Secretion Beta cells in the islets of Langerhans release<unk>  in two phases. The first-phase release is rapidly triggered in response to increased blood glucose levels, and lasts about 10 minutes. The second phase is a sustained, slow release of newly formed vesicles triggered independently of sugar, peaking in 2 to 3 hours. The two phases of the<unk>  release suggest that<unk>  granules are present in diverse stated populations or "pools". During the first phase of<unk>  exocytosis, most of the granules predispose for exocytosis are released after the calcium internalization. This pool is known as Readily Releasable Pool (RRP). The RRP granules represent 0.3-0.7% of the total<unk> -containing granule population, and they are found immediately adjacent to the plasma membrane. During the second phase of exocytosis,<unk>  granules require mobilization of granules to the plasma membrane and a previous preparation to undergo their release. Thus, the second phase of<unk>  release is governed by the rate at which granules get ready for release. This pool is known as a Reserve Pool (RP). The RP is released slower than the RRP (RRP: 18 granules/min; RP: 6 granules/min). Reduced first-phase<unk>  release may be the earliest detectable beta cell defect predicting onset of type 2 diabetes. First-phase release and<unk>  sensitivity are independent predictors of diabetes. The description of first phase release is as follows: * Glucose enters the β-cells through the glucose transporters, GLUT 2. At low blood sugar levels little glucose enters the β-cells; at high blood glucose concentrations large quantities of glucose enter these cells. * The glucose that enters the β-cell is phosphorylated to glucose-6-phosphate (G-6-P) by glucokinase (hexokinase IV) which is not inhibited by G-6-P in the way that the hexokinases in other tissues (hexokinase I – III) are affected by this product. This means that the intracellular G-6-P concentration remains proportional to the blood sugar concentration. * Glucose-6-phosphate enters glycolytic pathway and then, via the pyruvate dehydrogenase reaction, into the Krebs cycle, where multiple, high-energy ATP molecules are produced by the oxidation of acetyl CoA (the Krebs cycle substrate), leading to a rise in the ATP:ADP ratio within the cell. * An increased intracellular ATP:ADP ratio closes the ATP-sensitive SUR1/Kir6.2 potassium channel (see sulfonylurea receptor). This prevents potassium ions (K+) from leaving the cell by facilitated diffusion, leading to a buildup of intracellular potassium ions. As a result, the inside of the cell becomes less negative with respect to the outside, leading to the depolarization of the cell surface membrane. * Upon depolarization, voltage-gated calcium ion (Ca2+) channels open, allowing calcium ions to move into the cell by facilitated diffusion. * The cytosolic calcium ion concentration can also be increased by calcium release from intracellular stores via activation of ryanodine receptors. * The calcium ion concentration in the cytosol of the beta cells can also, or additionally, be increased through the activation of phospholipase C resulting from the binding of an extracellular ligand (hormone or neurotransmitter) to a G protein-coupled membrane receptor. Phospholipase C cleaves the membrane phospholipid, phosphatidyl inositol 4,5-bisphosphate, into inositol 1,4,5-trisphosphate and diacylglycerol. Inositol 1,4,5-trisphosphate (IP3) then binds to receptor proteins in the plasma membrane of the endoplasmic reticulum (ER). This allows the release of Ca2+ ions from the ER via IP3-gated channels, which raises the cytosolic concentration of calcium ions independently of the effects of a high blood glucose concentration. Parasympathetic stimulation of the pancreatic islets operates via this pathway to increase<unk>  secretion into the blood. * The significantly increased amount of calcium ions in the cells' cytoplasm causes the release into the blood of previously synthesized<unk> , which has been stored in intracellular secretory vesicles. This is the primary mechanism for release of<unk> . Other substances known to stimulate<unk>  release include the amino acids arginine and leucine, parasympathetic release of acetylcholine (acting via the phospholipase C pathway), sulfonylurea, cholecystokinin (CCK, also via phospholipase C), and the gastrointestinally derived incretins, such as glucagon-like peptide-1 (GLP-1) and glucose-dependent<unk> otropic peptide (GIP). Release of<unk>  is strongly inhibited by norepinephrine (noradrenaline), which leads to increased blood glucose levels during stress. It appears that release of catecholamines by the sympathetic nervous system has conflicting influences on<unk>  release by beta cells, because<unk>  release is inhibited by α2-adrenergic receptors and stimulated by β2-adrenergic receptors. The net effect of norepinephrine from sympathetic nerves and epinephrine from adrenal glands