Insulin signal transduction pathway and regulation of blood glucose

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The insulin transduction pathway is an important biochemical pathway beginning at the cellular level affecting 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 on the cellular 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 (Type 1,2,3), Hyperglycemia and Hypoglycemia.

Insulin signal transduction pathway[edit]

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 along the way. Insulin secretion mechanism is a common example of Signal transduction pathway mechanism.

Insulin is produced by the pancreas in a region called Islets of Langerhans. In the islets of Langerhans, there are beta-cells, which are responsible for production of insulin. Insulin is secreted as a response mechanism for counteracting the increasing excess amounts of glucose in the blood.

Glucose in the body increases after food consumption. This is primarily due to carbohydrate intake, but to much lesser degree protein intake ([1])([2]). Depending on the tissue type, the glucose enters the cell through facilitated or passive diffusion. In muscle and adipose tissue, glucose enters through GLUT 4 receptors via facilitated diffusion ([3]). In brain, kidney and retina, glucose enters passively. In the beta-cells of the pancreas, glucose enters through the GLUT 2 receptors (process described below).

Two aspects of this process are explained below: insulin secretion and insulin action on the cell.

Insulin Secretion process (Figure 1.1.1)

Insulin secretion[edit]

The glucose that goes in the bloodstream after food consumption also enters the beta cells in the Islets of Langerhans in the pancreas. The glucose passively diffuses in the beta cell through a GLUT-2 vesicle. Inside the beta cell, the following process occurs:

Glucose gets converted to Glucose-6-Phosphate (G6P) through Glucokinase; and G6P is subsequently oxidized to form ATP. This process inhibits the ATP sensitive potassium ion channels of the cell causing the Potassium ion channel to close and not function anymore. The closure of the Potassium channels causes Depolarization of the cell membrane causing the cell membrane to stretch which causes the voltage-gated Calcium channel on the membrane to open causing an influx of Ca2+ ions. This influx then stimulates fusion of the insulin vesicles (bubble like structure with insulin in them) to the cell membrane and secretion of insulin in the extracellular fluid outside the beta cell; thus making it enter the bloodstream. [Also Illustrated in Figure 1.1.1].[1]

Insulin action on the cell process (Figure 1.1.2)

Insulin action on the cell[edit]

After insulin enters the bloodstream, it is taken up by the cells, as glucose is the preferential fuel for human bodies. However, insulin does not directly go inside the cell in its original form. To activate the effects of insulin, it has to bind to an enzyme that activates its functions. Thus, the insulin binds to the α (alpha) subunit of the insulin receptor embedded in the cell membrane. The α-subunit acts as the insulin receptor and the insulin molecule acts as a ligand in an receptor-ligand complex.

This triggers the Tyrosine Kinase activity in the β-subunit that is attached to the α-subunit. The Tyrosine Kinase activity causes Phosphorylation (activation) of the enzymes.

The 2 enzymes, Mitogen-activated Protein Kinase (MAP-Kinase) and Phosphatidylinositol-3-Kinase (PI-3K, Phosphoinositide 3-kinase) are responsible for expressing the Mitogenic and Metabolic actions of Insulin respectively.

The activation of MAP-Kinase leads to completion of mitogenic functions like cell growth and gene expression.

The activation of PI-3K leads to crucial metabolic functions such as synthesis of lipids, proteins and glycogen. It also leads to cell survival and cell proliferation. Most importantly, the PI-3K pathway is responsible for the distribution of glucose for important cell functions. The GLUT-4 vesicle (responsible for passive diffusion of glucose in cell) binds to the PI-3K after bringing glucose in the cell. The PI-3K isolates the GLUT-4 Vesicle from the glucose and sends the vesicle back to the cell membrane. The glucose that is isolated is then sent to the Mitochondria to make ATP and excess glucose is stored in the cell as Glycogen. [This process is also illustrated in Figure 1.1.2].[2]

Thus, insulin’s role is more of a promoter for the usage of glucose in the cells rather than neutralizing or counteracting it.

