33. Insulin

Last updated on March 13, 2020 at 13:16

Summary

  • Insulin is synthesized in the Langerhans islets by β-cells
  • Insulin binds to the insulin receptor, a type of tyrosine kinase receptor
  • It increases the activity of the GLUT4 transporter
  • Its target effect is to decrease blood glucose, by storing glucose in fatty acids and glycogen
  • Insulin also works as a growth hormone, instructing the body to rebuild itself
  • It increases glycogen synthesis, fatty acid synthesis, glucose uptake and triacylglycerol (fat) synthesis
  • It decreases glycogen breakdown and β-oxidation

Insulin

Insulin is a hormone which is produced by beta-cells in the Langerhans islets in the pancreas. Its purpose is to stimulate the body to store glucose as fat and glycogen, and to stimulate the synthesis of proteins and division of cells, but only when the level of glucose in the blood is high.

Insulin is produced in response to high blood glucose level, and it stimulates processes which reduce the blood glucose level. These processes include:

  • Glycogenesis
  • Fatty acid synthesis
  • Lipid synthesis
  • Protein synthesis
  • Cholesterol synthesis
  • Uptake of glucose into the cell, via the GLUT transport proteins

It also inhibits processes which increase the blood glucose level, like:

  • Lipolysis
  • Beta oxidation
  • Proteolysis
  • Glycogenolysis
  • Gluconeogenesis

Right after a meal, when the GI tract has absorbed the carbohydrates from the meal, the level of glucose in the blood is high. Some of this glucose should be utilized for new cells and other anabolic processes, and the rest should be stored as glycogen or fat. Insulin mediates all these responses.

While there are many hormones which increase the blood glucose level, insulin is the only hormone which decreases it!

The insulin pathway

The signal transduction of insulin is described in more detail in topic 34.

The insulin receptor phosphorylates (tyrosine residues on) a protein called insulin receptor substrate, or IRS. IRS then activates PDE, the enzyme that decreases the signal of epinephrine and glucagon, to prevent them from having an effect while insulin is active. IRS also indirectly activates Protein Kinase B, or PKB. PKB inhibits FOXO-1, a transcription factor that increases transcription of PEPCK and G6Phase, enzymes related to gluconeogenesis, and we don’t want gluconeogenesis when insulin is active. PKB also prevents the cell from going into apoptosis, by stabilizing a protein called “Bad”, and it increases expression of some other genes. Lastly, PKB inactivates glycogen synthase kinase, the enzyme that inhibits glycogen synthase (GS). By inhibiting the enzyme that inhibits GS, PKB activates GS. PKB also activates eEF2 and eIF-4E.

Following a different pathway, insulin receptor also activates insulin sensitive kinase, or ISK. This kinase activates two enzymes that we’ve seen before, PP1 and PP2A. PP2A activates acetyl-CoA carboxylase and HMG-CoA reductase. The effects of PP1 are summed up in the tables below.

Enzymes affected by PP1 (and therefore by insulin, as insulin activates PP1)
Glycogen synthase Activated Glycogen synthesis
Glycogen phosphorylase Inactivated Glycogen breakdown
Glycogen phosphorylase kinase Inactivated Activates glycogen phosphorylase
Fructose 2,6-bisphosphatase Inactivated Decreases glycolysis
Phosphofructokinase-2 Activated Increases glycolysis
Pyruvate kinase (liver) Activated Glycolysis

Insulin decreases expression of only two genes, phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase (G6Phase), both related to gluconeogenesis. However, it increases subscription of many genes. Here are a few of them.

The enzymes that have increased expression in the presence of insulin
Hexokinase Glycolysis
Glucokinase (hexokinase IV) Glycolysis (liver, Langerhans islets)
Glucose 6-phosphatase dehydrogenase Pentose phosphate pathway
Acetyl-CoA carboxylase Fatty acid synthesis
Malic enzyme Fatty acid synthesis
Phosphofructokinase-2 Increases glycolysis
The (incomplete, but enough for us) insulin pathway. More details can be found here.

Synthesis of insulin

Insulin is synthesized by β-cells in the Langerhans islets. While GLUT4 transporters only take in glucose when insulin is present in the blood, the β-cell contains GLUT2 transporters, which only take in glucose when blood glucose is high (due to its high Km). This glucose is then phosphorylated by glucokinase, and the glucose is degraded to CO2 and water like usual. The β-cell uses glucokinase instead of hexokinase, because the product, glucose-6-phosphate, inhibits hexokinase, but not glucokinase. Thus, if hexokinase was used instead, glucose would simply accumulate in the cell and not be degraded. More about the difference between hexokinase and glucokinase here.

When blood glucose is high, more glucose will be broken down in the β-cell, so the concentration of ATP in the β-cell will be increased. When this happens, the increased [ATP] will close a channel on the cell surface, the ATP-gated K+ channel. With this channel closed, the cell depolarizes, which opens another channel on the cell surface, the voltage-dependent Ca2+ channel. This will cause Ca2+ to enter the cell, while Ca2+ is also released from ER. The increased concentration of Ca2+ in the cell causes it to secrete insulin into the blood.

How the β-cell releases insulin

Previous page:
32. Epinephrine and glucagon

Next page:
34. Cell signalling, receptors and kinases

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