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15.1: Insulin Signaling in the Liver

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    15013
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    In this section, we will discuss insulin signaling and glycogen synthesis. Recall that glycogen is a large polymer of glucose residues connected in the main chain by alpha 1 --> 4 linkages and with branching side chains about every 12 – 15 residues at the alpha 1 --> 6 position. The reducing ends of the carbohydrate (two for each polymer) are connected to the glycogenin dimeric protein at the center of the macromolecule (Figure \(\PageIndex{1}\)). With the branching nature of the polymer, many non-reducing ends of the molecule are present, allowing easy access and fast release of glucose for energy utilization.

    Most of the body’s pools of glycogen are stored in the liver, with 10% of the liver biomass in glycogen granules, and in the skeletal muscle, with glycogen comprising 2% of the biomass of the muscle. Each glycogen polymer may have upwards of 30,000 glucose residues, making the glycogen polymer visible using standard microscopic techniques. Storage of glycogen within muscle tissue is used by the muscle cells as a source of energy to fuel muscle contraction. In the liver, the purpose of glycogen storage is different. Glycogen stored at this location is used to maintain the homeostatic balance of blood glucose levels. The liver is the primary organ that can actively transport glucose into the bloodstream. Our only other major source of glucose within the blood is from our diet.

    Glycogen_structure.svg
    Figure \(\PageIndex{1}\): The Glycogen Polymer. The glycogen reducing ends of the glycogen polymer are connected with the dimeric glycogenin proten shown at the center of the diagram using the ribbon projection. The polymer is constructed predominantly of glucose monomers connected through alpha 1 --> 4 linkages. Alpha 1 --> 6 branches are apparent about every 12 - 15 residues. (Public Domain; Mikael Häggström via Wikipedia.

    Blood glucose homeostasis is critical for brain function (Figure \(\PageIndex{2}\)). The brain has a huge energy demand, but nearly zero storage of key energy molecules required for ATP production. Furthermore, glucose and ketone bodies are the only energy sources that can pass the blood brain barrier and be utilized by the brain for ATP production. Note that ketone bodies are only produced during starvation, or disease states such as diabetes, and are not a regular source of energy for the brain. Thus, glucose is critical for brain function. Nearly 10% of the whole body’s energy is used for nerve impulse transmission by the brain. If blood flow to the brain carrying critical oxygen and glucose is impeded, people will lose consciousness within approximately 20 seconds! And brain death/permanent damage occurs within 4 minutes of blood flow cessation. This exemplifies the importance of the liver in maintaining blood glucose levels, as well as the importance of oxygen maintenance.

    clipboard_e6d67cdf68786e2e251c6e757eac83215.png
    Figure \(\PageIndex{2}\): Cortical neuron stained with antibody to neurofilament subunit NF-L in green. In red are neuronal stem cells stained with antibody to alpha-internexin. Image created using antibodies from EnCor Biotechnology Inc. (CC BY-SA 3.0 Unported; GerryShaw via Wikipedia)

    Why is the Storage of Glycogen Useful?

    Glycogen in the liver or muscle can be broken down into glucose 1-phosphate (Figure \(\PageIndex{3}\)). This can be interconverted to glucose 6-phosphate which is then readily used in many cellular processes. The process of glycolysis (or the breakdown of glucose into pyruvate) occurs in all cells and produces a small amount of ATP in the process. Further processing of pyruvate can occur anaerobically (or in the absence of oxygen) to produce lactate, or the process can continue to occur in the aerobic pathway to complete oxidation to carbon dioxide and water in the Kreb cycle. Note that oxygen from breathing is used to create the water within this pathway. This fuels the process of oxidative phosphorylation within the mitochondria and produces large quantities of ATP (36 molecules/glucose). Within the liver, glucose can be freed from glycogen and released back into the blood stream to maintain homeostatic levels. Glucose 6-phosphate can also be utilized as a precursor for other major macromolecules such as ribose and deoxyribose, as well as the hexosamine compounds commonly found cushioning joints or attached to proteins of the plasma membrane.

    clipboard_e6bb669021071f1a44dc3491bef2d1cc8.png
    Figure \(\PageIndex{3}\): Pathways of Glycogen Utilization.

