When insulin binds to the insulin receptor, it leads to a cascade of cellular processes that promote the usage or, in some cases, the storage of glucose in the cell. The effects of insulin vary depending on the tissue involved, e.g., insulin is most important in the uptake of glucose by muscle and adipose tissue.
The insulin receptor is composed of two alpha subunits and two beta subunits linked by disulfide bonds. The alpha chains are entirely extracellular and house insulin binding domains, while the linked beta chains penetrate through the plasma membrane. The insulin receptor is a tyrosine kinase.
However, the initial step in insulin action, i.e. the engagement with its cell-surface receptor and the resulting conformational change, which propagates across the plasma membrane to the intracellular module, remains poorly understood.
The cellular receptor for insulin helps control the utilization of glucose by cells Cells throughout the body are fueled largely by glucose that is delivered through the bloodstream . A complex signaling system is used to control the process, ensuring that glucose is delivered when needed and stored when there is a surplus. Two hormones, insulin and glucagon, are at the center of this signaling system. When blood glucose levels drop, alpha cells in the pancreas release glucagon, which then stimulates liver cells to release glucose into the circulation. When blood glucose levels rise, on the other hand, beta cells in the pancreas release insulin, which promotes uptake of glucose for metabolism and storage. Both hormones are small proteins that are recognized by receptors on the surface of cells. Signal Transduction The receptor for insulin is a large protein that binds to insulin and passes its message into the cell. It has several functional parts. Two copies of the protein chains come together on the outside of the cell to form the receptor site that binds to insulin. This is connected through the membrane to two tyrosine kinases, shown here at the bottom. When insulin is not present, they are held in a constrained position, but when insulin binds, these constraints are released. They first phosphorylate and activate each other, and then phosphorylate other proteins in the signaling network inside the cell. Since the whole receptor is so flexible, researchers have determined its structure in several pieces: the insulin-binding portion is shown here from PDB entry 3loh , the transmembrane segment from 2mfr , and the tyrosine kinase from 1irk . When Things Go Wrong Problems with insulin signaling can impair the proper management of glucose levels in the blood, leading to Continue reading >>
It focuses on the recent discovery of how the hormone insulin actually binds to the receptor on the surface of cells, as determined by Professor Mike Lawrence's laboratory at the Walter and Eliza Hall Institute. Insulin binds to the receptor protein on the cell surface and instructs the cell to take up glucose from the blood for use as an energy source. In type 2 diabetes, we believe that insulin binds to the receptor normally, but the signal is not sent into the cell, the cells do not take up glucose and the resulting high blood glucose levels cause organ damage over time. Understanding how insulin interacts with its receptor is fundamental to the development of novel insulin for the treatment of diabetes. Maja Divjak, 2015 Continue reading >>
The insulin transduction pathway is a biochemical pathway by which insulin increases the uptake of glucose into fat and muscle cells and reduces the synthesis of glucose in the liver and hence is involved in maintaining glucose homeostasis. This pathway is also influenced by fed versus fasting states, stress levels, and a variety of other hormones. When carbohydrates are consumed, digested, and absorbed the pancreas senses the subsequent rise in blood glucose concentration and releases insulin to promote an uptake of glucose from the blood stream. When insulin binds to the insulin receptor, it leads to a cascade of cellular processes that promote the usage or, in some cases, the storage of glucose in the cell. The effects of insulin vary depending on the tissue involved, e.g., insulin is most important in the uptake of glucose by muscle and adipose tissue. This insulin signal transduction pathway is composed of trigger mechanisms (e.g., autophosphorylation mechanisms) that serve as signals throughout the cell. There is also a counter mechanism in the body to stop the secretion of insulin beyond a certain limit. Namely, those counter-regulatory mechanisms are glucagon and epinephrine. The process of the regulation of blood glucose (also known as glucose homeostasis) also exhibits oscillatory behavior. On a pathological basis, this topic is crucial to understanding certain disorders in the body such as diabetes, hyperglycemia and hypoglycemia. Transduction pathway The functioning of a signal transduction pathway is based on extra-cellular signaling that in turn creates a response which causes other subsequent responses, hence creating a chain reaction, or cascade. During the course of signaling, the cell uses each response for accomplishing some kind of a purpose al Continue reading >>
