxidase (NOX), xanthine oxidase, mitochondrial enzymes, myeloperoxidases and uncoupled eNOS.131,132 All systems contribute to atherosclerosis. However, NOX is the most crucial ROS generator system in the cardiovascular system, with the NOX2 subunit being of significant importance in atherosclerosis, increasing superoxide production and reducing the bioavailability of NO. 133 On the other hand, dysfunction of the myeloperoxidase system and smoking potentiate alterations in MAPK signaling, which mediates inflammation, cell proliferation and atherosclerosis; 131 MAPK is associated with the mitogenic effects of insulin, as previously mentioned. 6
Advanced glycation end-product generation occurs when cellular protein and lipid molecules are constantly exposed to elevated glucose levels, as in IR and diabetes; and AGEs are the cause of diabetic complications, such as diabetic retinopathy, nephropathy and CVD.134,135 Hyperglycemia favors their formation, induces chronic inflammation biomarkers and participates in ROS formation.6,136 AGEs activate NOX, inhibit eNOS activity and interact with the extracellular matrix to promote ROS generation after binding to AGE receptors, inducing further endothelial damage and reduced NO production. 135 AGEs also stimulate oxidative pathways, such as the protein kinase C signaling cascade. 137 Ultimately, AGEs are core elements in the generation of excess ROS levels.
Endothelial dysfunction
The endothelium comprises the innermost single-cell layer of the arterial wall and its functions are a cornerstone in maintaining vascular integrity. Vascular homeostasis ensures oxygen and nutrient transportation to tissues, conservation of optimal vascular tone, regulation of hemostasis and the inflammatory response. When endothelial cells cannot exert their function properly, conditions like atherosclerosis and hypertension rise. NO is a small lipophilic molecule that mediates vascular tone and its bioavailability determines vascular homeostasis, being the most potent vasodilator. It also has anti-inflammatory, antioxidant and anti-coagulant properties and inhibits leukocyte adhesion and smooth muscle cell proliferation.138–140 NO is produced from L-arginine by nitric oxide synthase (NOS) isoforms with the aid of various co-factors. NOS3, or eNOS, is abundant in endothelial cells. Post-translational modifications of eNOS along with ROS create the uncoupled form of eNOS and thus decrease NO production, which is also diminished by reduced availability of substrates or co-factors and increased NO breakdown.141,142 NOS2, or inducible NO synthase (iNOS), is widely expressed in macrophages, stimulated by inflammatory signals and regulated by pathways and agents linked to IR, namely MAPK and NF-kB. Finally, NOS1, or neuronal NO synthase, is found mainly in the ventromedial hypothalamus.143–145
Insulin mediates cardiovascular events via the L-arginine/NO pathway, and these elements appear to be part of a vicious, never-ending cycle. 146 Insulin enhances endothelial NO production and vasodilation via the PI3K cascade activation; however, in IR, insulin’s action is shifted towards vasoconstriction, hypertrophy of smooth muscle cells and accelerated atherosclerosis via activation of the MAPK pathway. 146 Vascular IR is prominent in obese and diabetic patients and increased vascular resistance related to obesity and diabetes is mainly attributed to diminished NO bioavailability. Defective NO synthesis in the vessels and impaired vasodilation are linked to hyperinsulinemia and IR, a state in which oxLDL is also elevated, as previously mentioned. In addition, elevated LDL-C levels extensively contribute to downregulating eNOS expression.147,148 Obesity, accompanied by IR, diminishes the expression of eNOS. Anti-obesogenic and insulin-sensitizing abilities are attributed to eNOS-derived NO; eNOS additionally mediates insulin and glucose transport in skeletal muscle and adipocytes and regulates gluconeogenesis. Absence of iNOS has been linked with ameliorated glucose tolerance and insulin sensitivity, whereas its overexpression in liver promotes hyperglycemia, hyperinsulinemia and hepatic IR. NOS1-derived NO is related to appetite stimulation and hyperphagia. 149 Nevertheless, glucose metabolism and insulin-stimulated NO production share common signaling pathways, underpinning a coupling between insulin’s metabolic and vascular effects. 150 Interestingly, a previous study demonstrated that glucosamine is a potent inhibitor of endothelial NO production; glucosamine production is enhanced by chronically elevated plasma glucose levels. 148 Overall, inadequate bioavailability of NO in the endothelium abolishes vasodilation and results in hypertension and inflammation while facilitating arterial stiffness, a precursor and predictor of CVD. 151
Hypertension