Feedback mechanism[edit]

Signal transduction is a mechanism in which the cell responds to a signal from the environment by activating several proteins and enzymes that will give a response to the signal. Feedback mechanism might involve negative feedback and positive feedback. In the negative feedback, the pathway is inhibited and the final result of the pathway is reduced or limited. In positive feedback, the transduction pathway is promoted and stimulated to produce more products.[3]

Positive feedback[edit]

Insulin secretion results in positive feedback in different ways. Firstly, insulin increases the uptake of glucose from blood by the translocation and exocytosis of GLUT4 storage vesicles in the muscle and fat cells. Secondly, it promotes the conversion of glucose into triglyceride in the liver, fat, and muscle cells. Finally, the cell will increase the rate of glycolysis within itself to break glucose in the cell into other components for tissue growth purposes.

An example of positive feedback mechanism in the insulin transduction pathway is the activation of some enzymes that inhibit other enzymes from slowing or stopping the insulin transduction pathway which results in improved intake of the glucose.

One of these pathways, involves the PI(3)K enzyme (Phosphoinositide 3-kinase). This pathway is responsible for activating glycogen, lipid-protein synthesis, and specific gene expression of some proteins which will help in the intake of glucose. Different enzymes control this pathway. Some of these enzymes constrict the pathway causing a negative feedback like the GSK-3 pathway. Other enzymes will push the pathway forward causing a positive feedback like the AKT and P70 enzymes. When insulin binds to its receptor, it activates the glycogen synthesis by inhibiting the enzymes that slow down the PI(3)K pathway such as PKA enzyme. At the same time, it will promote the function of the enzymes that provide a positive feedback for the pathway like the AKT and P70 enzymes.[4] The inactivation of the enzymes that stops the reaction and activating of enzymes that provide a positive feedback will increase glycogen, lipid & protein syntheses and therefore promoting the intake for glucose.

(Image to help explain the function of the proteins mentioned above in the positive feedback.)

Negative feedback[edit]

When Insulin binds to the cell's receptor, it will result in negative feedback by limiting or stopping some other actions in the cell. It inhibits the release and production of glucose from the cells which is an important part in reducing the glucose blood level. Insulin will also inhibit the breakdown of glycogen into glucose by inhibiting the expression of the enzymes that catalyzes the degradation of Glycogen.

An example of negative feedback is slowing or stopping the intake of glucose after the pathway was activated. Negative feedback is shown in the insulin signal transduction pathway by constricting the phosphorylation of the insulin-stimulated tyrosine.[5] The enzyme that deactivates or phosphorylates the insulin-stimulated tyrosine is called tyrosine phosphatases (PTPases). When activated, this enzyme provides a negative feedback by catalyzing the dephosphorylation of the insulin receptors.[6] The dephosphorylation of the insulin receptor slows the intake of the glucose from the blood by not allowing the other proteins in the insulin transduction pathway to be activated and consequently not do their job of transferring the signal to the other proteins in the pathway.

Trigger mechanism[edit]

Insulin is secreted in the beta cells of the islets of Langerhans. Before secretion, insulin is synthesized. Once insulin is synthesized, the beta cells are ready to release it in two different phases. As for the first phase, insulin release is triggered rapidly when the blood glucose level is increased.

The second phase is a slow release of newly formed vesicles that are triggered regardless of the sugar level. Glucose enters the beta cells and goes through glycolysis to form ATP that eventually cause depolarization of the beta cell membrane (as explained in Insulin secretion section of this article). The depolarization process causes voltage controlled calcium channels (Ca2+) opening and allowing the calcium to flow into the cells. An increased calcium level causes activation of phospholipase C, which cleaves the membrane phospholipid phosphtidyl inositol 4 into inositol 1 and diacylglycerol. Inositol 1,4,5-triphosphate (IP3) binds to receptor proteins in the membrane of endplasmic reticulum (ER). This allows the release of (Ca2+) from the ER via IP3 gated channels, and raises the cell concentration of calcium even more. The influx of Ca2+ ions push the Insulin molecules (that are inside their "bubble" surrounding) outside of the cell.

Therefore, the process of insulin secretion is an example of a trigger mechanism in a signal transduction pathway because insulin is secreted after glucose enters the beta cell and that triggers several other processes in a chain reaction.