    In healthy individuals hormone signaling is critical to maintain blood glucose homeostasis. Within this system, the hormones glucagon and insulin work together to maintain normal plasma glucose levels ( Figure \(\PageIndex{4}\)). During hyperglycemia, pancreatic beta (β) cells release insulin, which stimulates glucose uptake by energy-consuming cells and the formation of glycogen in the liver. During hypoglycemia, pancreatic alpha (α) cells release glucagon, which stimulates gluconeogenesis and glycogenolysis in the liver and the release of glucose to the plasma.

    clipboard_eb53969b8adbf2e158ca0aaa5f80f3913.png
    Figure \(\PageIndex{4}\): Hormone Signaling Involved in Blood Glucose Homeostasis. The hormones, glucagon and insulin, released by the pancreas are critical for regulating the release or the uptake of glucose from the bloodstream by the liver. In the upper diagram, when blood glucose levels rise, beta cells within the pancreas secrete the insulin hormone. Insulin signaling causes the liver to increase uptake of glucose from the bloodstream and promotes its storage as glycogen. Alternatively, when blood glucose levels are low, as shown in the lower diagram, alpha cells in the pancreas release the hormone, glucagon. Glucogon signaling in the liver leads to the breakdown of glycogen and the release of stored glucose into the the bloodstream. Hædersdal, S., et al (2018) Mayo Clinic Proceedings 93(2):217-239

    The first area we will focus our attention on, will be the mechanism utilized by insulin to reduce blood glucose levels. Figure 15.1.5 shows the structure of the pancreas and its anatomical relationship with the liver and the stomach. The pancreas is the sensor organ that detects blood glucose levels. It is responsible for signaling to the liver to either remove or release glucose in response to changing levels. Notably, the pancreas also produces most of the digestive enzymes utilized by the body, including proteases, amylases, and lipases.

    clipboard_e0a4f14acd1a40bd87405d3c6e907067c.png
    Figure 15.1.5 The Anatomy of the Liver and Pancreas. Akinlade, A., et al (2014) Int. Archives of Med 7(50):28

    Figure 15.1.6 shows a light microscope image of the pancreatic islet cells. They are responsible for the production of glucagon and insulin. The islets are distinguished from the surrounding tissue by a continuous connective tissue capsule and extensive vascularity.

    clipboard_ee5c0539b52def1d8133e9c3dc4a6ed43.png
    Figure 15.1.6 Pancreatic Islet Cells. In this diagram, the islet cells that secrete glucagon (known as alpha cells) are stained in red, while the beta cells that produce insulin are stained in blue. Akinlade, A., et al (2014) Int. Archives of Med 7(50):28

    Insulin is a peptide hormone composed of 51 amino acids (Figure 15.1.7). It is produced as a longer propeptide, called proinsulin, that needs to be processed by protein cleavage and folding to obtain proper structure.

    clipboard_e32e04294444f0ca5972f1587a6a0b6ed.png
    Figure 15.1.7 The Insulin Peptide Hormone. The upper diagram shows folded ribbon diagram of the insulin peptide. The lower diagram shows the proinsulin peptide prior to cleavage and modification to the mature form. Upper Image from Theislikerice and Lower Image from Image from Akinlade, A., et al (2014) Int. Archives of Med 7(50):28

    The peptide is first translated on ribosomes linked to the rough endoplasmic reticulum (ER), where a signal peptide docks the peptide to the ER membrane (Figure 15.1.8). The proinsulin is folded and the signal peptide cleaved. It is transported to the golgi where it is further packaged into secretory vesicles. Within the secretory vesicles, the proinsulin is cleaved to release the C-peptide. The A and B peptides are held together by disulfide bridges and form the active insulin component.

    clipboard_e2aa6d745b5bb7ce8b35f45809c9d11ff.png
    Figure 15.1.8 Insulin Production. The process of insulin production includes translation of the insulin mRNA into the rough endoplasmic reticulum. The peptide is transported through the golgi and packaged into secretory vesicles where protease cleavage by carboxypeptidase E produces the mature insulin peptide and peptide C. Image from Fred the Oyster

    The C-peptide is a bioactive peptide secreted at the same time and in equimolar amounts to the insulin hormone (Figure 15.1.9). It also has a longer half life than insulin and is excreted by the kidneys into the urine, making detection easy. Furthermore, it allows for the detection of patient produced insulin, even if they are receiving insulin injections. Thus, C-peptide detection is often utilized to help distinguish between patients with type 1 diabetes from patients with type 2 diabetes (or Maturity onset diabetes). Details about the different forms of diabetes will be discussed in greater detail in a later.