Hypertension is one of the most common clinical predicaments that stem from increased peripheral vascular resistance and, in some cases, increased cardiac output. Increased basal sympathetic tone activity and overactivation of the renin–angiotensin–aldosterone system (RAAS) characterize hypertension. 152 Hypertensive patients tend to be hyperinsulinemic and glucose intolerant. 153 As suggested by a meta-analysis of 10 230 hypertension patients, fasting insulin levels and IR constitute independent factors for hypertension development; the relative risk of hypertension for fasting insulin concentrations was 1.54, with a higher risk in women compared with men, and the RR for HOMA-IR, an IR index, was 1.43. 153 A previous study used the euglycemic hyperinsulinemic clamp method to demonstrate that 25% of the hypertensive subjects had concurrent IR. 154 On the other hand, other estimations predict that 50% of hypertensive patients are insulin resistant, 155 not to mention the recent finding that the triglyceride-glucose (TyG) index is a potentially useful index for IR screening in Asian patients with hypertension. 156 Association between increased plasma insulin levels and elevated plasma catecholamine levels, evidence demonstrating IR development in rodents fed a high-carbohydrate diet, as well as prospective epidemiological studies linking hyperinsulinemia with CAD have been enforcing the establishment of a relationship between IR, hypertension and CVD for more than 30 years. 157
Insulin regulates endothelial NO production and the secretion of endothelin-1 (ET-1), a strong vasoconstrictor agent. The balance between vasorelaxation and vasoconstriction in IR tilts towards the latter, leading to hypertension and endothelial dysfunction. Decreased NO production interferes with renal vascular tone, inducing vasoconstriction and increased sodium reabsorption.155,158 RAAS consists of hormones essential to maintaining homeostasis in arterial blood pressure. Renin converts angiotensinogen to angiotensin (Ang) I, which is in turn converted to Ang II by angiotensin converting enzyme (ACE). Ang II induces an increase in blood pressure via AT1 and AT2 receptors. In short, Ang II stimulates vasoconstriction and promotes sodium retention, acting on proximal tubules and the adrenal zona glomerulosa and releasing aldosterone, which also retains sodium and water in the distal tubules. Increased RAAS expression in WAT, especially in VAT, is associated with an increase in BMI. RAAS activity and increased body weight are positively correlated, and RAAS activity is decreased after weight loss. Adipose RAAS induces and exacerbates IR; Ang II and aldosterone disturb insulin-dependent glucose uptake and generate ROS, further promoting IR. 159 Hyperinsulinemia is involved in a vicious cycle of vasculopathy, smooth muscle cell proliferation, atherogenesis, cellular calcium overload and renal sodium reabsorption. 160 In addition, it might synergistically activate the MAPK pathway along with RAAS. 161 In diabetic patients, RAAS is upregulated with prominent elevations in plasma renin, arterial pressure and renal vascular resistance. On the other hand, losartan had a better antihypertensive result in hyperglycemic than normoglycemic patients. Hyperglycemia aids local Ang II production and enhances the tissue response to it, produces AGEs, which also cause stimulation of the Ang II/AT1R pathway, and finally downregulates ACE2, an enzyme producing Ang 1-7, causing a further imbalance in RAAS. In general, RAAS antagonists can reverse the diabetes-induced RAAS activation and its effects on hypertension and vasculopathy. 162 Furthermore, certain antidiabetic mediations exerting protective cardiovascular effects, such as SGLT2-i and glucagon-like peptide-1 (GLP-1) receptor agonists, appear to favorably interact with RAAS. 163 Finally, 10–15% of hypertensive patients, >50 years old, present with atherosclerotic renal artery stenosis (ARAS), a clinical condition predisposed by classic atherosclerotic risk factors, including MetS and diabetes mellitus. As the prevalence of MetS is increased in both patients with ARAS and patients with peripheral artery disease, and as patients with ARAS frequently have co-existing peripheral atherosclerotic lesions, it appears safe to postulate that both IR states and renal artery atherosclerosis are contributing to hypertension.164–166
A very recent large Chinese nationwide, prospective, cohort study, which was conducted on 111 576 adults without CVD at baseline, elucidated the causal relationship between IR and CVD in relation to the glucose tolerance status. 167 The study reached the following conclusions: (i) glucose intolerance status exacerbated the association between IR and CVD; (ii) prediabetic obese adults with IR were at a higher risk for CVD; (iii) in diabetic patients, IR increased the risk for CVD; however, this risk was not further increased by the presence of obesity. 167
A brief summary of the mechanisms by which IR promotes CVD is shown in Table 1. In addition, a schematic depiction of the pathophysiological factors linking IR with CVD is shown in Figure 1.
A brief summary of the mechanisms by which insulin resistance promotes cardiovascular disease.
