GSK3 Beta :: essays research papers

SECTION IScientific Rationale for filling of the TargetA.Characterization of TargetDiabetes Mellitus is a heterogeneous group of metabolous diseases characterized by the presence of excessive amounts of glucose and glucagon in the blood of diabetic patients. The most(prenominal) frequently cited reason for Diabetes Mellitus (DM) is either a lack of insulin secretion (DM font I) and/or, more commonly, the resistance to insulin in the off-base tissues, particularly muscle and fat tissue (DM figure II). Hence, insulin has long been a target for the treatment of DM. In DM Type I, intravenous or subcutaneous insulin injection has ofttimes been the norm. Iatrogenic insulin administration, insulino-mimetics, or insulin-secretagogues have been the major modalities of treatment for DM lineament II however, these treatments do not address the resistance in peripheral tissues to insulin. Essentially, these methods offer a brute-force method of treating hyperglycemia, by increasing level s of a decreasingly impelling hormone (Champ).Under normal physiological conditions, insulin binds to the insulin receptor and becomes phosphorylated as a result. The phosphorylated insulin receptor binds to and phosphorylates IRS proteins and Shc, which bind differentially to various downstream signaling proteins. Phosphatidylinositol 3-kinase (PI3-kinase), a downstream effector of IRS, is critical for the metabolic action of insulin - glucose transport, animal starch synthesis, and protein synthesis (FIGRURE 1) (Virkamaki). It has been discovered that protein kinase B (PKB), a downstream target of PI3-kinase nowadays phosphorylates and, as a result, inhibits glycogen synthase kinase-3 (GSK-3). GSK-3 is a kinase, present in two nearly identical isoforms (GSK 3a and GSK 3b), which are constitutively active in resting cells of various tissues. When active, GSK-3 phosphorylates and inhibits, glycogen synthase, effectively blocking the synthesis of glycogen and favoring the presenc e of glucose monomers in the blood. GSK-3 as well as phosphorylates and inhibits IRS-1, the presence of which is associated with insulin resistance (Eldar). Furthermore, GSK-3, which is responsible for blocking the synthesis of glycogen, is inhibited by insulin and therefore, effectively acts as a GSK-3 inhibitor. During peripheral resistance of insulin, as seen in DM type II patients, GSK-3 is no longer through natural covering of insulin to its receptor. Purportedly, GSK-3 limits insulin action via serine phosphorylation of IRS-1 and it also inhibits glycogen synthase by the same instrument. Hence by inhibiting IRS-1, PI3K is no longer activated to inhibit GSK-3. Essentially, GSK-3 triggers a negative feedback mechanism that results in its own disinhibition. (FIGURE 2) Novel methods in the treatment of DM type II, involves targeting the signaling pathway of insulin rather than increasing insulin concentrations in a patient.