Insulin Receptors: Structure, Functions and Action

Insulin Receptor

Insulin receptor, IGF-1 receptor, and IGF-2 receptor. All these three receptors have similar actions. The receptors for insulin receptors and IGF–1 are structurally the same. As can be seen from the diagram. Two alpha chains and two beta chains make it a tetramer receptor. In the internal domain of the beta chains, tyrosine kinase activity is there. Insulin has major action on its receptor and has certain actions on the IGF-1 receptor. IGF-1 has major action on its receptor but can also affect the insulin receptor but also the IGF-2 receptor.

Because IGF-1 also stimulates the insulin receptor, some of the actions of IGF-1 are like that of

insulin. Hence, this peptide is known as an insulin-like growth factor. The IGF-2 receptor is completely different from the other receptors. It can act on insulin receptors, IGF-1 receptors, and its receptors. When insulin is activating its receptor, the tyrosine kinase domain will be activated in the internal or cytoplasmic part of the receptor. When this domain is activated, it will cause the phosphorylation of various proteins. One such important protein is PI3-Kinase or Phosphatidyl inositol 3-Kinase. Because of the phosphorylation of PI3-kinase, it will act on vesicles present inside the cytoplasm of the cells. On the surface of the vesicles, GLUT-4 (mainly) and GLUT-12 (some) are present.

The vesicle will move close to the membrane. Due to this all the GLUT-4 that was inside the vesicle will be on the membrane. By doing so, the glucose from the blood will enter the cell. This way, the insulin acts on the cell. Insulin-sensitive GLUT - GLUT-4, GLUT-12 is also insulin-sensitive. Other GLUTs like GLUT-1, GLUT-3, GLUT-5, or GLUT-2, are constitutively expressed on the surface of the cell membrane because of which they are always open and do not need simulation. These transporters are insensitive to insulin, facilitating continuous glucose entry through them.

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Different GLUT and SGLT

SGLT is not insulin sensitive. SGLT 1, 2, and 3 are discussed here.

Insulin-Responsive or insulin-sensitive GLUT is GLUT-4 and GLUT-12. The insulin-responsive GLUT in blastocyst is GLUT-8. GLUT-5 and GLUT-11 are Fructose Transporters. GLUT-1, GLUT-3 and GLUT-5 are all located at the level of the central nervous system. GLUT-1 is present at the level of endothelium cell (blood-brain barrier) through which glucose will enter from the blood to the level of brain interstitial fluid. Glucose enters inside the neurons by GLUT-3. Glucose enters inside the astrocyte by GLUT-5. GLUT-1 is the major GLUT for the Placenta and the fetus.

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Tissue-Specific Action of Insulin

• Adipose tissue → GLUT-4
• Muscle → GLUT- 4
• Insulin mainly acts on cardiac and skeletal muscles, fat cells, prostrate, and mammary glands.
• Insulin also has certain action at the level of liver tissues, which is not due to GLUT.
• In the liver, GLUT- 4 is not present, and GLUT - 2, 9, 10, 11 are present.

How does Insulin have action in the liver?

In the liver, the enzyme glucokinase is stimulated. When glucose enters the liver cell, it will be phosphorylated by the glucokinase enzyme. The free glucose level inside the liver cell will be less causing it to take up more glucose from the blood. If the glucose is high outside, it will enter the liver cell. By converting the glucose into another form, the glucose level inside the liver cell is kept low.

Overall Effect of Insulin 

• Depending on time, insulin has rapid, intermediate, and late action, according to Ganong. 
• Rapid Action (sec)
  • ↑ transport of glucose, amino acids, and potassium into the cell. Insulin effectively treats acute hyperkalemia by rapidly lowering blood K⁺ levels. Administering insulin through infusion, along with glucose, facilitates the prompt reduction of blood K+ levels. 
• Intermediate action (min)
  • ↑ protein synthesis and decreased protein breakdown.
  • Activates glycolytic enzymes and glycogen synthesis.
  • It inhibits phosphorylase and gluconeogenic enzymes.
  • All these actions are trying to decrease the blood glucose level.
• Late actions (hours)
  • It is taking a long time because it is expressing genes or mRNA of certain enzymes like, for example, lipogenic and other enzymes.
• All these things are trying to cause the storage of carbohydrates, and protein fat in the body. Hence, insulin is an anabolic hormone.

