Synthesis, physiological effects, and degradation

Synthesis
Insulin is produced in the pancreas and released when any of the several stimuli is detected. The stimuli include ingested protein and glucose in the blood produced from digested food. Carbohydrate can be polymers of simple sugars or the simple sugars themselves. If the carbohydrate includes glucose then that glucose will be absorbed into the bloodstream and blood glucose level will begin to rise. In target cells, insulin initiates a signal transduction, which has the effect of increasing glucose uptake and storage. Finally, insulin is degraded, terminating the response.

Insulin undergoes extensive posttranslational modification along the production pathway. Production and secretion are largely independent; prepared insulin is stored awaiting secretion. Both C-peptide and mature insulin are biologically active. Cell components and proteins in this image are not to scale.
In mammals, insulin is synthesized in the pancreas within the beta cells (β-cells) of the islets of Langerhans. One million to three million islets of Langerhans (pancreatic islets) form the endocrine part of the pancreas, which is primarily an exocrine gland. The endocrine portion accounts for only 2% of the total mass of the pancreas. Within the islets of Langerhans, beta cells constitute 60–80% of all the cells.
In beta cells, insulin is synthesized from the proinsulin precursor molecule by the action of proteolytic enzymes, known as prohormone convertases (PC1 and PC2), as well as the exoprotease carboxypeptidase E.[9] These modifications of proinsulin remove the center portion of the molecule (i.e., C-peptide), from the C- and N- terminal ends of proinsulin. The remaining polypeptides (51 amino acids in total), the B- and A- chains, are bound together by disulfide bonds/disulphide bonds. Confusingly, the primary sequence of proinsulin goes in the order "B-C-A", since B and A chains were identified on the basis of mass, and the C peptide was discovered after the others.
The endogenous production of insulin is regulated in several steps along the synthesis pathway:
At transcription from the insulin gene
In mRNA stability
At the mRNA translation
In the posttranslational modifications
It has been shown that insulin and its related proteins, are also produced inside the brain and that reduced levels of these proteins are linked to Alzheimer's disease.[10][11][12]
Release
See also: Blood glucose regulation
Beta cells in the islets of Langerhans release insulin in two phases. The first phase insulin release is rapidly triggered in response to increased blood glucose levels. The second phase is a sustained, slow release of newly formed vesicles that are triggered independently of sugar. The description of first phase release is as follows:
Glucose enters the beta cells through the glucose transporter GLUT2
Glucose goes into glycolysis and the respiratory cycle where multiple high-energy ATP molecules are produced by oxidation
Dependent on ATP levels, and hence blood glucose levels, the ATP-controlled potassium channels (K+) close and the cell membrane depolarizes
On depolarization, voltage controlled calcium channels (Ca2+) open and calcium flows into the cells
An increased calcium level causes activation of phospholipase C, which cleaves the membrane phospholipid phosphatidyl inositol 4,5-bisphosphate into inositol 1,4,5-triphosphate and diacylglycerol.
Inositol 1,4,5-triphosphate (IP3) binds to receptor proteins in the membrane of endoplasmic reticulum (ER). This allows the release of Ca2+ from the ER via IP3 gated channels, and further raises the cell concentration of calcium.
Significantly increased amounts of calcium in the cells causes release of previously synthesized insulin, which has been stored in secretory vesicles
This is the main mechanism for release of insulin. In addition some insulin release takes place generally with food intake, not just glucose or carbohydrate intake, and the beta cells are also somewhat influenced by the autonomic nervous system. The signaling mechanisms controlling these linkages are not fully understood.
Other substances known to stimulate insulin release include amino acids from ingested proteins, acetylcholine released from vagus nerve endings (parasympathetic nervous system), gastrointestinal hormones released by enteroendocrine cells of intestinal mucosa and glucose-dependent insulinotropic peptide (GIP). Three amino acids (alanine, glycine and arginine) act similarly to glucose by altering the beta cell's membrane potential. Acetylcholine triggers insulin release through phospholipase C, while the last acts through the mechanism of adenylate cyclase.
The sympathetic nervous system (via Alpha2-adrenergic stimulation as demonstrated by the agonists clonidine or methyldopa) inhibit the release of insulin. However, it is worth noting that circulating adrenaline will activate Beta2-Receptors on the Beta cells in the pancreatic Islets to promote insulin release. This is important since muscle cannot benefit from the raised blood sugar resulting from adrenergic stimulation (increased gluconeogenesis and glycogenolysis from the low blood insulin: glucagon state) unless insulin is present to allow for GLUT-4 translocation in the tissue. Therefore, beginning with direct innervation, norepinephrine inhibits insulin release via alpha2-receptors, then subsequently, circulating adrenaline from the adrenal medulla will stimulate beta2-receptors thereby promoting insulin release.
When the glucose level comes down to the usual physiologic value, insulin release from the beta cells slows or stops. If blood glucose levels drop lower than this, especially to dangerously low levels, release of hyperglycemic hormones (most prominently glucagon from Islet of Langerhans' alpha cells) forces release of glucose into the blood from cellular stores, primarily liver cell stores of glycogen. By increasing blood glucose, the hyperglycemic hormones prevent or correct life-threatening hypoglycemia. Release of insulin is strongly inhibited by the stress hormone norepinephrine (noradrenaline), which leads to increased blood glucose levels during stress.
Evidence of impaired first phase insulin release can be seen in the glucose tolerance test, demonstrated by a substantially elevated blood glucose level at 30 minutes, a marked drop by 60 minutes, and a steady climb back to baseline levels over the following hourly time points.
[edit] Oscillations
Main article: Insulin release oscillations

