Endocrinology and Metabolism Clinics of North America
Insulin Resistance and Atherosclerosis
Section snippets
Prevention of cardiovascular disease in insulin resistance (current approaches)
Current primary prevention treatment modalities in patients with the metabolic syndrome and/or diabetes rely on risk factor modification (ie, reduction of hyperlipidemia, hypertension, obesity, and lifestyle changes). Although beyond the focus of this review, a few treatment options are especially worthy of mention. Beginning in the 1990s, large clinical trials demonstrated the enormous clinical utility of two classes of drugs, statins and angiotensin-converting enzyme inhibitors
Is modulation of insulin resistance beneficial for cardiovascular disease prevention?
As described above, the classical approach to the treatment of insulin resistance and diabetes is risk-factor modification (ie, directed treatment of the most skewed parameters of the disorders). Despite clear successes with this approach, it represents a reaction to long-standing metabolic derangements rather than treatment for a potentially unifying process, such as insulin resistance. Thiazolidinediones are a class of drugs known to improve insulin resistance that were found to act by
Insulin resistance and proatherogenic lipids
Despite the traditional focus on LDL and CVD risk, a portion of the connection between blunted insulin signaling, abnormal lipid metabolism, and atherosclerosis appears to be mediated by aberrations in triglyceride/very low-density lipoprotein and HDL levels instead of LDL [27]. Derangements in adipocyte and hepatocyte function play a central role in these abnormalities [28], [29].
Insulin resistance reduces the ability of adipose tissue to clear/store circulating lipids, in part because of
The role of insulin resistance in inflammatory signaling and atherosclerosis
An obvious connection between insulin resistance and atherosclerosis is derived from observations that obesity and insulin resistance often occur in concert with significant increases in inflammatory mediators [39], [40]. Atherosclerosis acts in many ways like an inflammatory condition with prominent cellular infiltration and robust cytokine expression [41]. One of the first links between obesity, insulin resistance, and inflammation was the demonstration that mouse adipose tissue can produce
NF-κB signaling and atherogenesis
A central mediator of inflammatory signaling in the vasculature of an insulin-resistant individual is the NF-κB family of nuclear transcription factors (Fig. 2). The classical and most prominent member of this family is a heterodimer of the p65/RelA and p50 proteins. In the cytoplasm, this dimer is bound to IκB proteins in an inactive state [50]. The arrival of extracellular signals (including several of the cytokines described above including TNFα and IL-1), stimulates the membrane-associated
JNK signaling and atherosclerosis
JNK is a member of the mitogen-activated protein (MAP) kinase family (which also includes extracellular signal-related kinase [ERK1/2], big MAP kinase [BMK1], and p38 MAP kinase) (reviewed in Ref. [57]). Although these serine/threonine kinases are responsive to a variety of stimuli, JNK signaling is potently activated by mediators of inflammatory and stress responses including cytokines and environmental stresses. Upon activation, JNK can phosphorylate a host of transcription factors, including
Direct effects of insulin resistance on the vasculature and atherogenesis
One of the early events in the pathophysiology of atherosclerosis appears to be endothelial dysfunction, a state of blunted vasodilatory capacity and reduced ability to protect against platelet aggregation, blood cell adhesion, and smooth muscle proliferation. A pivotal factor involved in vascular health is nitric oxide (NO), which is dynamically controlled by signaling processes [64], [65]. As patients with either the metabolic syndrome or diabetes have impaired NO-mediated vasodilation [66],
Are the direct effects of insulin resistance always pro-atherogenic or can insulin resistance play a paradoxical protective role?
