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... ; Evidence of Therapeutic/Diagnostic Significance Although the concept of developing a GSK- 3 inhibitor is new to pharmacology, some of the small molecules / drugs are not. There exist several naturally occurring GSK- 3 inhibitors that have been used as treatments for other diseases as well as synthetic compounds that have been identified through the use of high-throughput screens (FIGURE 8). One class of natural inhibitors is the metal ions. The first metal ion discovered as a GSK- 3 inhibitor was lithium. A long-standing treatment for bipolar disorder, lithium has been known to activate both glycogen synthase and glycogen synthesis. Further evidence suggests that lithium promotes both the basal and insulin-induced glucose efflux into adipocytes.
These characteristics have since been attributed to lithium's ability to inhibit GSK- 3. Several other metal ion, typically residents of the Group II A in the periodic table, share a similar ionic radius with lithium have been shown to be potent GSK- 3 inhibitors. Bivalent zinc, which is present in the body naturally, as opposed to lithium and other group IIa metals), has also been shown to be a potent inhibitor of GSK- 3. (Wagman) It has been described as a very potent and selective inhibitor of GSK- 3 that promotes in vitro insulin-like functions, including stimulation of lipo genesis, glycogen synthesis and glucose transport. Another class of drugs designated as GSK- 3 inhibitors, is the naturally occurring "ATP-competitive inhibitors. " These include induribine- 3 '-monoxide, the active ingredient of the traditional Chinese medicine for myelocyte leukaemia, hymednialdisine, from the marine sponge, and toyocamycin, from fungus (falavopiridol and alsterpaullones also fall into this class). These five drugs have been described previously as potential CDK inhibitors and with several metal ions exhibit potential as possible natural treatment for DM type II (Wagman) Following the discovery of natural GSK- 3 inhibitors and with the use of chemical combinatorial libraries and rapid high-throughput screens, small molecule inhibitors of GSK- 3 have also been discovered. Glaxo Smith Kline and Chiron have developed possible lead targets for GSK- 3 that are effective at low Nan molar range.
Chiron's compounds are very promising but they are known inhibit both GSK 3 a and GSK 3 b. They were also selective against 20 protein kinases tested, including cdc- 2. Despite this non-specificity, Chir 98014, Chir 99021, and Chir 98023 have been shown to activate glycogen synthase, enhance insulin-induced glucose uptake and GLUT 4 translocation to the cell surface, in vitro and ex vivo. Improvement of oral glucose tolerance tests and increased liver glycogen content were seen in vivo. Glaxo Smith Kline has developed ATP-competitive inhibitors that have shown insulin-like effects, including "activation of glycogen synthase, glycogen synthesis, and suppression of the expression of the gluconeogenesis enzymes phospho enol pyruvate carboxy-kinase (PEPCK) and glucose- 6 -phosphatase in liver cells" (Eldar). They have also developed a lead molecule in pyridine 1, which selectively inhibits GSK 3 a at low nano molar concentrations.
However, it was rendered useless since it inhibited another kinase in the same family as GSK 3 a, known as CDK- 2. E. Drugability/Tractability There seems to be much promise in the durability / tractability of GSK- 3 inhibitors given that several are already drugs given orally for the treatment of other diseases. However, if there is to be a future for the treatment of DM type II by GSK 3 inhibitors, then these non-specifically inhibiting activities must be considered. Most of the inhibitors on the market are small molecules and have shown to have insulin like effects pre-clinically. These drugs activate glycogen synthase, suppress gluconeogenesis enzymes, improve oral glucose tolerance tests in normal and diabetic animals, and promote translocation of GLUT 4 glucose transporter to the plasma membrane.
Many of these different classes of GSK- 3 inhibitors show increased GS activity, enhanced glucose tolerance, etc. in several in vitro, ex vivo, and even in vivo animal models. However, despite these important characteristics, the successful target product should be less toxic, more selective and more effective as a GSK- 3 inhibitor. SECTION II Discovery Strategy A.
Target Validation Glycogen synthase kinase 3 (GSK 3) was identified as a potential target for Type 2 Diabetes Mellitus due to its vital role in the regulation of glycogen synthase (GS). According to literature, GSK 3 is a central negative regulator in the insulin-signaling pathway. Negative regulation of GSK 3 by insulin, which occurs in hepatocytes, myocytes, and adipocytes, is responsible for increasing glucose transport and increasing glycogen synthesis. Therefore, dis regulation or over-expression of GSK 3 in these cells could lead to insulin resistance. Studies in vitro show that hyperactive mutants of GSK 3 expressed in cells lead to a reductions in (GS) activity (Eldar). As a result, inhibiting GSK 3 in glucose metabolism should increase (GS) and improve glycogen deposition in critical glucose-controlling tissues.
GSK 3 is considered to be a potential target for the therapeutic development of T 2 D Mellitus, based on various model systems reported in previous studies. Literature suggests that a key concept of the diabetic phenotype, which is pertinent to the studies of GSK 3, is that muscle glycogen synthesis is the major pathway for glucose metabolism in the body and is defective in T 2 D (Wagman et al. ). Studies performed in Drs. Schulman and Henry labs showed that muscle tissue from type 2 diabetics, in comparison to normal tissue, had reduced glycogen content that correlated with decreased glycogen synthase activity and impaired GS responsiveness to insulin (Shulman). Chiron Corporation also reported that their selective inhibitors CT 98014 and 98023 tested on human skeletal muscle were pivotal in increasing glucose uptake to a magnitude slightly greater than insulin or lithium but with delayed kinetics (FIGURE 5) (Nikoulina). Also, studies performed in ZDF fa / fa GMI rats that showed a potential link to GSK 3 stemmed from a report that ZDF fatty rats exhibited down regulated IRS- 1 and IRS- 2 in liver and muscle (Wagman et al).
Based on these studies and observations, we proposed that GSK 3 was a validated novel target in the therapeutic treatment of Type 2 Diabetes Mellitus, a disease that is influentially controlled by factors affecting glucose metabolism. B. High Throughput Screening For our High Throughput Screening, candidate inhibitors will be selected from our compound library, based on structure based approach using the following properties that are commonly shared by most inhibitors of GSK 3, such as: (a) low molecular weight (
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Research essay sample on Type 2 Diabetes Glucose Tolerance