on<unk>  release is inhibition due to dominance of the α-adrenergic receptors. When the glucose level comes down to the usual physiologic value,<unk>  release from the β-cells slows or stops. If the blood glucose level drops 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 the liver glycogen stores, supplemented by gluconeogenesis if the glycogen stores become depleted. By increasing blood glucose, the hyperglycemic hormones prevent or correct life-threatening hypoglycemia. Evidence of impaired first-phase<unk>  release can be seen in the glucose tolerance test, demonstrated by a substantially elevated blood glucose level at 30 minutes after the ingestion of a glucose load (75 or 100 g of glucose), followed by a slow drop over the next 100 minutes, to remain above 120 mg/100 ml after two hours after the start of the test. In a normal person the blood glucose level is corrected (and may even be slightly over-corrected) by the end of the test. An<unk>  spike is a 'first response' to blood glucose increase, this response is individual and dose specific although it was always previously assumed to be food type specific only. Oscillations<unk>  release from pancreas oscillates with a period of 3–6 minutes. Even during digestion, in general, one or two hours following a meal,<unk>  release from the pancreas is not continuous, but oscillates with a period of 3–6 minutes, changing from generating a blood<unk>  concentration more than about 800 p mol/l to less than 100 pmol/l (in rats). This is thought to avoid downregulation of<unk>  receptors in target cells, and to assist the liver in extracting<unk>  from the blood. This oscillation is important to consider when administering<unk> -stimulating medication, since it is the oscillating blood concentration of<unk>  release, which should, ideally, be achieved, not a constant high concentration. This may be achieved by delivering<unk>  rhythmically to the portal vein, by light activated delivery, or by islet cell transplantation to the liver. Blood<unk>  level The idealized diagram shows the fluctuation of blood sugar (red) and the sugar-lowering hormone<unk>  (blue) in humans during the course of a day containing three meals. In addition, the effect of a sugar-rich versus a starch-rich meal is highlighted. The blood<unk>  level can be measured in international units, such as µIU/mL or in molar concentration, such as pmol/L, where 1 µIU/mL equals 6.945 pmol/L. A typical blood level between meals is 8–11 μIU/mL (57–79 pmol/L). Signal transduction The effects of<unk>  are initiated by its binding to a receptor, the<unk>  receptor (IR), present in the cell membrane. The receptor molecule contains an α- and β subunits. Two molecules are joined to form what is known as a homodimer.<unk>  binds to the α-subunits of the homodimer, which faces the extracellular side of the cells. The β subunits have tyrosine kinase enzyme activity which is triggered by the<unk>  binding. This activity provokes the autophosphorylation of the β subunits and subsequently the phosphorylation of proteins inside the cell known as<unk>  receptor substrates (IRS). The phosphorylation of the IRS activates a signal transduction cascade that leads to the activation of other kinases as well as transcription factors that mediate the intracellular effects of<unk> . The cascade that leads to the insertion of GLUT4 glucose transporters into the cell membranes of muscle and fat cells, and to the synthesis of glycogen in liver and muscle tissue, as well as the conversion of glucose into triglycerides in liver, adipose, and lactating mammary gland tissue, operates via the activation, by IRS-1, of phosphoinositol 3 kinase (PI3K). This enzyme converts a phospholipid in the cell membrane by the name of phosphatidylinositol 4,5-bisphosphate (PIP2), into phosphatidylinositol 3,4,5-triphosphate (PIP3), which, in turn, activates protein kinase B (PKB). Activated PKB facilitates the fusion of GLUT4 containing endosomes with the cell membrane, resulting in an increase in GLUT4 transporters in the plasma membrane. PKB also phosphorylates glycogen synthase kinase (GSK), thereby inactivating this enzyme. This means that its substrate, glycogen synthase (GS), cannot be phosphorylated, and remains dephosphorylated, and therefore active. The active enzyme, glycogen synthase (GS), catalyzes the rate limiting step in the synthesis of glycogen from glucose. Similar dephosphorylations affect the enzymes controlling the rate of glycolysis leading to the synthesis of fats via malonyl-CoA in the tissues that can generate triglycerides, and also the enzymes that control the rate of gluconeogenesis in the liver. The overall effect of these final enzyme dephosphorylations is that, in the tissues that can carry out these reactions, glycogen and fat synthesis from glucose are stimulated,
Insulin
Regular insulin
Pulsatile insulin
Lente insulin
Proglucagon
Ultralente insulin
Glucuronide
Glucagon 