Counter mechanism[edit]

Function of glucagon[edit]

While insulin is secreted by the pancreas to lower blood glucose levels, glucagon is secreted to raise blood glucose levels. This is why glucagon has been known for decades as a counter-regulatory hormone.[7] When blood glucose levels are low, the pancreas secretes glucagon, which in turn causes the liver to convert stored glycogen polymers into glucose monomers, releasing glucose into the blood. This process is called glycogenolysis. Liver cells, or hepatocytes, have glucagon receptors which allow for glucagon to attach to them and thus stimulate glycogenolysis.[8] Contrary to insulin, which is produced by pancreatic β-cells, glucagon is produced by pancreatic α-cells.[9] It is also known that an increase in insulin suppresses glucagon secretion, and a decrease in insulin, along with low glucose levels, stimulates the secretion of glucagon. So, this proves that insulin is a β-cell product that reciprocally regulates the α-cell glucagon secretion.[9]

Oscillatory behavior[edit]

When blood-glucose levels are too low, the pancreas is signaled to release glucagon, which is essentially the opposite of insulin and therefore creates glucose in the body. Glucagon is delivered directly to the liver, where it connects to the glucagon receptors on the membranes of the liver cells, which allows the liver to convert the glycogen already stored there into glucose. This process is called glycogenolysis.

Conversely, when the blood-glucose levels are too high, the pancreas is signaled to release insulin. Insulin is delivered to the liver and other muscle tissues throughout the body. When the insulin is introduced to the liver, it connects itself to the insulin receptors already present, called a tyrosine kinase receptor.[10] These receptors have two alpha subunits (extracellular) and two beta subunits (intercellular) which are connected through the cell membrane via disulfide bonds. When the insulin binds to these alpha subunits, glucose transport 4, or Glut4, is released and goes to the surface of the cell to regulate glucose transport in and out of the cell. With the release of Glut4, the allowance of glucose into cells is increased, and therefore the concentration of blood-glucose is able to decrease. This, in other words, increases the utilization of the glucose already present in the liver. This is shown in the image to the right. As glucose increases, production of insulin increases, which thereby increases the utilization of the glucose, which maintains the glucose levels in an efficient manner and creates an oscillatory behavior.

References[edit]

  1. ^ Arthur C. Guyton; John E. Hall (2006). "Chapter 78: Insulin, Glucagon, and Diabetes Mellitus". Textbook of Medical Physiology (11th ed.). Philadelphia: Elsevier Saunders. pp. 963–68. 
  2. ^ Vinay Kumar; Abul K. Abbas; Nelson Fausto (2005). "Chapter 24: The Endocrine System". Robbins and Cotran Pathologic Basis of Disease (7th ed.). Philadelphia: Elsevier Saunders. pp. 1191–193. 
  3. ^ Feedback
  4. ^ Brady, M. J.; Nairn, A. C.; Saltiel, A. R. (1997). "The regulation of glycogen synthase by protein phosphatase 1 in 3T3-L1 adipocytes. Evidence for a potential role for DARPP-32 in insulin action". J. Biol. Chem 272: 29698–29703. doi:10.1074/jbc.272.47.29698. 
  5. ^ Craparo, A.; Freund, R.; Gustafson, T. A. (1997). "14-3-3 (;) interacts with the insulin-like growth factor I receptor and insulin receptor substrate I in a phosphoserine-dependent manner". J. Biol. Chem 272: 11663–11669. 
  6. ^ Saltiel, Alan R.; Kahn, C. R. (2001). "Insulin signalling and the regulation of glucose and lipid metabolism". Nature 414 (6865): 799. doi:10.1038/414799a. 
  7. ^ Brubaker, Patricia; Younes Anini (November 2003). "Direct and indirect mechanisms regulating secretion of glucagon-like peptide-1 and glucagon-like peptide-2.". Canadian Journal of Physiology & Pharmacology 81 (11): 1005–1012. doi:10.1139/y03-107. PMID 14719035. 
  8. ^ Estall, J.L.; Drucker, D. J. (May 2006). "Glucagon and Glucagon-Like Peptide Receptors as Drug Targets". Current Pharmaceutical Design 12 (4): 1731–1750. doi:10.2174/138161206776873671. 
  9. ^ a b Cooperburg, Benjamin; Cryer, Philip E (November 2010). "Insulin Reciprocally Regulates Glucagon Secretion in Humans". Diabetes 59 (11): 2936–2940. doi:10.2337/db10-0728. 
  10. ^ Khan, A. H.; Pessin, J. E. (2002). "Insulin regulation of glucose uptake: a complex interplay of intracellular signalling pathways". Diabetologia 45: 1475–1483.