Last updated on January 11, 2020 at 14:20
- 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
This pathway is much more difficult than the previous
When the insulin receptor binds to insulin, it becomes phosphorylated. The receptor is a tyrosine kinase receptor, meaning that it works by phosphorylating tyrosine residues on other molecules. The insulin receptor has four subunits: two α-subunits and two β-subunits. The two α-subunits bind the insulin, while the β-subunits have tyrosine kinase activity.
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|
|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|
|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|
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.
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.
32. Epinephrine and glucagon
34. Cell signalling and kinases