اذهب الى الأسفل


مُساهمة من طرف TAMER في الأحد مايو 18, 2008 3:24 pm

Is composed of two peptide chains referred to as the A chain and B chain. A and B chains are linked together by two disulfide bonds, and an additional disulfide is formed within the A chain. In most species, the A chain consists of 21 amino acids and the B chain of 30 amino acids.
The molecule viewer below can be used to examine the structure of bovine insulin. Setting the Color parameter to "Chain" will color the A chain green and the B chain red.
Although the amino acid sequence of insulin varies among species, certain segments of the molecule are highly conserved, including the positions of the three disulfide bonds, both ends of the A chain and the C-terminal residues of the B chain. These similarities in the amino acid sequence of insulin lead to a three dimensional conformation of insulin that is very similar among species, and insulin from one animal is very likely biologically active in other species. Indeed, pig insulin has been widely used to treat human patients.
Insulin molecules have a tendency to form dimers in solution due to hydrogen-bonding between the C-termini of B chains. Additionally, in the presence of zinc ions, insulin dimers associate into hexamers.
These interactions have important clinical ramifications. Monomers and dimers readily diffuse into blood, whereas hexamers diffuse poorly. Hence, absorption of insulin preparations containing a high proportion of hexamers is delayed and somewhat slow.
This phenomenon, among others, has stimulated development of a number of recombinant insulin analogs. The first of these molecules to be marketed - called insulin lispro - is engineered such that lysine and proline residues on the C-terminal end of the B chain are reversed; this modification does not alter receptor binding, but minimizes the tendency to form dimers and hexamers.
Biosynthesis of Insulin
Insulin is synthesized in significant quantities only in B cells in the pancreas. The insulin mRNA is translated as a single chain precursor called preproinsulin, and removal of its signal peptide during insertion into the endoplasmic reticulum generates proinsulin.
Proinsulin consists of three domains: an amino-terminal B chain, a carboxy-terminal A chain and a connecting peptide in the middle known as the C peptide. Within the endoplasmic reticulum, proinsulin is exposed to several specific endopeptidases which excise the C peptide, thereby generating the mature form of insulin. Insulin and free C peptide are packaged in the Golgi into secretory granules which accumulate in the cytoplasm. When the B cell is appropriately stimulated, insulin is secreted from the cell by exocytosis and diffuses into islet capillary blood. C peptide is also secreted into blood, but has no known biological activity.
Control of Insulin Secretion
Insulin is secreted in primarily in response to elevated blood concentrations of glucose. This makes sense because insulin is "in charge" of facilitating glucose entry into cells. Some neural stimuli (e.g. sight and taste of food) and increased blood concentrations of other fuel molecules, including amino acids and fatty acids, also promote insulin secretion.
Our understanding of the mechanisms behind insulin secretion remain somewhat fragmentary. Nonetheless, certain features of this process have been clearly and repeatedly demonstrated, yielding the following model:
Glucose is transported into the B cell by facilitated diffusion through a glucose transporter; elevated concentrations of glucose in extracellular fluid lead to elevated concentrations of glucose within the B cell.
Elevated concentrations of glucose within the B cell ultimately leads to membrane depolarization and an influx of extracellular calcium. The resulting increase in intracellular calcium is thought to be one of the primary triggers for exocytosis of insulin-containing secretory granules. The mechanisms by which elevated glucose levels within the B cell cause depolarization is not clearly established, but seems to result from ****bolism of glucose and other fuel molecules within the cell, perhaps sensed as an alteration of ATP:ADP ratio and transduced into alterations in membrane conductance.
Increased levels of glucose within B cells also appears to activate calcium-independent pathways that participate in insulin secretion.
Stimulation of insulin release is readily observed in whole animals or people.
The normal fasting blood glucose concentration in humans and most mammals is 80 to 90 mg per 100 ml, associated with very low levels of insulin secretion.
The figure to the right depicts the effects on insulin secretion when enough glucose is infused to maintain blood levels two to three times the fasting level for an hour. Almost immediately after the infusion begins, plasma insulin levels increase dramatically. This initial increase is due to secretion of preformed insulin, which is soon significantly depleted. The secondary rise in insulin reflects the considerable amount of newly synthesized insulin that is released immediately. Clearly, elevated glucose not only simulates insulin secretion, but also tran******ion of the insulin gene and translation of its mRNA.
Physiologic Effects of Insulin

Stand on a street corner and ask people if they know what insulin is, and many will reply, "Doesn't it have something to do with blood sugar?" Indeed, that is correct, but such a response is a bit like saying "Mozart? Wasn't he some kind of a musician?"
Insulin is a key player in the control of intermediary ****bolism. It has profound effects on both carbohydrate and lipid ****bolism, and significant influences on protein and mineral ****bolism. Consequently, derangements in insulin signaling have widespread and devastating effects on many organs and tissues.
The Insulin Receptor and Mechanism of Action

Like the receptors for other protein hormones, the receptor for insulin is embedded in the plasma membrane. The insulin receptor is composed of two alpha subunits and two beta subunits linked by disulfide bonds. The alpha chains are entirely extra cellular and house insulin binding domains, while the linked beta chains penetrate through the plasma membrane.
The insulin receptor is a tyrosine kinase. In other words, it functions as an enzyme that transfers phosphate groups from ATP to tyrosine residues on intracellular target proteins. Binding of insulin to the alpha subunits causes the beta subunits to phosphorylate themselves (autophosphorylation), thus activating the catalytic activity of the receptor. The activated receptor then phosphorylates a number of intracellular proteins, which in turn alters their activity, thereby generating a biological response.
Several intracellular proteins have been identified as phosphorylation substrates for the insulin receptor, the best-studied of which is insulin receptor substrate 1 or IRS-1. When IRS-1 is activated by phosphorylation, a lot of things happen. Among other things, IRS-1 serves as a type of docking center for recruitment and activation of other enzymes that ultimately mediate insulin's effects. A more detailed look at these processes is presented in the section on Insulin Signal Transduction.
Insulin and Carbohydrate ****bolism

Glucose is liberated from dietary carbohydrate such as starch or sucrose by hydrolysis within the small intestine, and is then absorbed into the blood.
Elevated concentrations of glucose in blood stimulate release of insulin, and insulin acts on cells thoughout the body to stimulate uptake, utilization and storage of glucose. The effects of insulin on glucose ****bolism vary depending on the target tissue. Two important effects are:

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1. Insulin facilitates entry of glucose into muscle, adipose and several other tissues. The only mechanism by which cells can take up glucose is by facilitated diffusion through a family of hexose transporters. In many tissues - muscle being a prime example - the major transporter used for uptake of glucose (called GLUT4) is made available in the plasma membrane through the action of insulin.

In the absence of insulin, GLUT4 glucose transporters are present in cytoplasmic vesicles, where they are useless for transporting glucose. Binding of insulin to receptors on such cells leads rapidly to fusion of those vesicles with the plasma membrane and insertion of the glucose transporters, thereby giving the cell an ability to efficiently take up glucose. When blood levels of insulin decrease and insulin receptors are no longer occupied, the glucose transporters are recycled back into the cytoplasm.
The animation to the right depicts how insulin signaling leads to trans******** of glucose transporters from the cytoplasm into the plasma membrane, allowing glucose (small blue balls) to enter the cell. Click on the "Add

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تاريخ التسجيل : 23/03/2008

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