Schematic depiction of the pathophysiological factors linking insulin resistance (IR) with cardiovascular disease (CVD). FFA, free fatty acids; LDL-C, low-density lipoprotein cholesterol; sdLDL-C, small dense LDL-C; TGs, triglycerides; HDL-C, high-density lipoprotein cholesterol; ROS, reactive oxygen species; oxLDL-C, oxidized LDL-C; AGEs, advanced glycation end-products; NO, nitric oxide; RAAS, renin–angiotensin–aldosterone system; ET-1, endothelin-1.
Management of insulin resistance
Modification in lifestyle choices along with medications constitute the core of the management of IR states. Nutritional guidelines and meta-analyses propose a low glycemic index diet, preferably low-carbohydrate, rich in fibers (both soluble and insoluble), with an adequate protein and low-fat content, combined with at least 150 minutes of moderately intensive aerobic exercise, or 75 min of strenuous aerobic activity, or a combination of them, per week. These nutritional routines have been proved to improve IR, decrease BMI due to fat loss, reduce HbA1c and render the gut microbiota more balanced. Plant-based proteins and carbohydrates induced more notable effects toward improvement of IR and achievement of target weight. Undoubtedly, clinicians ought to personalize and tailor dietary and exercise plans to each patient’s metabolic profile, preferences, habits and lifestyle for maximum efficacy.168,169
Dietary adjustments and bariatric surgery
A 24-week randomized, open, parallel study on 74 patients with T2D, assigned an isocaloric, calorie-restricted vegetarian diet versus a conventional diabetic diet to the experimental and control groups, respectively, along with exercise in the second half of the study.
170
The findings demonstrated that insulin sensitivity improved significantly with vegetarian meals compared with the control group: 30% (95% confidence interval [CI] 24.5, 39) versus 20% (95% CI 14, 25), respectively (
Nevertheless, another study disputes the supremacy of the MedDiet, suggesting that high-protein dietary patterns achieve better results in minimizing IR. 174 In 16 women that completed the 21-day randomized, controlled, inpatient crossover feeding trial, the high-protein diet reduced IR more effectively than the MedDiet, while improving glycemic variability and favorably altering the gut microbiota. 174 Either way, low-carbohydrate intake is generally well tolerated in humans who can utilize ketone bodies as an alternative fuel. Ketotic states maintain low insulin levels, improve insulin sensitivity, potentiate the breakdown of fat stores and spare lean muscles, while improving metabolic and inflammatory parameters; hence, ketosis could also be helpful for lean weight loss, fat loss and improvement of insulin resistant states. 175 Finally, a systematic review pertaining to a ubiquitous IR manifestation in females, PCOS, assessed dietary interventions on 1193 participants with PCOS. 176 Results revealed that IR markers and body composition might be optimally benefited from the Dietary Approaches to Stop Hypertension diet and calorie-restricted diets, respectively, with results comparable with metformin. 176
Typical eating patterns in modern societies comprise at least three meals a day. Routines based on intermittent fasting (IF), namely early-time restricted feeding (eTRF), have been the main subject of interest for various studies. IF and periodic fasting in rodents may be able to delay the development and evolution of various diseases, including diabetes, CVD, Alzheimer’s disease and stroke. IF has also been proven to be efficient in humans, prompting weight loss and favorably affecting IR and other risk factors for CVD. A randomized controlled trial tested the efficacy of eTRF in prediabetic men compared with a control diet for 5 weeks.
177
This pattern suggests a 6-h eating period with dinner prior to 15:00, followed by an extended fasting period; all patients that completed the study exceeded expectations with regard to compliance. Results concluded that eTRF is useful in lowering insulin levels and arterial blood pressure, improving insulin sensitivity, and reducing appetite and oxidative stress, thus rendering it an efficient strategy for prediabetic and prehypertensive patients with no apparent significant impact on lipid profile, arterial stiffness or inflammatory markers. Overall health improvement relies on signaling cascades related to mitochondrial function, DNA repair mechanisms and autophagy.177,178 Another randomized controlled trial studied the impact of intermittent and continuous energy restriction (IER and CER, respectively) on metabolic disease markers and weight loss in 107 premenopausal women with a BMI varying from 24 to 40 kg/m2.
179
Both IER and CER were equally effective in weight loss (–6.4 kg [95% CI –7.9, –4.8 kg] for IER versus –5.6 kg [95% CI –6.9, –4.4 kg] for CER).