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    Figure 15.1.9 C-peptide hormone. Image from JaGa

    Once insulin is released from the pancreas, it travels throughout the body and binds with cellular targets that contain the insulin receptor. The Insulin Receptor is a tyrosine kinase receptor that dimerizes upon insulin binding (Figure 15.1.10). Insulin receptors are located on most cell types throughout the body causing pleiotropic effects during insulin response. Primary targets of insulin action are the liver, where it promotes the uptake of glucose and the production of the glycogen storage molecule, as well as skeletal muscle and fat. The tyrosine kinase portion of the receptor located on the internal side of the plasma membrane is quite flexible.

    clipboard_e3f69b8e70f883c25c9c83ed8b055156c.png
    Figure 15.1.10 The Insulin Receptor. The lefthand diagram shows a space-filling model of the activated insulin receptor dimer embedded into the plasma membrane (shown as the gray bar). The tyrosine kinase portion of the receptor is shown on the inside of the cell whereas the insulin binding domain is present on the external side of the plasma membrane. The middle and righthand diagrams show the inactive (middle) and active forms (far right) of the tyrosine kinase domain of an insulin receptor monomer. When activated the tyrosine kinase domain binds to ATP (hot pink) and phosphorylates downstream targets, including several of its own tyrosine residues (green). In the inactive state (middle), a mobile loop (turquoise) binds in the ATP binding site and prevents ATP association. When the insulin receptor is activated, the mobile loop opens, allowing for the binding of ATP and self-phosphorylation of tyrosine residues, as well as other signaling proteins (a small peptide from one is shown in light pink). Images from Goodsell, D., et al (2015) RCSB PDB-101 ‘Molecule of the Month’

    Activation of the insulin receptor in the liver when insulin is present initiates a phosphorylation signaling cascade (Figure 15.1.11) One function of the signaling cascade results in the activation of the Rab10 protein. Rab 10 promotes the fusion of the GLUT-4 containing secretory vesicles (GSVs) with the plasma membrane allowing for increased surface expression of GLUT4. GLUT4 is a glucose transporter protein. Thus, increased concentration of the protein in the plasma membrane results in the upregulation of glucose import into the cell. Having GLUT4 proteins stored within secretory vesicles makes it available more readily than having to activate gene transcription pathways and production of the protein de novo. This allows a faster response to help lower blood glucose levels. The result is increased glucose uptake from the bloodstream into liver cells and other cellular targets, reducing blood glucose levels.

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    Figure 15.1.11 Insulin Activation of Liver Cells and Glucose Uptake. The insulin receptor is a receptor tyrosine kinase, which undergoes dimerization and autophosphorylation of Tyr residues upon insulin binding. The phosphorylated receptor also recruits and phosphorylates the insulin receptor substrate 1 (IRS-1) on tyrosine residues, which then recruits dimeric Phosphoinositol (PI)3-kinase (p85/p110 in the diagram above) and phosphorylates the p85 regulatory subunit. The PI3 kinase catalyses the phosphorylation of phosphatidylinositol bisphosphate (PIP2) within the plasma membrane to form phosphoinositol, 3,4,5-triphosphate (PIP3). PIP3 then recruits PIP3-dependent kinase (PDK) which phosphorylates and activates Akt. Once activated, Akt dissociates from the membrane into the cytosol where one of its downstream targets is AS160. AS160 is a GTPase that normally binds with Rab10 (a G-protein) causing the cleavage of GTP to GDP. Thus, AS160 downregulates the activity of Rab10. In the phosphorylated state, AS160 cannot bind or inhibit Rab10, enabling Rab10 to release GDP and bind with a molecule of GTP. In the activated state, Rab10 helps promote the fusion of GLUT4-containing secretory vesicles (GSVs) secretory vesicles with the plasma membrane. Image from Carmichael, R.E., et al (2019) Scientific Reports 9:6477

    Figure 15.1.12 provides a deeper look at some of the initial activation steps in the insulin signaling pathway. This step shows the phosphorylation of Phosphoinositol 4,5-bisphosphate (PIP2) to Phosphotidylinositol 3,4,5-triphosphate (PIP3). PIP2 is a common phospholipid within the lipid bilayer structure. In future lectures, we will see the utilization of this phospholipid in other signaling pathways as well.

