Secretion 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, 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 insulin release suggest that insulin granules are present in diverse stated populations or "pools". During the first phase of insulin 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 insulin-containing granule population, and they are found immediately adjacent to the plasma membrane. During the second phase of exocytosis, insulin granules require mobilization of granules to the plasma membrane and a previous preparation to undergo their release. Thus, the second phase of insulin 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 insulin release may be the earliest detectable beta cell defect predicting onset of
type 2 diabetes. First-phase release and
insulin 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. • 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 insulin secretion into the blood. • The significantly increased amount of calcium ions in the cells' cytoplasm causes the release into the blood of previously synthesized insulin, which has been stored in intracellular
secretory vesicles. This is the primary mechanism for release of insulin. Other substances known to stimulate insulin 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 insulinotropic peptide (GIP). Release of insulin 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 insulin release by beta cells, because insulin 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 insulin release is inhibition due to dominance of the α-adrenergic receptors. When the glucose level comes down to the usual physiologic value, insulin 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 insulin 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 insulin 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 of
insulin receptors in target cells, and to assist the liver in extracting insulin from the blood.
Blood insulin level (red) and the sugar-lowering hormone
insulin (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 insulin 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 insulin are initiated by its binding to a receptor,
the insulin 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. Insulin 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 insulin binding. This activity provokes the autophosphorylation of the β subunits and subsequently the phosphorylation of proteins inside the cell known as insulin 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 insulin. 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, and glucose production by the liver through
glycogenolysis and
gluconeogenesis are inhibited. The breakdown of triglycerides by adipose tissue into
free fatty acids and
glycerol is also inhibited.
Physiological effects and influx of glucose (3),
glycogen synthesis (4),
glycolysis (5) and triglyceride synthesis (6). The actions of insulin on the global human metabolism level include: • Increase of cellular intake of certain substances, most prominently glucose in muscle and
adipose tissue (about two-thirds 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 (indirect and direct) on cells include: • Stimulates the uptake of glucose – Insulin decreases blood glucose concentration by inducing
intake of glucose by the cells. This is possible because Insulin causes the insertion of the GLUT4 transporter in the cell membranes of muscle and fat tissues which allows glucose to enter the cell. • Decreased
gluconeogenesis and
glycogenolysis – decreases production of glucose from noncarbohydrate substrates, primarily in the liver (the vast majority of endogenous insulin arriving at the liver never leaves the liver); decrease of insulin causes glucose production by the liver from assorted substrates. • Increased amino acid uptake – forces cells to absorb circulating amino acids; decrease of insulin inhibits absorption. • Increase in the secretion of
hydrochloric acid by parietal cells in the stomach. • Increased potassium uptake – forces cells synthesizing
glycogen (a very spongy, "wet" substance, that
increases the content of intracellular water, and its accompanying K+ ions) to absorb potassium from the extracellular fluids; lack of insulin inhibits absorption. Insulin's increase in cellular potassium uptake lowers potassium levels in blood plasma. This possibly occurs via insulin-induced translocation of the
Na+/K+-ATPase to the surface of skeletal muscle cells. • Decreased renal sodium excretion. • In hepatocytes, insulin binding acutely leads to activation of protein phosphatase 2A (PP2A), which dephosphorylates the bifunctional enzyme
fructose bisphosphatase-2 (PFKB1), activating the phosphofructokinase-2 (PFK-2) active site. PFK-2 increases production of fructose 2,6-bisphosphate.
Fructose 2,6-bisphosphate allosterically activates
PFK-1, which favors glycolysis over gluconeogenesis. Increased glycolysis increases the formation of
malonyl-CoA, a molecule that can be shunted into lipogenesis and that allosterically inhibits of
carnitine palmitoyltransferase I (CPT1), a mitochondrial enzyme necessary for the translocation of fatty acids into the intermembrane space of the mitochondria for fatty acid metabolism. Insulin also influences other body functions, such as
vascular compliance and
cognition. Once insulin enters the human brain, it enhances learning and memory and benefits
verbal memory in particular. Enhancing brain insulin signaling by means of intranasal insulin administration also enhances the acute thermoregulatory and glucoregulatory response to food intake, suggesting that central nervous insulin contributes to the co-ordination of a wide variety of
homeostatic or regulatory processes in the human body. Insulin also has stimulatory effects on
gonadotropin-releasing hormone from the
hypothalamus, thus favoring
fertility.
Anabolic vs. Reponic Classification Historically, insulin has been broadly classified as an anabolic hormone because it stimulates the synthesis of complex molecules. However, recent medical literature has proposed reclassifying insulin specifically as a reponic hormone (from the Latin
repono, meaning "to store") to better distinguish its metabolic role from that of classic anabolic hormones like testosterone or growth hormone. While classic anabolic hormones drive energy-intensive processes to build metabolically active lean tissue, the primary physiological function of a reponic hormone is to conserve and store systemic energy. Insulin achieves this by driving the cellular uptake of glucose and lipids for storage (lipogenesis and glycogenesis) while simultaneously inhibiting the breakdown of stored energy (lipolysis and glycogenolysis). Researchers argue this distinction provides a clearer framework for understanding why hyperinsulinemia is uniquely characterized by central adiposity and metabolic syndrome rather than lean tissue growth.
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. The two primary sites for insulin clearance are the
liver and the
kidney. It is broken down by the enzyme,
protein-disulfide reductase (glutathione), which breaks the disulphide bonds between the A and B chains. The liver clears most insulin during first-pass transit, whereas the kidney clears most of the insulin in systemic circulation. Degradation normally involves
endocytosis of the insulin-receptor complex, followed by the action of
insulin-degrading enzyme. An insulin molecule produced endogenously by the beta cells is estimated to be degraded within about one hour after its initial release into circulation (insulin
half-life ~ 4–6 minutes).
Regulator of endocannabinoid metabolism Insulin is a major regulator of
endocannabinoid (EC)
metabolism and insulin treatment has been shown to reduce
intracellular ECs, the
2-arachidonoylglycerol (2-AG) and
anandamide (AEA), which correspond with insulin-sensitive expression changes in enzymes of EC metabolism. In insulin-resistant
adipocytes, patterns of insulin-induced enzyme expression is disturbed in a manner consistent with elevated EC
synthesis and reduced EC degradation. Findings suggest that
insulin-resistant adipocytes fail to regulate EC metabolism and decrease intracellular EC levels in response to insulin stimulation, whereby
obese insulin-resistant individuals exhibit increased concentrations of ECs. This dysregulation contributes to excessive
visceral fat accumulation and reduced
adiponectin release from abdominal adipose tissue, and further to the onset of several cardiometabolic risk factors that are associated with obesity and
type 2 diabetes. == Hypoglycemia ==