179
There was a more significant impact of IER on IR reduction and fasting insulin levels: the difference between the groups for fasting insulin was –1.2 µU/ml (95% CI –1.4, –1.0 µU/ml); and for insulin resistance it was –1.2 μU/mmol/l (95% CI –1.5, –1.0) (both comparisons
Gut microbiota alterations in IR, diabetes and obesity is a significant, ongoing field of investigation. There is some evidence suggesting that overweight people present an altered
Vitamin D deficiency characterizes patients with T1D and T2D, and numerous observational and preclinical trials underline the importance of this nutrient in their pathogenesis; 70% of prediabetic patients with hypovitaminosis D eventually become diabetic. Vitamin D receptors are abundant in pancreatic beta cells and in immune cells, plausibly explaining why vitamin D potentiates improvement in insulin sensitivity and inflammatory states. Hence, nutritional vitamin D supplementation might retard the conversion of prediabetes to diabetes and improve IR by up to 60%, also favorably affecting other conditions related to IR, such as PCOS and MetS. Dosage must be calibrated accordingly, taking into account parameters like the degree of deficit, age, possible bariatric surgery status and other malabsorption factors.
181
Nonetheless, the hypothesis that vitamin D supplementation may potentiate insulin sensitivity, thus improving IR, is supported mainly by observational studies, whereas pertinent relative clinical evidence to this day has not been conclusive.
181
In a randomized clinical trial, 2423 prediabetic adults were assigned to receive either vitamin D3 (4000 IU daily) or placebo on a daily basis.
182
Within 2.5 years, 9.39 and 10.66 events of diabetes per 100 person-years occurred, respectively, with the hazard ratio for vitamin D being 0.88 compared with placebo (
Metabolic or bariatric surgery is the most effective therapeutic choice for obese patients leading to weight loss and amelioration of diabetes and IR. Meta-analyses report that, along with weight loss, diabetes remitted after bariatric surgery, with a chance for remission being as high as 65%, and simultaneous favorable 5-year changes in glycated hemoglobin were also noted. These improvements were noticed shortly after the performance of the operation; some suggested mechanisms include alterations in gut microbiota and decreased caloric intake with depletion of liver fat and improvement of IR and the associated inflammatory profile. A systematic review of the literature, which assessed 19 543 patients subjected to metabolic surgery, demonstrated a reduction in the incidence of cardiovascular risk factors, such as T2D, hypertension and dyslipidemia, in those patients, which would potentially lead to a reduction in the occurrence of adverse cardiovascular events. 183 Notably, in this study, 73% of the patients with T2D presented resolution or remission of diabetes. 183 Additionally, following bariatric operations, adaptive immunity shifts in favor of an anti-inflammatory state, along with an increase of anti-oxidant properties and reduction of oxidative stress, thus establishing an overall low-inflammation phenotype and a reduction in IR. 184
Exercise
The link between exercise, longevity and delayed onset of diseases has been noted for more than 2000 years by Hippocrates and was proven epidemiologically for the first time in the 1950s when sedentary lifestyle was correlated to increased prevalence of CHD. T2D development can be delayed or even reversed in prediabetic patients with systematic exercise, regardless of race. Studies in China, Finland and the US concluded that the onset of T2D was reduced by 46% in 6 years with exercise. On the other hand, diet alone reduced T2D by 31%. A combination of diet and exercise increased that percentage to 58%, which was more efficacious than metformin alone. During exercise, muscle fiber contraction generates metabolic and mitochondrial adaptations, facilitating insulin-dependent glucose uptake by skeletal muscles, thus improving hyperinsulinemia and promoting cross-talk between tissues through myokine secretion. Myokines released from muscles after bouts of exercise have an endocrine function and seem to increase GLP-1 secretion, lipolysis and glucose uptake by adipocytes, all of which are related to the promotion of insulin sensitivity. 185 High-intensity interval training and high-intensity functional training effectively improve all health markers, induce the secretion of vascular endothelial growth factor, an enhancing factor for NO production, and stimulate anti-oxidant enzymes and IGF-1, all favorably affecting insulin sensitivity. 186
Exercise has been shown to play a strong beneficial role in patients with MetS. For example, a study of 19 223 men demonstrated that the relative risk (RR) for all-cause and CVD mortality was 1.29 and 1.89, respectively, for men with MetS compared with healthy men. 187 However, this difference was smoothed out and became non-statistically significant once cardiorespiratory fitness (CRF) was included in lifestyle, with RR being 0.98 for all-cause and 1.23 for CVD mortality. 187 CRF impact was dose-dependent. 187 Another trial on the same group demonstrated the alleviation of statistical significance of RRs for all-cause and CVD mortality in normal, overweight and obese people with and without MetS after the inclusion of CRF in their lifestyles. 188 Time spent on physical activity is another determinant, with 60 minutes a week of leisure-time vigorous physical activity significantly reducing rates of MetS among unfit and fit men. 189 A meta-analysis of the impact of structured exercise programs on IR in 846 diabetic patients demonstrated clear evidence for the effectiveness of structured exercise programs in reducing IR in patients with T2D. 190 Another randomized controlled trial confirmed the effectiveness of an 8-week aerobic exercise protocol on diabetic women in decreasing glucose plasma levels, insulin levels and IR with HOMA-IR being the evaluation tool. 191
Current literature involving numerous studies suggests that resistance training enhances insulin sensitivity and glucose tolerance among different population groups, including young and old subjects, postmenopausal women and hypertensive or diabetic patients. Emerging evidence also suggests that aerobic exercise and resistance training provide benefits through distinct mechanisms of action, which are worthy of further investigation.
