Background information on the Hormone
Structure
mRNA encodes for a polypeptide chain known as Preproinsulin, which then passively folds into, via amino acid affinity, Insulin.[1]
Insulin is a peptide hormone (hormone made from amino acids) that is composed of two chains, an alpha chain 21 amino acids in length and a beta chain 30 amino acids in length.[2][1] It is connected by sulfide bridges between chains (A7-B7, A20-B19) and in the alpha chain (A6-A11)[1], which give it a hydrophobic core.[3]
This tertiary protein structure can exist by itself as a monomer[4], together with another as a dimer[5], and as a hexamer.[6]
These forms of insulin are metabolically inert[7] and become active when conformational (structural) changes occur when binding to the insulin receptor.[1]
Roles in the Body
In vivo synthesis, degradation, and regulation
Insulin is synthesized in the Pancreas, in a subset of the Pancreas[8] known as the 'Islets of Langerhans' exists beta-cells which are the sole producers of insulin.[9]
Insulin, after its synthesis, is released into the blood.
Once done its job, it is degraded by Insulin Degrading Enzyme (Insulysin)[10], which is ubiquitously expressed[11] and declines with age[12].
The insulin receptor signalling cascade
For simplicity, select intermediates that hold a critical spot in the signalling cascade have been bolded.
Insulin stimulation works via insulin acting on the outer side of the insulin receptor (which is embedded in the cell membrane, exposed to both the outside and inside), and causing structural (Conformational) changes that induce a tyrosine kinase on the inside portion of the receptor, and multiple phosphorylations.[13] The compounds that are directly phosphorylated by the inside portion of the insulin receptor include the four denoted substrates (Insulin Receptor Substrate, IRS, 1-4) as well as some other proteins known as Gab1, Shc, Cbl, APD, and SIRPs.[13] Phosphorylation of these intermediates causes structural changes to them that start the post-receptor signalling cascade.
PI3K (activated through the IRS1-4 intermediate) is sometimes seen as the main second tier intermediate[14] and acts through phosphoinositides to activate an intermediate known as Akt, which has its activity highly correlated with GLUT4 translocation.[15] Inhibition of PI3k by wortmannin completely abolishes insulin-mediated glucose uptake, suggesting the criticality of this pathway.[16]
GLUT4 translocation (the ability to take sugars into a cell) seems to be co-dependent on both PI3K activation (as stated above) as well as a CAP/Cbl cascade.[17][18] Activation of PI3K in vitro is not sufficient to explain all of insulin-mediated glucose uptake.[19][20] Activation of the primary intermediate APS recruits both CAP and c-Cbl to the insulin receptor where the form a dimer complex (bind together)[21][22] and then travel via lipid rafts[23] to GLUT4 vesicles, and via a GTP binding protein facilitate their movement to the cell surface.[24]
For a visual representation of the above, please refer to the KEGG metabolic pathway for insulin.
Effects on Carbohydrate Metabolism
Insulin is the main metabolic regulator of blood glucose (also known as blood sugar) levels. It acts in concert with its sister hormone Glucagon to balance blood glucose levels in the body. Insulin has both roles that increase and decrease glucose levels in the blood, namely by increasing synthesis of glucose and increasing deposition of glucose into cells; both anabolic (tissue-building) reactions which are generally in opposition to glucagons catabolic (tissue-destroying) actions.
Regulation of Glucose synthesis and degradation
Glucose can be generated from non-glucose sources in the liver and kidneys.[25] The kidneys tend to resorb approximately as much glucose as they synthesis however, indicating that they may be self-sustaining. This is the reason why the liver is seen as the main centre for gluconeogenesis (gluco = glucose, neo = new, genesis = create; to create new glucose).[26]
Insulin is secreted from the pancreas, and does so in response to when beta-cells detect rising glucose levels in the blood.[27] There are also neural sensors which can work vicariously through the pancreas.[28][29] When sugar in the blood rises, insulin (and other factors) mediate a systemic (whole-body) flux of glucose out of the blood and into the liver and other tissues (such as fat and muscle). Sugar can flux into and out of the liver via GLUT2, and is fairly independent of hormonal regulation[30] although some exists in the gut GLUT2.[31] In particular, the sensation of sweetness can upregulate GLUT2 activity in the gut.[32] The flux of glucose into the liver hinders creation of more glucose, and begins to favor production of glycogen via hepatic glycogenesis (glyco = glycogen, genesis = create; to create glycogen).[33][34]
Glucose Uptake into cells
Insulin acts to deliver glucose from the blood into muscle and fat cells via the transport known as GLUT4.[35] There are 6 GLUTs in the body (1-7, in which 6 is a pseudogene) but GLUT4 is the most commonly expressed and significant for muscle and fat tissue[35][13] and GLUT5 responding to fructose.[36]
GLUT4 is not a surface transport, but is contained in small vesicles inside the cell.[37] These vesicles can be moved to the surface of the cell (cytoplasmic membrane) by either insulin stimulation[38] of its receptor or by calcium release from the sarcoplasmic reticulum (muscle contraction).[39]
As mentioned earlier, a synergy of PI3K activation (via insulin signalling) and CAP/Cbl signalling (partially via insulin) is required for effective GLUT4 mobilization and uptake of glucose into fat and muscle cells (where GLUT4 is most commonly expressed).
Effects on Fat Metabolism
Effects on Protein Metabolism
Insulin Sensitivity and Resistance
Insulin resistance is also seen in high-fat diets (typically 60% total calories or greater), which may be due to adverse interactions with the CAP/Cbl signalling cascade required for GLUT4 translocation,[40][41] as the actual insulin receptor phosphorylation is unaffected and the phosphorylation of IRS intermediates only slightly adversed affected.[42]