Insulin release from pancreas oscillates with a period of 3–6 minutes.[13]
Even during digestion, generally one or two hours following a meal, insulin release from pancreas is not continuous, but oscillates with a period of 3–6 minutes, changing from generating a blood insulin concentration more than ~800 pmol/l to less than 100 pmol/l.[13] This is thought to avoid downregulation of insulin receptors in target cells and to assist the liver in extracting insulin from the blood.[13] This oscillation is important to consider when administering insulin-stimulating medication, since it is the oscillating blood concentration of insulin release, which should, ideally, be achieved, not a constant high concentration.[13] It is also important to consider in that all methods of insulin replacement can never hope to replicate this delivery mechanism precisely. This may be achieved by delivering insulin rhythmically to the portal vein or by islet cell transplantation to the liver.[13] Future insulin pumps hope to address this characteristic. (See also Pulsatile Insulin.)
Signal transduction
There are special transporter proteins in cell membranes through which glucose from the blood can enter a cell. These transporters are, indirectly, under blood insulin's control in certain body cell types (e.g., muscle cells). Low levels of circulating insulin, or its absence, will prevent glucose from entering those cells (e.g., in Type 1 diabetes). However, more commonly there is a decrease in the sensitivity of cells to insulin (e.g., the reduced insulin sensitivity characteristic of Type 2 diabetes), resulting in decreased glucose absorption. In either case, there is 'cell starvation', weight loss, sometimes extreme. In a few cases, there is a defect in the release of insulin from the pancreas. Either way, the effect is, characteristically, the same: elevated blood glucose levels.
Activation of insulin receptors leads to internal cellular mechanisms that directly affect glucose uptake by regulating the number and operation of protein molecules in the cell membrane that transport glucose into the cell. The genes that specify the proteins that make up the insulin receptor in cell membranes have been identified and the structures of the interior, transmembrane section, and the extra-membrane section of receptor have been solved.
Two types of tissues are most strongly influenced by insulin, as far as the stimulation of glucose uptake is concerned: muscle cells (myocytes) and fat cells (adipocytes). The former are important because of their central role in movement, breathing, circulation, etc., and the latter because they accumulate excess food energy against future needs. Together, they account for about two-thirds of all cells in a typical human body.
Physiological effects

Effect of insulin on glucose uptake and metabolism. Insulin binds to its receptor (1), which in turn starts many protein activation cascades (2). These include: translocation of Glut-4 transporter to the plasma membrane and influx of glucose (3), glycogen synthesis (4), glycolysis (5) and fatty acid synthesis (6).
The actions of insulin on the global human metabolism level include:
Control of cellular intake of certain substances, most prominently glucose in muscle and adipose tissue (about ⅔ of body cells).
Increase of DNA replication and protein synthesis via control of amino acid uptake.
Modification of the activity of numerous enzymes.
The actions of insulin on cells include:
Increased glycogen synthesis – insulin forces storage of glucose in liver (and muscle) cells in the form of glycogen; lowered levels of insulin cause liver cells to convert glycogen to glucose and excrete it into the blood. This is the clinical action of insulin, which is directly useful in reducing high blood glucose levels as in diabetes.
Increased fatty acid synthesis – insulin forces fat cells to take in blood lipids, which are converted to triglycerides; lack of insulin causes the reverse.
Increased esterification of fatty acids – forces adipose tissue to make fats (i.e., triglycerides) from fatty acid esters; lack of insulin causes the reverse.
Decreased proteolysis – decreasing the breakdown of protein.
Decreased lipolysis – forces reduction in conversion of fat cell lipid stores into blood fatty acids; lack of insulin causes the reverse.
Decreased gluconeogenesis – decreases production of glucose from non-sugar substrates, primarily in the liver (remember, the vast majority of endogenous insulin arriving at the liver never leaves the liver); lack of insulin causes glucose production from assorted substrates in the liver and elsewhere.
Decreased autophagy - decreased level of degradation of damaged organelles. Postprandial levels inhibit autophagy completely.[14]
Increased amino acid uptake – forces cells to absorb circulating amino acids; lack of insulin inhibits absorption.
Increased potassium uptake – forces cells to absorb serum potassium; lack of insulin inhibits absorption. Insulin's increase in cellular potassium uptake lowers potassium levels in blood.
Arterial muscle tone – forces arterial wall muscle to relax, increasing blood flow, especially in micro arteries; lack of insulin reduces flow by allowing these muscles to contract.
Increase in the secretion of hydrochloric acid by Parietal cells in the stomach.
Degradation
Once an insulin molecule has docked onto the receptor and effected its action, it may be released back into the extracellular environment, or it may be degraded by the cell. Degradation normally involves endocytosis of the insulin-receptor complex followed by the action of insulin degrading enzyme. Most insulin molecules are degraded by liver cells. It has been estimated that an insulin molecule produced endogenously by the pancreatic beta cells is degraded within approximately one hour after its initial release into circulation (insulin half-life ~ 4–6 minutes).