According to the medical literature, type 2 diabetes is a disease characterized by chronic hyperglycemia, i.e., abnormally high concentrations of blood sugar (serum glucose), in the presence of adequate amounts of insulin. This hyperglycemia is attributed to insulin resistance, a faulty condition in which serum insulin cannot act on insulin receptors in the walls of cells. This condition prevents the receptors from allowing glucose to pass from the blood into the cells. According to the biochemical literature, an insulin receptor is a protein molecule located in the wall of a cell. The structure of the molecule is such that a smaller molecule called a ligand may attach to it. There are two kinds of ligands: an agonist, which causes the receptor to function, and an antagonist, which does nothing but prevent the agonist from attaching to the receptor. Without an attached ligand, an insulin receptor cannot allow glucose molecules to pass from the blood into a cell. An insulin molecule is an agonist, and when one becomes a ligand, an insulin receptor can allow glucose molecules to pass into a cell. But the hormone cortisol is an insulin antagonist, and when a cortisol molecule becomes a ligand, it prevents an insulin molecule from becoming a ligand, which prevents glucose from passing from the blood into the cell involved. I believe that the action of cortisol as an insulin antagonist is a reasonable explanation of the condition that we call insulin resistance, in which case there is nothing wrong with the insulin receptors or the insulin. Insulin resistance, then, would be part of the natural functioning of an insulin receptor. There are reasons to believe that the brain is responsible for the production of excess cortisol for the purpose of preventing the loss of serum gl Continue reading >>
When Insulin interacts with the , a part of the Insulin Receptor (IR), it triggers a phosphorylation cascade starting in the holoreceptor's tyrosine kinase domain. This leads to the introduction of glucose into the cell. Without Insulin, glucose is prevented from entering the cell; thus, Insulin's interaction with the IR regulates the intracellular concentration of glucose. Until recently, the Insulin-IR binding mechanism was unknown. We will uncover the newly discovered mechanisms between Insulin and its receptor by highlighting the interactions that solidify its binding. II. General Structure Turn spin on/off Insulin is stored as a zinc-coordinated hexamer. However, this hexamer dissociates into zinc-free monomers that are able to bind to the IR. A single Insulin monomer has two chains - and - that are connected by three disulfide bonds (Figure 1), one of which is an intramolecular disulfide bond on Chain A. Both of these chains are needed for Insulin to interact with its receptor. Figure 1: Disulfide Bonds in an Insulin Monomer The Insulin receptor is a heterotetramer consisting of multiple subunits. Each IR monomer includes an alpha-subunit leucine-rich repeat domain (L1 Beta Two Sheet) combined with a cysteine-rich domain (CR) , as well as an alpha-subunit C-terminal segment (alpha-CT) . These are located in the extracellular matrix and constitute the . The supplementary image shows an additional leucine-rich repeat domain (L2) and the first, second, and third fibronectin type III domains, which, combined with the microreceptor, constitute the holoreceptor. There are two isoforms of th Continue reading >>
The insulin receptor (IR) is a large, disulphide-linked, glycoprotein that spans the cell membrane with its insulin binding surfaces on the outside of the cell and its tyrosine kinase domains on the inside. IR is a symmetrical homodimer that contains two identical binding pockets, each created by the juxtapositioning of two distinct binding sites involving residues from both IR monomers (IR and IR´). The two binding pockets comprise site 1/site 2´ on one side of IR and site 1´ and site 2 on the opposite side. The current model for IR activation is that two distinct surfaces of insulin engage sequentially with either the site 1/site 2´ binding pocket or the site 1´/site 2 pocket. The formation of a site 1 – insulin - site 2 high-affinity, cross-link involves structural changes in both insulin and IR resulting in the activation of the intracellular tyrosine kinase and the initiation of the phosphorylation cascades that drive insulin signaling. Understanding how insulin binding induces signal transduction requires structures of: (i) insulin and IR in their basal states, (ii) insulin bound to the IR ectodomain, (iii) the activated IR kinase domain and (iv) the domain rearrangements associated with the formation of the high affinity insulin/IR complex that initiates activation of the intracellular kinase. Continue reading >>
In type 1 diabetes, the body's immune system destroys the cells that release insulin, eventually eliminating insulin production altogether from the body. Without insulin, cells cannot absorb sugar (glucose), which they need to produce energy. Type 2 diabetes (formerly called mature-onset or non�insulin-dependent diabetes) can develop at any age, but most commonly becomes apparent during adulthood. However, the incidence of type 2 diabetes in children is rising. Type 2 diabetes accounts for the vast majority of people with diabetes�more than 90%. In contrast to type 1 diabetes, type 2 diabetes is characterized by insulin resistance. Insulin resistance refers to the inability of the body tissues to respond properly to insulin. Insulin resistance develops because of multiple factors, including genetics, obesity, increasing age, and having high blood sugar over long periods of time. How are these diseases different? Type 1 diabetes Type 2 diabetes Symptoms usually start in childhood or young adulthood. People often seek medical help because they are seriously ill from sudden symptoms of high blood sugar. May not have symptoms before diagnosis. Usually the disease is discovered in adulthood; however, there is an increasing number of children being diagnosed with the disease. Episodes of low blood sugar level (hypoglycemia) common No episodes of low blood sugar level, unless taking insulin or certain oral diabetes medic Continue reading >>