192
Resistance training in diabetic adults was found to be more effective than aerobic training at increasing maximal oxygen consumption within 12 weeks or longer with no apparent differences in HbA1c, BMI and lipid profile.
193
Exercise intervention is also strongly recommended with regard to juvenile IR, as it can moderately improve insulin levels and IR.
194
Another meta-analysis involving obese children and adolescents showed that physical exercise improved fasting insulin levels and HOMA-IR (fasting insulin: –3.37 μU/ml [95% CI –5.16, –1.57 μU/ml];
Medications
It ought to be mentioned that there are currently no medications approved specifically for the treatment of IR. However, various studies confirm the efficacy of certain antidiabetic drugs in reducing IR, including metformin, TZDs, SGLT2-i and GLP-1 receptor agonists, which will be described below.
Metformin is an oral biguanide and one of the oldest antidiabetic drugs in use. Its glucose lowering effects rely on the inhibition of hepatic glucose production, reduction of lipid secretion from intestinal cells and increased fatty acid oxidation in muscle cells and adipocytes. Therapeutic doses are beneficial in hepatic cellular respiration. Its action in intestinal cells is notable, affecting oxidative phosphorylation, glycolysis, lactate production and the gut microbiota, though doses exceeding the recommended range interfere with mitochondrial respiration. 196 Metformin potentiates the increase of GLUT4 production and expression, as confirmed by numerous trials on animals and humans, including women with PCOS, thus facilitating glucose uptake. Involved mechanisms include interference with the insulin signaling pathway, activation of AMPK signaling pathways and GLUT4 transport mediators and epigenetic modification, suggesting that metformin improves IR via AMPK dependent and independent mechanisms and delays or prevents T2D development with a concomitant improvement in cardiovascular outcomes.197,198
An ongoing double-blind, randomized controlled trial on 40 adults, the INTIMET study, aims to quantify the beneficial effects of metformin on liver, muscle and adipose tissue IR in patients with T1D and may also identify factors that predict an individual's response to metformin in T1D. 199 Metformin has been found to improve endothelial function by reducing PAI-1, CRP and ET-1 levels, improving NO synthesis and positively affecting oxidative stress conditions. Most importantly, a 32.5% reduction in IR, as measured by HOMA-IR, during metformin administration was noted. 200 Another double-blind, placebo-controlled clinical trial on 37 overweight or obese young T1D patients favored metformin in terms of improving IR, both whole-body and peripheral, but it did not affect endogenous glucose release. 201 A particular reference ought to be made for metformin and PCOS, a prediabetic state that affects 5–10% of women of reproductive age and has a negative impact on body weight and overall cardiovascular risk factors. Metformin can modify hyperandrogenemia and irregular menstrual cycles in PCOS by exerting its effects on IR, and its combination with myoinositol and TZDs exert a superior effect.202–205 However, neither exogenous insulin administration nor metformin can prevent pancreatic beta cells from losing their function in young patients with impaired glucose tolerance or recently diagnosed T2D. 206
Thiazolidinediones, rosiglitazone, pioglitazone and troglitazone, are oral antidiabetic drugs, known to be beneficial in IR conditions. Their mechanism of action comprises activation of PPAR-γ, a nuclear receptor that modifies the transcription of various genes, namely those encoding GLUT4 receptors, LPL and other enzymes involved in energy homeostasis. IR is reduced in adipose tissue, muscle cells and the liver. PPAR-γ is abundant in adipocytes, suggesting endocrine communication with skeletal muscles and hepatocytes; molecules like FFAs and TNF-α might also be a part of signaling. Along with the improvement of dyslipidemia, IR amelioration leads to a consequent reduction of CVD risk. Pioglitazone has also been found to reduce MI and ischemic strokes. Thus, after extensive comprehension of the risk for side-effects, clinicians are now more capable of selecting patients eligible for TZD prescription, balancing benefits and risks.207–212 Administration of TZDs has been proven to delay beta cell dysfunction, as measured by certain specific indices, by exerting protective effects against oxidative stress and preserving the composition of the islets.213,214
Several studies including randomized controlled trials confirm the value of TZDs in IR management. For example, in the DREAM study, 8 mg of rosiglitazone daily reduced the incidence of T2D by 60% and increased normoglycemia by 70% in people free of CVD.
