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Insulin Release See also: Blood glucose regulation Beta cells in the islets of Langerhans release insulin in two

phases. The first phase release is rapidly triggered in response to increased blood glucose levels. The second phase is a sustained, slow release of newly formed vesicles triggered independently of sugar. The description of first phase release is as follows: Glucose enters the β-cells through the glucose transporter GLUT2 Glucose goes into glycolysis and the respiratory cycle, where multiple highenergy ATPmolecules are produced by oxidation  Dependent on the ATP:ADP ratio, and hence blood glucose levels, the ATPdependentpotassium 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 4,5bisphosphate into inositol 1,4,5-triphosphate anddiacylglycerol.  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
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This is the main mechanism for release of insulin. Also, in general, some release takes place with food intake, not just glucose or carbohydrate intake, and the β-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 β-cell's membrane potential. Acetylcholine triggers insulin release through phospholipase C, whereas the last acts through the mechanism of adenylate cyclase. The sympathetic nervous system (via α2-adrenergic stimulation as demonstrated by the agonistsclonidine or methyldopa) inhibit the release of insulin. However, it is worth noting that circulatingadrenaline will activate β2-receptors on the β-cells in the pancreatic islets to promote insulin release.[citation needed] 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 α2-receptors, then subsequently, circulating adrenaline from the adrenal medulla will stimulate β2-receptors, thereby promoting insulin release. When the glucose level comes down to the usual physiologic value, insulin release from the β-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

. PKB phosphorylates glycogen synthase kinase (GSK) and thereby inactivates GSK[21] 5. PI3K catalyzes the reaction PIP2 + ATP → PIP3 3. in turn. Two types of tissues are most strongly influenced by insulin. and the extra-membrane section of receptor have been solved. will prevent glucose from entering those cells (e. there is a decrease in the sensitivity of cells to insulin (e. More commonly. a marked drop by 60 minutes. the effect is the same: elevated blood glucose levels. which leads to increased blood glucose levels during stress. Either way. Low levels of circulating insulin. they account for about two-thirds of all cells in a typical human body. and a steady climb back to baseline levels over the following hourly time points.g. and the latter because they accumulate excess food energy against future needs. Insulin binds to the extracellular portion of the alpha subunits of the insulin receptor. however. These transporters are. 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. transmembrane section. In either case.. breathing.g. resulting in an increase in GLUT4 transporters in the plasma membrane[22] . This. resulting in decreased glucose absorption. there is a defect in the release of insulin from the pancreas. the reduced insulin sensitivity characteristic of type 2 diabetes).. etc. circulation. PIP3 activates protein kinase B (PKB) 4. unphosphorylated GS makes more glycogen 7. and the structures of the interior. muscle cells). Release of insulin is strongly inhibited by the stress hormonenorepinephrine (noradrenaline). The activated kinase domain autophosphorylates tyrosine residues on the C-terminus of the receptor as well as tyrosine residues in the IRS-1 protein. Signal transduction Special transporter proteins in cell membranesallow glucose from the blood to enter a cell. as far as the stimulation of glucose uptake is concerned: muscle cells (myocytes) and fat cells (adipocytes). or its absence. the hyperglycemic hormones prevent or correct lifethreatening hypoglycemia. causes a conformational change in the insulin receptor that activates the kinase domain residing on the intracellular portion of the beta subunits. phosphorylated IRS-1. The former are important because of their central role in movement.g.. binds to and activates phosphoinositol 3 kinase (PI3K) 2. PKB also facilitates vesicle fusion. GSK can no longer phosphorylate glycogen synthase (GS) 6. in type 1 diabetes). The genes that specify the proteins that make up the insulin receptor in cell membranes have been identified. there is 'cell starvation' and weight loss.increasing blood glucose. Together. under blood insulin's control in certain body cell types (e. indirectly. sometimes extreme. In a few cases. 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. 1. in turn.

Physiological effects Effect of insulin on glucose uptake and metabolism.  Decreased gluconeogenesis – decreases production of glucose from nonsugar substrates. The actions of insulin on the global human metabolism level include: Control of cellular intake of certain substances. Insulin binds to its receptor (1).  Decreased autophagy . glycolysis (5) and fatty acid synthesis (6). lack of insulin causes the reverse. glycogen synthesis (4). Postprandial levels inhibit autophagy completely.  Increased esterification of fatty acids – forces adipose tissue to make fats (i.  Increased lipid synthesis – insulin forces fat cells to take in blood lipids. These include translocation of Glut-4 transporter to the plasma membrane and influx of glucose (3).[26]  . most prominently glucose in muscle and adipose tissue (about two-thirds of body cells)  Increase of DNA replication andprotein synthesisvia control of amino acid uptake  Modification of the activity of numerous enzymes  The actions of insulin (indirect and direct) on cells include: Increased glycogen synthesis – insulin forces storage of glucose in liver (and muscle) cells in the form of glycogen. which are converted totriglycerides. lack of insulin causes the reverse. triglycerides) from fatty acid esters.e. which starts many protein activation cascades (2). lack of insulin causes the reverse. lowered levels of insulin cause liver cells to convert glycogen to glucose and excrete it into the blood. which is directly useful in reducing high blood glucose levels as in diabetes. primarily in the liver (the vast majority of endogenous insulin arriving at the liver never leaves the liver).  Decreased proteolysis – decreasing the breakdown of protein  Decreased lipolysis – forces reduction in conversion of fat cell lipid stores into blood fatty acids. This is the clinical action of insulin.. lack of insulin causes glucose production from assorted substrates in the liver and elsewhere.decreased level of degradation of damaged organelles.

 Increase in the secretion of hydrochloric acid by parietal cells in the stomach  Decreased renal sodium excretion.  Increased potassium uptake – forces cells to absorb serum potassium. lack of insulin inhibits absorption. especially in microarteries. Insulin's increase in cellular potassium uptake lowers potassium levels in blood. lack of insulin reduces flow by allowing these muscles to contract.Increased amino acid uptake – forces cells to absorb circulating amino acids. This possible occurs via insulin-induced translocation of the Na+/K+-ATPase to the surface of skeletal muscle cells. lack of insulin inhibits absorption.[29]  .[27][28]  Arterial muscle tone – forces arterial wall muscle to relax. increasing blood flow.