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The Impact of Insulin Resistance on Endothelial Function

Kayla Parker

Introduction

Summary Video

Background

The human body is a complex organism that scientists and doctors have been studying for centuries. Even today, new discoveries are constantly unfolding as the research process continues. Advancements in technology and measurement techniques have allowed researchers to deepen their understanding of physiological processes, which has been fundamental to developing treatments for various diseases of the human body. One such groundbreaking discovery was that of insulin.

History

In 1889 two German scientists determined that the removal of the pancreas in animals resulted in the development of severe diabetes. 1 They subsequently theorized that glucose homeostasis must be regulated by a substance released by the pancreas.1 This hypothesis was refined over the next few decades, and this substance was coined “insuline” in 1909 by a Belgian researcher.1 It was not until 1921 that insulin was finally isolated and made available for medicinal administration.1 The first human experiments began in January of 1922,1 and since then, insulin has been the focus of countless physiological studies.

Purpose

It is well established that insulin is an important regulator of many metabolic processes. While it is primarily known for its role in glucose storage, 2 it also plays a significant role in regulating endothelial function in blood vessels.3 The purpose of this article is to provide an overview of the relationship between insulin and endothelial function, as well as discuss the impact of insulin resistance on endothelial dysfunction. Areas of future research on this topic will also be mentioned.

Insulin and Endothelial Function

Role of Insulin

Insulin is a peptide hormone produced in the pancreas that is crucial for maintaining normal metabolism.1 It is secreted by the beta cells of the pancreatic islets of Langerhans,1 primarily in response to glucose. However, other nutrients, including free fatty acids, amino acids, and other hormones such as leptin, estrogen, and growth hormone may augment the insulin response as well.2 After its release from the pancreas, insulin signals the transporter GLUT4 to uptake glucose from the bloodstream into skeletal muscle and adipose tissue, respectively.4

The Role of the Endothelium

Beyond its well-known storage functions, insulin also functions as a regulator of the endothelium.5 Endothelial cells form the inner-most layer of blood vessels in the body and serve as a selectively permeable barrier between the blood and vessel wall.5 The endothelial lining also functions as an endocrine organ involved in clotting, angiogenesis, immune response, inflammation, and modulation of vascular tone and blood flow.5

Insulin and Nitric Oxide

Under normal, healthy conditions, insulin signaling results in vasodilation of the smooth muscle in blood vessels. It is important to note that this process is mediated by nitric oxide (NO).6 Through a long signaling cascade, insulin activates NO synthase (eNOS), which increases the production of NO (see Figure 1) and subsequent vasodilation.6 Nitric oxide is an important regulator of vascular tone, but it also has antiatherogenic effects as it inhibits proliferation of smooth muscle cells, reduces leukocyte adhesion, opposes inflammation, and prevents thrombosis.6 Under healthy conditions, the endothelium initiates an appropriate inflammatory response, and any endothelial injuries are efficiently repaired by endothelial progenitor cells (EPC).6

Insulin Resistance and Endothelial Dysfunction

Insulin and Endothelin-1

In an insulin sensitive state, proper endothelial functioning and NO production is usually maintained. However, insulin also stimulates the release of other mediators, such as endothelin-1 (ET-1) (see Figure 1), that have opposite and potentially detrimental effects on endothelial function.6 Endothelin-1 serves as the natural counterpart of NO – it causes vasoconstriction, promotes thrombosis, increases leukocyte adhesion, and increases migration of smooth muscle cells.6 Upregulation of ET-1 results from increased sympathetic activity, norepinephrine release, angiotensin II, and vascular shear stress.6 Dysregulation of ET-1 synthesis can occur in insulin-resistant states, causing endothelial dysfunction and potential.6

Figure 1: Schematic view of insulin-signaling pathways in endothelium. Binding of insulin to its own tyrosine kinase receptor results in insulin receptor substrate-1 (IRS-1)/phosphatidylinositol 3-kinase (PI3K) branch activation, with subsequent phosphorylation of Akt and activation of eNOS leading to increased production of NO. The mature form of ET-1 is released from biologically inactive precursors (big endothelins) by the ECEs. Activation of Ras/Raf/mitogen-activated protein kinase (MAPK) branch of insulin-signaling pathways increases the secretion of ET-1. MEK, MAPK kinase.6

Insulin Resistance

Insulin resistance is characterized by the inability of the body to properly respond to insulin, causing impaired glucose and fatty acid uptake in select tissues, namely the muscle, liver, and fat tissue.7 Insulin resistance may lead to several metabolic disorders including hypertension, hyperglycemia, dyslipidemia, and elevated inflammatory markers,7 all of which disrupt normal endothelial function and promote pro-atherosclerotic states.6