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A DREAM substudy revealed reduction of hepatic and visceral fat and an increase in subcutaneous fat and adiponectin levels; however, these changes cannot explain the normoglycemic effects of TZDs.
216
The ADOPT study indicated that glucose levels were better regulated with rosiglitazone compared with metformin and glibenclamide (risk reduced by 32% and 63% compared with metformin and glibenclamide, respectively;
Glucagon-like peptide-1 is an incretin secreted by the distal ileus, colon, pancreas and central nervous system. Its half-time is narrowed to 2 minutes, mainly due to its catabolism by dipeptidyl-peptidase 4 (DPP-4). GLP-1 binds to GLP-1 receptors, which are abundant throughout the body and exert a variety of actions, amongst which effects that contribute to energy homeostasis, namely reduced hepatic gluconeogenesis and steatosis, increased survival, proliferation and decreased apoptosis of pancreatic beta cells, increased insulin sensitivity and glucose uptake from muscle cells, increased lipolysis and glucose uptake from adipocytes and reduction of appetite. GLP-1 receptor agonists, liraglutide, exenatide, semaglutide, lixisenatide, dulaglutide, albiglutide, were manufactured to reproduce the multisystemic actions of GLP-1 via binding to GLP-1 receptors. The aforementioned effects of GLP-1 explain the wide use of GLP-1 receptor agonists in the management of IR and coexisting conditions, namely T2D, NASH and PCOS, with encouraging data concerning protection from CVD. Studies have demonstrated improved IR parameters and reduced lipotoxicity related to NASH, reduced hepatic and visceral fat accumulation and improved glucose permeability through the blood–brain barrier.221–225 In addition, these receptor agonists have been proven to be useful treatment agents in PCOS patients with IR. 226 Administration of liraglutide as monotherapy or combined with metformin also induced weight loss and reduction of testosterone but with mixed results concerning IR improvement. 222
Many clinical studies confirm the efficacy of GLP-1 receptor agonists in glycemic control and weight loss management with insignificant risks of hypoglycemia. Different GLP-1 receptor agonists may exhibit different pharmacokinetic and clinical effects, with convincing evidence regarding their cardioprotective capacity. 227 Liraglutide in particular inhibits kinase pathways, such as PI3K/AKT and ERK 1/2 on one hand, reducing vascular smooth muscle cell proliferation related to hyperglycemia, and MKK4/JNK on the other hand, leading to the improvement of the hypoadiponectinemia-induced inflammatory stress in NASH. 227 Other beneficial effects of GLP-1 receptor agonists related to atherosclerosis include the moderation of inflammation in plaques, as well as the amelioration of dyslipidemia and endothelial dysfunction.225,228 Liraglutide, semaglutide and albiglutide reduce the risk of major adverse cardiac events, while exenatide and lixisenatide exhibit neutral effects. 229 Another meta-analysis suggested that all GLP-1 receptor agonists are capable of reducing cardiovascular incidents, cardiovascular mortality and all-cause mortality to different degrees, with no significant adverse effects, allowing for the personalization of drugs and regimens. 230 A dual gastric inhibitory peptide and GLP-1 receptor agonist, tirzepatide, favorably modulated metabolites related to IR and future T2D risk with more significant reductions of HbA1c levels, HOMA-IR and amelioration of dyslipidemic profile, as compared with dulaglutide and placebo, leading to an overall improvement of metabolic health. 231 GLP-1 receptor agonists enhance NO production and activate several kinases in cardiomyocytes, including Akt-1, PI-3K and MAPK, potentiating glucose uptake and further cardioprotection against ischemia; additionally, NO production by GLP-1 receptor agonists in endothelial cells promotes vasodilation. 232
Sodium-glucose cotransporter 2 inhibition constitutes a novel and effective therapeutic strategy for managing T2D with concomitant cardiovascular benefits. Empagliflozin, dapagliflozin, canagliflozin and ertugliflozin are currently approved and used in everyday clinical practice. These medications inhibit the glucose reabsorption by the S1 segment of the proximal tubules in nephrons where SGLT2 are located. SGLT2 are responsible for the reabsorption of 80–90% of glucose. 233 Hence, SGLT2-i achieve glycemic control via glucosuria; HbA1c levels decrease by 0.5–1.0% and there are also prominent improvements in BMI, lipid profile, endothelial function and a reduction of arterial blood pressure. 233 Empagliflozin is an SGLT2-i, ideal as monotherapy or as an add-on antidiabetic agent due to its once-a-day dosage regimen, preferred and prescribed for T2D patients with elevated CV risk in the EU, USA, Japan and other countries. 