Insulin biochemistry perspective

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Diabetes is an ailment which is caused due to high amount of glucose (sugar) in the blood. The main reason for high glucose levels in blood is due to the inability of body to utilize it properly. Glucose comes from the digestion of sugar and foods rich in carbohydrates that enable the liver to create glucose. The high concentration level of glucose in blood is termed as Hyperglycemia. In 1910, Sir Edward Albert Sharpey-Schafer suggested people with diabetes were deficient in a single chemical that was normally produced by the pancreas.

He proposed calling this substance insulin. The term is derived from the Latin insula, meaning island, in reference to the islets of Langerhans in the pancreas that produce insulin. (Patlak, 2002) Insulin: An Introduction Insulin is a polypeptide containing 51 amino acids arranged in two chains. The chain A contains 21 amino acids and chain B contains 30 residues. These two chains are cross linked by two sulphur bridges by cysteine residues. Insulin is formed by proteolytic cleavage of its 84 amino acid prescursor Proinsulin.

Insulin has a molecular weight of 5808 Da. It has the molecular formula C257H383N65O77S6. Insulin structure varies slightly between species. Its carbohydrate metabolism regulatory function strength in humans also varies. Porcine which is pig insulin is close to humans. The image above is computer-generated image of insulin hexamers. The zinc ions holding it together and the histidine residues are involved in zinc binding. Insulin Action A pharmacological action of insulin includes carbohydrate metabolism, protein metabolism, lipid metabolism and other actions.

Insulin increases the use of sugar in the tissue and stimulates transportation of glucose into the cells. Insulin also stimulates protein synthesis and growth. It increases synthesis of messenger RNA and decreases gluconeogenesis. A gluconeogenesis is a formation of glucose from glycogen. It also increases amino acid uptake in the muscle. In adipose tissues, insulin increases fatty acid synthesis, glycerol phosphate synthesis and triglyceride deposition.

Other action of insulin includes prevention of ketone boy formation and increases potassium uptake. After the release of insulin from the pancreatic beta cell into the interstitial compartment, it enters the circulation after crossing endothelial barrier. Insulin action effect at the cellular level is achieved by activating and suppressing the activity of enzyme. It can also be achieved by changing the rate of synthesis of enzymes at the level of transcription and translation.

Insulin stimulate glucose uptake into fat cells by glucose transporters. Glucose transporters are small vesicles which contain specific protein macromolecules. Insulin increases the rate of fusion of these vesicles with the plasma membrane, and activates the transporters to transfer glucose across the plasma membrane into the cell. Insulin synthesize hoxokinase, an enzyme which phosporylates glucose as soon as it enters the cell. Insulin is an anabolic hormone. It encourages the storage of fats and the synthesis of proteins.

Each receptor of insulin contain a pair of alpha subunits, which are located on the outer surface of the membrane, and a pair of beta subunits which crosses the membrane and stick out at both the outer and inner surfaces. Both alpha and beta subunits are held together by disulphide (S-S) bonds to form an aggregate. In humans, the insulin receptor gene is located on chromosome 19. Insulin binds to the receptor at a specific site on the alpha subunit. This causes increased phosphorylation of the receptor by ATP, mostly tyrosine residues of the intracellular portion of the beta subunit.

Increased phophorylation of these tyrosine residues activates the beta subunit to function as a kinase enzyme. Some intracellular effects of insulin that occur after insulin-receptor binding may be mediate through nucleotide regulatory proteins (G proteins) a family of proteins associated with the inner surface of the plasma membrane. Cyclic AMP also has some intracellular effects of insulin. The major function of insulin is to counter the concerted action of a number of hyperglycemia-generating hormones and to maintain low blood glucose levels.

Because there are numerous hyperglycemic hormones, untreated disorders associated with insulin generally lead to severe hyperglycemia and shortened life span. In addition to its role in regulating glucose metabolism, insulin stimulates lipogenesis, diminishes lipolysis, and increases amino acid transport into cells. Insulin also modulates transcription, altering the cell content of numerous mRNAs. It stimulates growth, DNA synthesis, and cell replication, effects that it holds in common with the insulin-like growth factors (IGFs) and relaxin.

Specific protease activity cleaves the center third of the molecule, which dissociates as C peptide, leaving the amino terminal B peptide disulfide bonded to the carboxy terminal A peptide. Insulin secretion from beta cells is principally regulated by plasma glucose levels. Increased uptake of glucose by pancreatic b-cells leads to a concomitant increase in metabolism. The increase in metabolism leads to an elevation in the ATP/ADP ratio. This in turn leads to an inhibition of an ATP-sensitive K+ channel.

The net result is a depolarization of the cell leading to Ca2+ influx and insulin secretion. In fact, the role of K+ channels in insulin secretion presents a viable therapeutic target for treating hyperglycemia due to insulin insufficiency. Insulin, secreted by the beta-cells of the pancreas, is directly infused via the portal vein to the liver, where it exerts profound metabolic effects. These effects are the response of the activation of the insulin receptor which belongs to the class of cell surface receptors that exhibit intrinsic tyrosine kinase activity as shown in the figure.

Insulin produces its action through specific insulin receptors which consist of two subunits ? and ?. Insulin receptor complex then initiates a chain of biochemical reaction involving cAMP, protein phosphorylase, protein kinase, phosphatase and lipase. A diabetic condition result when receptor of insulin is desensitization. Therefore, Insulin is used medically in diabetes mellitus. Patients with type 1 diabetes mellitus depend on insulin (commonly injected subcutaneously) for their survival because they make no hormone.

Patients with type 2 diabetes mellitus have either low insulin production or insulin resistance or both. Therefore, they require insulin administration when other medications become inadequate in controlling blood glucose levels. Actions of insulin-insulin receptor interactions at the level of IRS1 and activation of the kinase cascade leading to altered activities of glycogen phosphorylase and glycogen synthase. The insulin receptor is a heterotetramer of 2 extra cellular alpha-subunits disulfide bonded to 2 transmembrane beta-subunits.

With respect to hepatic glucose homeostasis, the effects of insulin receptor activation are specific phosphorylation events that lead to an increase in the storage of glucose with a concomitant decrease in hepatic glucose release to the circulation. Only those responses at the level of glycogen synthase and glycogen phosphorylase are represented. This image shows Insulin-insulin receptor actions on glycogen homeostasis showing the role of protein targeting glycogen, PTG in complex formations involving many of the enzymes and substrates together.

Also diagrammed is response of insulin at the level of glucose transport into cells via GLUT4 translocation to the plasma membrane. GS/GP kinase = glycogen synthase: glycogen phosphorylase kinase. PPI = protein phosphatase inhibitor. Arrows denote either direction of flow or positive effects, T lines represent inhibitory effects. In most nonhepatic tissues, insulin increases glucose uptake by increasing the number of plasma membrane glucose transporters: GLUTs. Glucose transporters are in a continuous state of turnover.

Increases in the plasma membrane content of transporters stem from an increase in the rate of recruitment of new transporters into the plasma membrane, deriving from a special pool of preformed transporters localized in the cytoplasm. GLUT1 is present in most tissues, GLUT2 is found in liver and pancreatic b-cells, GLUT3 is in the brain and GLUT4 is found in heart, adipose tissue and skeletal muscle. In liver glucose uptake is dramatically increased because of increased activity of the enzymes glucokinase, phosphofructokinase-1 (PFK-1), and pyruvate kinase (PK), the key regulatory enzymes of glycolysis.

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