As discussed above, the direct effects of insulin on the vasculature implicate insulin resistance in vascular/endothelial dysfunction. However, it should be noted that there are limited data extending this connection to atherosclerosis; regardless of the experimental system, most published studies use NO-mediated vascular reactivity/signaling as end points rather than more direct ones such as plaque formation/atherosclerotic burden. When one highlights studies assessing the role of insulin
Emerging themes: the concept of “protective macrophages” in insulin resistance and atherosclerosis
The discovery of adipose tissue as a secretory organ, capable of producing inflammatory markers especially in states of nutrient excess/obesity, was an important step in understanding the initiation of insulin resistance. In the past few years, this concept has been advanced and refined by implicating specific cellular events in the obesity-insulin resistance link. Immunohistochemical analysis of obesity-induced pathologic changes reveals a progressive accumulation of bone-marrow derived
Insulin resistance, oxidative/mitochondrial stress, and atherosclerosis
Mitochondria are the major source of ATP production by harboring both the enzymes of the tricyclic acid cycle and oxidative phosphorylation. The continuous flow of electrons from complex I through IV of the electron transport chain and pumping of protons though the inner mitochondrial membrane is contingent on steady-state nutrient delivery. In cases of nutrient excess, the surplus of effluxed protons leads to slowed electron transport chain kinetics and augmentation of alternative electron
Insulin resistance, genomic stress, and atherosclerosis
Damage to mitochondrial DNA is not the only consequence of excessive production of ROS; the nuclear genome is also susceptible to damage and alterations of relevant genes involved in DNA repair and stress response contribute to insulin resistance, vascular dysfunction, and atherosclerosis (reviewed in Ref. [105]). Patients with established CAD and diabetes have increased markers of genomic instability and oxidative DNA damage in peripheral blood mononuclear cells [106], [107]. FISH analysis of
Summary
The metabolic syndrome and diabetes are in large part varied manifestations of an underlying process known as insulin resistance. Normally insulin sensitive metabolic organs develop a progressive inability to respond to this signal with resultant metabolic derangements. Cardiovascular disease is associated with insulin-resistant states, although the presence of a myriad of insulin-signaling pathways potentially affecting vascular function precludes a simple explanation for this association.
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Cited by (88)
Beta-caryophyllene protects against diet-induced dyslipidemia and vascular inflammation in rats: Involvement of CB2 and PPAR-γ receptors
2019, Chemico-Biological InteractionsCitation Excerpt :However, BCP decreased all the atherogenic risk indices, in the present study, via CB2R while PPAR-γ receptors seemed to have a non-significant role. The inflammation is a common factor between dyslipidemia, insulin resistance, and atherosclerosis which is considered as an inflammatory condition with prominent cellular infiltration and cytokine expression [48]. Therefore, and to further support atherogenic risk indices predictability in the present model, we tracked inflammatory cascade, oxidative/nitrosative stress, in addition to the changes of aortic expression of VCAM-1 and eNOS as main contributors of atherogenesis and wellbeing of the vasculature.
Monocyte-Macrophages and T Cells in Atherosclerosis
2017, ImmunityCitation Excerpt :However, this potential has not been met as a result of a variety of issues, one example of which is the counteracting effects of obesity-induced insulin resistance. Insulin resistance is a potent risk factor for atherosclerotic heart disease because of its links to dyslipidemia and inflammation and because of the effects of high insulin and glucose on atherosclerotic lesional cells (Razani et al., 2008; Bornfeldt and Tabas, 2011). Indeed, largely as a result of the massive increase in the prevalence of obesity and insulin resistance, atherosclerotic vascular disease remains the leading cause of death in the industrialized world, and its prevalence is expected to rise over the next 20 years (Go et al., 2013; Behn and Ur, 2006; American Heart Association and American Stroke Association, 2017).
Insulin Resistance and Insulin Handling in Chronic Kidney Disease
2023, Comprehensive PhysiologyThe Relationship Between Admission Insulin Resistance Index (AIRI) and In-Hospital Outcome in Non-Diabetic Acute Coronary Syndrome
2023, Journal of the ASEAN Federation of Endocrine Societies
This work was supported by Grants HL083762 and DK076729 from the National Institutes of Health.