234 Empagliflozin increases adipose tissue utilization and browning in WAT and attenuates IR and obesity-derived inflammation via activation of M2 macrophages. 235 Furthermore, it reverses brain IR by increasing responsiveness of the hypothalamus to insulin, a plausible mechanism concerning the regulation of energy metabolism and reduction of fasting glucose levels and hepatic fat. 236 The action of empagliflozin is superior to that of sitagliptin, a DPP-4 inhibitor, with regard to amelioration of IR and improvement of cardiometabolic health in early-stage T2D. 237 Additionally, glucosuria induced by empagliflozin has been shown to improve beta cell function and IR, regardless of elevated endogenous glucose production and decreased insulin secretion, with a further reduction in fasting and postprandial hyperglycemia. 238 Several systematic reviews and meta-analyses provide data in favor of SGLT2-i for the management of NAFLD, the hepatic component of IR and precursor to NASH, and PCOS.239–243 Empagliflozin and dapagliflozin, along with hepatic fat reduction, also aid in reducing total body weight, alanine aminotransaminase and aspartate aminotransaminase levels, IR and liver fibrosis; and in women with PCOS, these agents have been shown to reduce body weight, fasting plasma glucose levels, HOMA-IR and androgen levels.239–243 Literature suggests that several molecular mechanisms favor the promotion of insulin sensitivity by SGLT2-i:244,245 (i) suppression of glucotoxicity, attributed to the decrease of chronically elevated blood glucose levels via excretion of glucose through urine; (ii) enhanced caloric disposition and weight reduction, which is a consequence of reduction in the absolute number of adipocytes, reduction in the levels of adipocytokines and amelioration of lipotoxicity; (iii) attenuation of inflammation, including regulation of RAAS and immune responses, decrease of proinflammatory cytokines and increase of anti-inflammatory cytokines (IL-10), lowered activity of NLRP3 inflammasomes, modulation of expression of inflammatory-related genes and modification of the redox state; (iv) improvement of pancreatic beta cell function, via interference with the cascades responsible for cell apoptosis; (v) amelioration of oxidative stress, favoring proper mitochondrial function and RAAS regulation, decreasing pro-oxidant enzymes, free radicals and AGEs.
Literature confirms the favorable effects of SGLT2-i in the prevention of the cardiovascular complications attributed to T2D. SGLT2-i promote the alteration in the metabolic preferences of the heart, liver and kidneys to ketone bodies and short-chain fatty acids rather than glucose, along with water preservation and improvement of glomerular hemodynamics, thus contributing to cardiac, hepatic and renal protection in patients with or without T2D.246,247 Cardiovascular protection is also attributed to decreased plasma volume due to natriuresis and decreased oxidative stress, as well as decreased plasma uric acid levels, decreased proteinuria and reduced formation of AGEs, along with improved vascular and endothelial function. At the same time, in addition to the aforementioned favorable changes in myocardial metabolism, SGLT2-i have been also shown to improve calcium handling and myocardial energetics within the cardiomyocytes, effects that may lead to an improvement of HF outcomes.248,249 Evidence indicates that SGLT2-i moderately affect the incidence of major adverse cardiovascular events related to atherosclerosis but robustly favor the reduction of hospitalizations due to HF and delay of renal disease, regardless of patient history, with an associated reduction of cardiovascular and all-cause mortality.250,251 Several studies concerning SGLT2-i and GLP-1 receptor agonists suggest their tailored use in diabetic patients with CVD and chronic kidney disease, according to properly structured clinical guidelines.252–256
A summary of the results of the main trials discussed in this review is shown in Table 2 (non-pharmacological interventions) and Table 3 (pharmacological interventions).
A summary of the clinical trials reporting on the non-pharmacological interventions used in the management of insulin resistance (IR).
T2D, type 2 diabetes mellitus; CI, confidence interval; CVD, cardiovascular disease; MedDiet, Mediterranean diet; BMI, body mass index; HOMA-IR, homeostasis model assessment-insulin resistance; PCOS, polycystic ovary syndrome; AUC, area under the curve; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; hs-CRP, high-sensitivity C-reactive protein; IL-6, interleukin-6; IER, intermittent energy restriction; CER, continuous energy restriction; RR, relative risk; MetS, metabolic syndrome; HbA1c, glycosylated hemoglobin.
