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Example research essay topic: Diabetes Mellitus Type Ii - 1,088 words

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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, insulin-mimetic's, 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 phosphorylated IRS proteins and Shc, which bind differentially to various downstream signaling proteins. Phosphatidylinositol 3 '-kinase (PI 3 -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 PI 3 -kinase directly phosphorylated and, as a result, inhibits glycogen synthase kinase- 3 (GSK- 3). GSK- 3 is a kinase, present in two nearly identical isoforms (GSK 3 a and GSK 3 b), which are constitutively active in resting cells of various tissues.

When active, GSK- 3 phosphorylated and inhibits, glycogen synthase, effectively blocking the synthesis of glycogen and favoring the presence of glucose monomers in the blood. GSK- 3 also phosphorylated 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 binding 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 mechanism. Hence by inhibiting IRS- 1, PI 3 K is no longer activated to inhibit GSK- 3.

Essentially, GSK- 3 triggers a negative feedback mechanism that results in its own dis inhibition. (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. Based on GSK 3 b association to the Insulin Signaling Pathway, a clear target would be to inhibit either GSK 3 a or GSK 3 b with a small molecule so that disinhibtion will be prevented. B. Structural Identity GSK 3 is a serine / threonine protein kinase found in two nearly identical isoforms, GSK 3 a and GSK 3 b, which are expressed ubiquitously in mammalian tissues.

Both isoforms exhibit a high degree of sequence identity, 85 % in overall sequence and 93 % in catalytic sites, and this can account for their nearly identical biochemical functions and substrate affinities (Wagman). The main difference between the two isoforms is the attachment of a long 83 -residue, mostly poly-glycine, tail to the N-terminus of the alpha-isoform. However, in vitro studies have shown, that the beta-isoform is far more stable than the alpha-isoform (Wagman) Despite their structural and enzymatic similarities their genomes reside on different chromosomes. GSK 3, like many other kinases, is affected by various phosphorylation events, and thus can require "prime phosphorylation." Phosphorylation of the N-terminal serine in GSK 3 at ser 21 in alpha and ser 9 in beta, results in inhibition of the enzyme. Inactivation of GSK 3 & # 946; can be reversed by protein phosphatase 2 A, which would return GSK 3 to its active state (Wagman).

Auto-phosphorylation of a tyrosine in the activation segment (tyr 279 in alpha, tyr 216 in beta) increases the enzymatic activity of both isoforms moderately. GSK 3 transfers the gamma-phosphate from ATP to either a serine or threonine, typically four residues N-terminal to a previously phosphorylated site, though not always. According to literature, five crystal structures of GSK 3 b have been eluded but none for GSK 3 a, although the active site would be very similar. These crystal structures have shown that GSK 3 shares the canonical fold typically seen in serine / threonine kinases and is comprised of an N-terminal b-sheet lobe and a C-terminal a-helical domain (Wagman) The activation segment, which contains the tyr 216, is part of the c-terminal & # 945; -helical domain, which is also the location for the majority of the substrate-binding site (Figure 4). The ATP-binding site is the catalytic domain formed at the interface of the N- and C-terminal domains.

A mutation within this pocket greatly reduces the selectivity of GSK 3 & # 946; or substrates with a C-terminal phosphate at the N+ 4 position (Wagman). Most inhibitors of GSK 3 & # 946; beta are known to inhibit the ATP binding site. This unique structure signifies a potential target in drug discovery, as it would target pre-primed substrates such as glycogen synthase. C. Disease Association In the United States, Diabetes is a disease of 15. 7 million, diagnosed, with an estimated 6 million more, undiagnosed. The great majority (approximately 90 %) of patients are afflicted with the DM Type II variety.

In recent years, there has been a dramatic increase in the global prevalence of diabetes and obesity. This places a large burden on our current healthcare system and identifies a large unmet need for better treatment options, including education and prevention. "It is a disproportionately expensive disease; patients diagnosed with diabetes accounted for 5. 8 % of the US population in 1997, or 15. 7 million people, but their per capita health care cost was $ 10, 071, while it was $ 2, 699 for those without diabetes" (Vote). Diabetes has a well-known and extensive morbidity and mortality rate. It is the major cause of blindness in adults aged 20 - 74 years, as well as the leading cause of non traumatic lower-extremity amputation and end-stage renal disease (ESRD) (Vote). Hypoglycemia, hyperglycemia, increased risk of infection, microvascular complications, i.

e. retinopathy, nephropathy, neuropathic complications, and microvascular disease are all possible and common complications of untreated hyperglycemia. D. &...


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Research essay sample on Diabetes Mellitus Type Ii

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