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Action of Insulin on Individual Tissues

Insulin on Adipose Tissue

A diagram of an adipose tissue or a fat cell and capillary located near the adipose tissue is drawn. The endothelium of this capillary expresses an enzyme called lipoprotein lipase (LPL) which is stimulated by insulin. This protein breaks up the triglyceride (TG) molecule into free fatty acid (FFA) molecules which can easily enter the fat cell.

The fat cell will take up more free fatty acid because lipoprotein lipase is causing the breakdown of the TG molecule. Insulin will also cause stimulation of GLUT-4 which is present in the fat cell. Because of stimulation, glucose will enter the cell. Inside the cell, the free fatty acid and glucose will again combine to form triglycerides. This triglyceride will be deposited inside the fat cells. This is why insulin causes more fat deposition in the adipose tissue.

This triglyceride molecule can be broken down into free fatty acid, by another enzyme called

hormone-sensitive lipase, and FFA it can again enter the blood. The hormone-sensitive lipase is inhibited by insulin. Hormone-sensitive lipase is stimulated by hormones like cortisol, which is why cortisol increases free fatty acid levels inside the blood. Similarly, epinephrine and norepinephrine also stimulate the hormone-sensitive lipase, break down the cell fat, and increase the free fatty acid level in the blood.

Insulin is causing increased glucose entry inside the fat cell, it is causing increased triglyceride deposition, activation of lipoprotein lipase, inhibition of the hormone-sensitive lipase, and increasing potassium uptake.

Insulin on Muscles

The main action of insulin is to form more protein inside the muscle cells. Insulin will stimulate GLUT-4 present inside the muscle cells. ↑ Glucose entry (↑↑ glycogen synthesis). Increased amino acid uptake will be there which will cause more protein synthesis. It will prevent the breakdown of the protein (↓protein catabolism), therefore, depositing huge amounts of protein and glycogen inside the muscle cells. Increased potassium and Ketone uptake are also seen.

Increased insulin causes increased glucose uptake in the muscle cells if the glucose level is high in the blood, which happens after a meal. Increased glucose uptake inside the muscle cell depends on insulin because insulin will stimulate the GLUT-4. After meals → dependent on Insulin.

When one is exercising, glucose will enter the cell. This is independent of insulin. On exercise, there will be increased production of cAMP inside the cell, which will be converted into 5' AMP inside the cell. 5' AMP will stimulate GLUT-4 causing the glucose to enter inside the cell. Even if insulin is low, the glucose uptake in the blood will be enhanced on exercise. This is why for the treatment of diabetes mellitus exercises are always prescribed. Because on exercise the requirement of insulin inside the body will be reduced.

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Insulin on Liver

The main action of insulin on the liver is that it increases the glucokinase activity, because of which the free glucose concentration in the liver cell will be less, leading to increased glucose uptake. It also increases glycogen, lipid, and protein synthesis. Protein synthesis is increased by decreasing gluconeogenesis. Decreased ketogenesis is also done by insulin.

To understand the regulation of insulin secretion, beta cells of the pancreas are drawn. The GLUT-2 is present in this β cell. When the blood glucose level is >70 mg/dl, it will enter the β cell of the pancreas through GLUT-2. GLUT-2 is a constitutively expressive GLUT, so whenever the blood glucose level is very high it will enter the cell through GLUT-2.

Glucose will enter the glycolytic pathway, followed by the citric acid pathway, and produce huge amounts of adenosine triphosphate (ATP). The β cell contains ATP-sensitive K+ channels which normally remain open allowing K+ efflux, but when the ATP level is high inside the beta cell, it will inhibit the ATP- sensitive K+ channels. So, whenever the blood glucose is high, the ATP- sensitive potassium channel will be closed.

The K+ that was supposed to go outside will stay inside the cell. K+ contains a positive charge and there will be more deposition of positive charge on the cell membrane of the interior of the beta cell. This will cause depolarization of the β cell. The depolarization will cause the opening of the voltage-gated calcium channel, resulting in the entry of a huge amount of calcium into the cell.

In the presence of calcium, the vesicles that are present inside the beta cell (which contains peptides and a combination of A and B peptides, that is insulin) will reach close to the membrane. Then, there will be a fusion of the vesicular membrane and the cell membrane, because of which the contents of the vesicle will be released, including insulin and equal amounts of C-peptide, and very little amount of amylin will also be released. This is a mechanism by which increased blood glucose is secreting more insulin.

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Regulation of Insulin Secretion