A summary of the clinical trials reporting on the pharmacological interventions used in the management of insulin resistance (IR).
T1D, type 1 diabetes mellitus; PCOS, polycystic ovary syndrome; BMI, body mass index; HOMA-IR, homeostasis model assessment-insulin resistance; AUC, area under the curve; T2D, type 2 diabetes mellitus; HbA1c, glycosylated hemoglobin; CI, confidence interval; CVD, cardiovascular disease; MI, myocardial infarction; NASH, non-alcoholic steatohepatitis; NAFLD, non-alcoholic fatty liver disease; TZD, thiazolidinediones; MD, mean difference; SMD, standardized mean difference; OR, odds ratio; GLP-1, glucagon-like peptide-1; HR, hazard ratio; HDL-C, high-density lipoprotein cholesterol; SGLT2, sodium-glucose cotransporter 2; ALT, alanine aminotransaminase; WMD, weighted mean difference; AST, aspartate aminotransaminase; TG, triglycerides; TC, total cholesterol; LDL-C, low-density lipoprotein cholesterol.
Conclusions and future directions
In conclusion, insulin constitutes an anabolic hormone with a pivotal role in energy homeostasis, exerting numerous effects in muscle cells, hepatocytes and adipocytes. Its overall action involves the facilitation of glucose uptake via insulin-dependent mechanisms that promote GLUT4 potentiation, thus maintaining normal circulating blood glucose levels. Different signaling pathways involving various kinases are activated and vessels can be affected positively or negatively, depending on the affected cascade. When insulin cannot fully exert its effects on target tissues, a clinical condition known as IR develops. IR is characterized by hyperglycemia and compensatory hyperinsulinemia, which can exhaust beta cells in the long term. Its measurement and quantification rely on various indices, mainly fasting insulin levels, HOMA-IR and glucose clamp technique. 257 IR is a precursor to many pathological conditions that characterize Western societies and are considered risk factors for the development of CVD, namely obesity, inflammation, dyslipidemia, endothelial dysfunction, oxidative stress and hypertension. In addition, IR accompanies prediabetes, NAFLD and NASH, PCOS and HF; all conditions associated with an increased CVD risk. Thus, IR is a condition predisposing to CVD via various complex, as yet not fully elucidated, mechanisms. Its management involves primary prevention strategies, including abandoning the Western lifestyle with proper diet modifications and avoidance of a sedentary lifestyle. Specific pharmacological agents have also been demonstrated to improve insulin sensitivity, such as metformin, TZDs, GLP-1 receptor agonists and SGLT-2-i, with a concomitant proven efficacy regarding the prevention of cardiovascular events, especially in the case of the latter classes of agents.
Future directions regarding IR have endless potential. Firstly, further
The search term ‘Insulin Resistance’ in ClinicalTrials.gov revealed over 3000 studies with different perspectives. Indicatively, researchers have focused on identifying novel urinary biomarkers for IR screening, the effect of specific diet modifications and dietary supplements, gut microbiota alterations and exercise in people according to age and sex, novelties concerning maternal IR screening and further investigation of classic antidiabetic drug use in IR. A recent phase 1b randomized controlled clinical trial studied an agent known by the name of BFKB8488A, a bispecific agonist antibody targeting fibroblast growth factor receptor 1c and Klothoβ. 266 In this study, BFKB8488A proved its safety and tolerability and showed encouraging effects in T2D and NAFLD, improving the patients’ lipid profile at the same time. 266 This sets the ground for further conduction of related trials and assessment of its potential as a novel pharmacological agent in the management of IR. Nevertheless, the future can move in a myriad of different directions. Undoubtedly, the scientific community still has a long way ahead on the journey of clarifying the mechanisms involved in IR, as well as its association with CVD. Vast efforts shall be made to discover and add new pharmacological agents in the armamentarium of IR management.
Footnotes
Author contributions
Conceived the concept: Constantine E. Kosmas; analyzed the data: Constantine E. Kosmas; wrote the first draft of the manuscript: Constantine E. Kosmas and Maria D. Bousvarou; contributed to the writing of the manuscript: Christina E. Kostara, Evangelia J. Papakonstantinou, Evdokia Salamou and Eliscer Guzman; made critical revisions of the manuscript: Constantine E. Kosmas and Maria D. Bousvarou; agreed with the manuscript results and conclusions: all authors; reviewed and approved the final version of the manuscript: all authors.
Declaration of conflicting interests
The authors declare that there are no conflicts of interest.
Funding
This research received no specific grant from funding agency in the public, commercial, or not-for-profit sectors.
