This pathway is also influenced by fed versus fasting states, stress levels, and a variety of other hormones.
On a pathological basis, this topic is crucial to understanding certain disorders in the body such as diabetes, hyperglycemia and hypoglycemia.
Insulin is secreted as a response mechanism for counteracting the increasing excess amounts of glucose in the blood.
Depending on the tissue type, the glucose enters the cell through facilitated diffusion or active transport.
In muscle and adipose tissue, glucose enters through GLUT 4 receptors via facilitated diffusion ([3]).
In the beta-cells of the pancreas and in liver cells, glucose enters through the GLUT 2 receptors [3] (process described below).
The exposure of rat Langerhans islets to glucose for 1 hour is able to remarkably induce the intracellular proinsulin levels.
The glucose that goes into the bloodstream after food consumption also enters the beta cells in the islets of Langerhans in the pancreas.
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.
The Ca2+ influx generated by R-type Ca2+ channels is not enough to cause insulin exocytosis, however, it increases the mobilization of the vesicles towards the cell membrane.
Long-chain acyl-CoA has the ability to acylate proteins that are essential in the insulin granule fusion.
Estrogen is correlated with an increase of insulin secretion by depolarizing the β-cells membrane and enhancing the entry of Ca2+.
[4] After insulin enters the bloodstream, it binds to a membrane-spanning receptor tyrosine kinase (RTK).
Binding of insulin to the α-subunit results in a conformational change of the protein, which activates tyrosine kinase domains on each β-subunit.
Hence, AKT possesses a crucial role in the linkage of the glucose transporter (GLUT4) to the insulin signaling pathway.
The activated GLUT4 will translocate to the cell membrane and promotes the transportation of glucose into the intracellular medium.
It was noted that an increase of P85 a (isoform of P85) results in a competition between the later and the P85-P110 complex to the IRS binding site, reducing the PI3K activity and leading to insulin resistance.
It was also noted that increased serine phosphorylation of IRS is involved in the insulin resistance by reducing their ability to attract PI3K.
Firstly, insulin increases the uptake of glucose from blood by the translocation and exocytosis of GLUT4 storage vesicles in the muscle and fat cells.
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.
Negative feedback is shown in the insulin signal transduction pathway by constricting the phosphorylation of the insulin-stimulated tyrosine.
When activated, this enzyme provides a negative feedback by catalyzing the dephosphorylation of the insulin receptors.
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 blood sugar level.
An increased calcium level activates phospholipase C, which cleaves the membrane phospholipid phosphatidylinositol 4,5-bisphosphate into Inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG).
The influx of Ca2+ ions causes the secretion of insulin stored in vesicles through the cell membrane.
Conversely, when the blood glucose levels are too high, the pancreas is signaled to release insulin.