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GSK3 Beta SECTION I Scientific Rationale for Selection of the Target A. Characterization of Target Diabetes Mellitus is a heterogeneous group of metabolic diseases
Submitted by johannaor on April 20, 2005
Category: Science
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SECTION I
Scientific Rationale for Selection of the Target
A. Characterization of Target
Diabetes Mellitus is a heterogeneous group of metabolic diseases characterized by the presence of excessive amounts of glucose and glucagon in the blood of diabetic patients. The most frequently cited reason for Diabetes Mellitus (DM) is either a lack of insulin secretion (DM Type I) and/or, more commonly, the resistance to insulin in the peripheral tissues, particularly muscle and adipose tissue (DM type II). Hence, insulin has long been a target for the treatment of DM. In DM Type I, intravenous or subcutaneous insulin injection has often been the norm. Iatrogenic insulin administration, insulino-mimetics, or insulin-secretagogues have been the major modalities of treatment for DM type 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 levels of a decreasingly effective 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, glycogen synthesis, and protein synthesis (FIGRURE 1) (Virkamaki). It has been discovered that protein kinase B (PKB), a downstream target of PI3-kinase directly 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...
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