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    Figure 5.1.12 Phosphyrlation of phosphotidylinositol-4,5-bisphosphate During Insulin Signaling.

    Once glucose enters a cell, it is rapidly converted to glucose 6-phosphate via the enzyme hexokinase (Figure 5.1.13). This enzyme is covered in more detail in our section on glycolysis. Importantly, phosphorylation traps the glucose inside the cell and does not allow it to be redistributed back into the blood stream. This helps to maintain the homeostasis of glucose within the bloodstream. In addition, glucose 6-phosphate is the first step in many pathways utilizing glucose, including energy utilization and the formation of building blocks such as ribose and deoxyribose used in RNA and DNA synthesis.

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    Figure 5.1.13 Coversion of Glucose to Glucose-6-Phosphate by Hexokinase. Image from Jmun7616

    Another important enzyme in glucose metabolism is phosphoglucomutase. This enzyme falls into the isomerase class of enzymes and is able to effectively transfer the phosphate group from the 6- to the 1-position (Figure 15.1.14). This reaction is fully reversible, as shown below. Within this mechanism, a serine residue of the enzyme is covalently linked to a phosphate group. In the reaction shown, the 6’-Oxygen of glucose attacks the phosphate attached to serine in the enzyme active site. The ser-OH acts as a good leaving group. This creates a glucose bisphosphate intermediate. As the reaction proceeds, the ser-Oxygen attacks the phosphate group at the alternate position restoring the phosphorylated serine residue of the enzyme and releasing the glucose-phosphate isomer. For glycogen biosynthesis glucose 1-phosphate will be required.

    clipboard_e7d1f3669f4891c987b51d3c339c2b3ce.png
    Figure 15.1.14 Phosphoglucoisomerase Reaction Mechanism. Image from Wikimedia Commons and Jag123

    In Figure 15.1.11, we saw that insulin signaling increases the number of GLUT4 transporters in the plasma membrane causing an increased uptake of glucose into the cell. Within liver and muscle tissue, if the glucose is not required for energy or other metabolic intermediates, it is then converted to glycogen for storage. The major enzyme required for glycogen synthesis is also activated via insulin signaling (Figure 15.1.15). In addition to phosphorylating the AS160 protein, Activated Akt also phosphorylates the Glycogen Synthase Kinase enzyme (GSK-3) which inactivates this protein. This causes protein phosphorylase 1 (PP1) to dephosphorylate the Glycogen Synthase enzyme shifting it into a more active state, causing glycogen synthesis to commence.

    clipboard_ec04703e43b04f4a80281cea614fff3b2.png
    Figure 15.1.15 Activation of Glycogen Synthase During Insulin Signaling. Image modified from Carmichael, R.E., et al (2019) Scientific Reports 9:6477

    In this section, we have covered two pathways activated during cellular response to insulin signaling, and I am sure that you are feeling a bit overwhelmed with the complexity. However, biological processes are incredibly complex and signaling pathways have multiple pleiotropic downstream effects. For insulin signaling, we have only touched the tip of the iceberg, as evidenced in Figure 15.1.16. This figure give a more complete representation of the chemical changes induced within a liver cell in response to insulin signaling. For our purposes, we will restrict coverage to the two downstream effects: increase in GLUT4 transporters in the plasma membrane and increased activity of glycogen synthase.

    clipboard_e82a03a6cccdda2b5f80f99932b3f34c8.png
    Figure 15.1.16 Insulin Signaling Pathway. Image by Cell Signaling Technology

    15.1: Insulin Signaling in the Liver is shared under a not declared license and was authored, remixed, and/or curated by Henry Jakubowski.

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