《生物技术药物》之重组多肽蛋白质类激素药物PPT.pptVIP

各论五;重组多肽、蛋白质类激素药物;胰腺;重组胰岛素;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, high-energy ATP molecules are produced by oxidation, 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 build up of potassium ions. As a result, the inside of the cell becomes more positive with respect to the outside, leading to the depolarisation of the cell surface membrane. On depolarisation, voltage-gated calcium ion (Ca2+) channels open which allows calcium ions to move into the cells by facilitated diffusion. An increased intracellular calcium ion concentration causes the activation of phospholipase C, which cleaves the membrane phospholipid phosphatidyl inositol 4,5-bisphosphate into inositol 1,4,5-trisphosphate and diacylglycerol. Inositol 1,4,5-trisphosphate (IP3) 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, and further raises the intracellular concentration of calcium ions. Significantly increased amounts of calcium ions in the cells causes the release of previously synthesized insulin, which has been stored in secretory vesicles.;;Effect of insulin on glucose uptake and metabolism. Insulin binds to its receptor (1), which, in turn, starts many protein activation cascades (2). These include: translocation of Glut-4 transporter to the plasma membr