Impact on Insulin Resistance on Endothelial Dysfunction

Loss of NO bioactivity and bioavailability is one of the first consequences of insulin resistance.6 A decline in eNOS expression and activation is observed, followed by a decreased production of NO.6 This results in greater proliferation of smooth muscle cells, increased leukocyte adhesion, increased inflammation, and elevated reactive oxygen species.6 Paired with an increase in ET-1 release,6 the health of the endothelium can quickly deteriorate. Dysfunctional endothelium greatly contributes to the development of atherosclerosis and many other diseases of the heart, arteries, and other organs.6

Figure 2: Endothelial dysfunction under insulin resistance and hyperinsulinemia. Decreased eNOS protein expression or function, increased reactive oxygen species (ROS) formation/NO degradation, and enhanced ET-1 release are among mechanisms by which insulin resistance and hyperinsulinemia may contribute to endothelial dysfunction. Endothelial dysfunction increases expression of adhesion molecules, favors macrophage infiltration and release of proinflammatory cytokines (green spheres), induces proliferation of VSMC, and increases platelet aggregation. VCAM, vascular cell adhesion molecule; ICAM, intercellular adhesion molecule.6

Future Research

The research makes it clear that there is a strong link between insulin resistance and endothelial dysfunction, mediated mainly by nitric oxide impairment.7 Many treatments have been explored, including both lifestyle prescriptions and pharmacological therapies.7 Interventions including dietary modification, increased physical activity, and insulin-sensitizing medications have shown promising effectiveness; however, additional studies are needed in this area.7

Currently, there is a lack of research regarding long-term effectiveness of these various treatments.7 Furthermore, these treatments have not been thoroughly tested in all populations (children, older adults, pregnant women, different races, etc.).8 Ideal timing and degree of intervention is yet to be determined and is notably difficult to resolve, given the large variation in individual response to treatment and the ranges of disease severity.8 Future studies should be designed to focus on these gaps in the research.

Figure 3: Current and Future Approaches for the Treatment of Insulin Resistance9

Conclusion

In conclusion, insulin is an important regulator of the body’s metabolic processes. Its well-known role in glucose storage, however, may cause individuals to overlook its significant role in the functioning of the endothelium. Research shows that insulin resistance greatly impairs the production of nitric oxide, which is one of the main regulators of vascular health. In states of insulin resistance and accompanying endothelial dysfunction, serious conditions such as atherosclerosis and heart disease may result. Both pharmaceutical and lifestyle interventions are promising, however, additional research on their effectiveness is needed.

References

1. Wilcox G. Insulin and insulin resistance. Clin Biochem Rev. 2005;26(2):19-39.

2. Fu Z, Gilbert ER, Liu D. Regulation of insulin synthesis and secretion and pancreatic Beta-cell dysfunction in diabetes. Curr Diabetes Rev. 2013;9(1):25-53.

3. Tousoulis D, Tsarpalis K, Cokkinos D, Stefanadis C. Effects of insulin resistance on endothelial function: possible mechanisms and clinical implications. Diabetes Obes Metab. 2008;10(10):834-842. doi:10.1111/j.1463-1326.2007.00818.x

4. Watson RT, Pessin JE. Intracellular organization of insulin signaling and GLUT4 translocation. Recent Prog Horm Res. 2001;56:175-193. doi:10.1210/rp.56.1.175

5. Sumpio BE, Riley JT, Dardik A. Cells in focus: endothelial cell. Int J Biochem Cell Biol. 2002;34(12):1508-1512. doi:10.1016/s1357-2725(02)00075-4

6. Potenza MA, Addabbo F, Montagnani M. Vascular actions of insulin with implications for endothelial dysfunction. Am J Physiol Endocrinol Metab. 2009;297(3):E568-E577. doi:10.1152/ajpendo.00297.2009

7. Freeman AM, Pennings N. Insulin Resistance. In: StatPearls. Treasure Island (FL): StatPearls Publishing; July 10, 2021.

8. Cersosimo E, DeFronzo RA. Insulin resistance and endothelial dysfunction: the road map to cardiovascular diseases. Diabetes Metab Res Rev. 2006;22(6):423-436. doi:10.1002/dmrr.634

9. Kumar Anil, Mittal Ruchika and Kaur Ashmeen , Insulin Resistance in Diabetes: Present and Future Prospective of Treatment, Current Psychopharmacology 2018; 7(2)

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