Changes in Cells Associated with Insulin Resistance

Abstract

Insulin is a polypeptide hormone synthesized and secreted by pancreatic β-cells. It plays an important role as a metabolic hormone. Insulin influences the metabolism of glucose, regulating plasma glucose levels and stimulating glucose storage in organs such as the liver, muscles and adipose tissue. It is involved in fat metabolism, increasing the storage of triglycerides and decreasing lipolysis. Ketone body metabolism also depends on insulin action, as insulin reduces ketone body concentrations and influences protein metabolism. It increases nitrogen retention, facilitates the transport of amino acids into cells and increases the synthesis of proteins. Insulin also inhibits protein breakdown and is involved in cellular growth and proliferation. On the other hand, defects in the intracellular signaling pathways of insulin may cause several disturbances in human metabolism, resulting in several chronic diseases. Insulin resistance, also known as impaired insulin sensitivity, is due to the decreased reaction of insulin signaling for glucose levels, seen when glucose use in response to an adequate concentration of insulin is impaired. Insulin resistance may cause, for example, increased plasma insulin levels. That state, called hyperinsulinemia, impairs metabolic processes and is observed in patients with type 2 diabetes mellitus and obesity. Hyperinsulinemia may increase the risk of initiation, progression and metastasis of several cancers and may cause poor cancer outcomes. Insulin resistance is a health problem worldwide; therefore, mechanisms of insulin resistance, causes and types of insulin resistance and strategies against insulin resistance are described in this review. Attention is also paid to factors that are associated with the development of insulin resistance, the main and characteristic symptoms of particular syndromes, plus other aspects of severe insulin resistance. This review mainly focuses on the description and analysis of changes in cells due to insulin resistance.

Keywords: cellular changes associated with insulin resistance; insulin; insulin cellular signaling; insulin resistance; syndromes of insulin resistance.

Figure 1

Process of biosynthesis and secretion of insulin. After transcription of preproinsulin mRNA from the INS gene, it is translated into preproinsulin peptides. Then, preproinsulin transits through the rough endoplasmic reticulum and trans-Golgi network, causing the preproinsulin to change to its mature form and be stored in mature secretory granules in pancreatic β-cells [2,17,22].

Figure 2

Structure of insulin receptor [4,28]. The insulin receptor is composed of two extracellular insulin-binding α-subunits and two signal transduction β-subunits, which are bound together by disulfide bonds. Conformational change of α-subunits due to binding of insulin to the receptor enables binding of adenosine triphosphate (ATP) to the β-subunit. Binding of ATP activates a tyrosine kinase in the β-subunits, causing autophosphorylation of the receptor. The phosphorylated insulin receptor in turn phosphorylates other protein substrates, such as IRS-1 and IRS-2.