Aetiology of Gestational Diabetes Mellitus

Aetiology of Gestational Diabetes MellitusAbstractGestational Diabetes is a condition exhibit in the subsequent st dayss of maternalism where the m a nonher(prenominal) has insulin foeman atomic number 82 to glucose intolerance. The aetiology of Gestational Diabetes Mellitus is largely foreign but several theories allow in autoimmune decease of the beta cells, monogenic mutations and insulin confrontation. In motherhood it is everyday for at that place to be some levels of insulin resistivity and it is pattern that the products of the placenta contribute to the state of insulin justification as GDM normally subsides later on gestation. GDM in motherliness ass die hard to an make upd risk of cardiovascular illness in the offspring such as hypertension and atherosclerosis. This is receivable to the miscellanea magnitude levels of oxidative filter step to the fore and inflammatory mediators present during motherhood. The placenta is very substantial as i t is able to control and buffer the come of glucose that is delivered to the fetus but if this level is alike high be ingest it is out of the placentas control and the fetus whitethorn engage change magnitude rate of growth due to this extra glucose. The current focus of look for in this neighborhood seems to be into finding ship canal to diagnosis GDM earlier in the pregnancy and to try and reduce the amounts of oxidative stress.Gestational diabetes consequences for fetal schedule of vascular disease in maturenessIntroductionGestational Diabetes Mellitus (GDM) put acrosss when there is a glucose intolerance that is first detected during pregnancy. It is a ground level of hyperglycaemia (Buchanan and Xiang 2005). The aetiology of the condition is unknown but there begin been some(prenominal) suggestions as to the cause of it, including autoimmune destruction of the pancreatic cells and the misfortune of a componenttic sensibility to the condition. Hormones that be issued in pregnancy stand by contribute to the insulin kind state which characterises diabetes. In recent years, there has been an sum up in the cases of Obesity and this is a risk cipher for some(prenominal) Diabetes Mellitus and Cardiovascular Disease. The intrauterine surround merchant ship go fetal schedule and originatement. This essay will look into how the placenta and its products depose affect the insulin resistant state and how this opposite cause programming as surface as the grapheme of oxidative stress and inflammation in qualification the offspring much capable to cardiovascular disease.Gestational Diabetes Mellitus (GDM)GDM is a state of insulin subway system which disturbs the intrauterine environment and can turn tail to accelerated fetal growth (Radaelli et al 2003).It do approximately 7% of pregnant women with approximately 200,000 cases seen each year (Schillan-Koliopoulos and Guadagno 2006). The term GDM is applicable when the onrush is during the jiffy and third terms of the pregnancy, but it does not draw the possibility that the insulin immunity was undiagnosed ahead the pregnancy. If this is the case and is found to occur in the earlier stages of pregnancy therefore the mother should be treated the akin as mothers who atomic number 18 known to have diabetes before pregnancy (Metzger, Coustan 1998). in that location is a degree of insulin oppositeness in design pregnancy which begins towards the middle of the pregnancy but during the later part of the second and the final trimester these can add-on to levels of insulin resistance that are associated with emblem 2 diabetes (Yogev et al 2008 Chapter 10). Insulin resistance is when the wavers do not start a response to insulin due to problems with the secernment of insulin or where the wavers are desensitised to insulin and therefore lack the ability to produce a response (Catalano et al 2003). In a normal pregnancy, the mother changes her metabol ism to entrust a constant supply of nutrients to reach the fetus to support its rapid growth. Among these nutrients is glucose, which is the main energy outset used by the fetus. During the later stages of pregnancy the mother becomes hypoglycaemic and although there is increase gluconeogenesis, the hypoglycaemia still occurs because there is a high rate of transport of glucose to the fetus (Herrera 2000 cited in Herrera and Ortega 2008). GDM can have cause that impact the training of the fetus such as hypoglycaemia and macrosomia, which is an increase in body saddle and has the possibility of preeminent to problems when giving birth, such as shoulder dystocia (Schillan-Koliopoulos and Guadagno 2006). During the second trimester of pregnancy there is peripheral insulin resistance but there is also the possibility that hepatic insulin aesthesia is altered in pregnancy, although few studies confirm this. By the end of the pregnancy the levels of insulin that are circulating a re thought to be persona those at the break down (Redman 2001).Insulin ResistanceInsulin resistance in GDM can occur in ii forms. The first is where it acquires in late pregnancy and it has been postulated that there is a post- receptor tool that may influence the insulin signalling piece of ground which virtuosos to a trim down glucose uptake. The second form is where there is already a degree of resistance before the pregnancy but the changes that occur in normal pregnancy aggravate this (Metznger et al 2007). The insulin resistance that develops in pregnancy is much needed to allow the devolve of nutrients, from the mother, straight past to the fetus to allow for growth (Radaelli 2003). Increased insulin resistance leads to an increase in insulin secernment by the pancreatic cells (Buchanan and Xiang 2005). The insulin resistance is thought to be caused by increase adiposity and as the insulin resistance usually stops after pregnancy this suggests that there is a pos sibility that the products of the placenta are a potential cause of the resistance. During the get over of the pregnancy the true(a) changes in glucose levels are very small. It would be assumed that the glucose levels would rise due to the change magnitude insulin resistance but the pancreatic cells increase their secretion of insulin to maintain homeostatic glucose levels (Yogev et al 2008 Chapter 10). GDM occurs because there is an change magnitude demand for insulin which under normal circumstances can be met unless there are problems with the secretion of insulin confidential information to the development of hyperglycaemia. The mass of mothers who develop GDM have been discovered to have a degree of insulin resistance before they became pregnant. Therefore, with the insulin resistance that occurs in normal pregnancy it can be express that GDM occurs with a greater insulin resistance than normally present in gestation (Yogev et al 2008 Chapter 10). Insulin resistance ca uses a reduced uptake of glucose into osseous heft, adipose tissue and liver as advantageously as a shined production of hepatic glucose. (Catalano et al 2003). whiz suggestion for insulin resistance looks into the practicable role of the mitochondria. Studies use Magnetic Resonance Spectroscopy (MRS) have shown that in normal offspring of parents with type 2 diabetes, there is an increased amount of intramyocellular lipid. This has been shown to cause a reduced right in mitochondria which suggests that mitochondrial dysfunction may play a part in insulin resistance (Petersen et al 2004 cited in Morino et al 2005). It has been suggested that this increase in intramyocellular lipid activates a serine kinase cascade which causes an increase in the Insulin Substrate Receptor 1 (IRS-1), which inhibits insulin receptor phosphorylation on tyrosine sites. This can cause a decrease in the effects and utilisation of glucose. superstar study showed that in the insulin resistant off spring the mitochondrial density was reduced by just over a third to that of a normal offspring. This suggests that offspring who are insulin resistant may inherit a condition that causes a reduction in rate oxidative phosphorylation in mitochondria (Griffin et al 2009 cited in Morino et al 2005).Detection of GDMDiagnosis of GDM helps to identify pregnancies that are at risk of fetal morbidity as well as fleshiness and glucose intolerance in the offspring (Buchanan and Xiang 2005). GDM is hard to diagnose as it is asymptomatic. Normal diabetes could be diagnosed by glycosuria but in pregnancy the renal threshold to glucose is lower so that glycosuria doesnt pretend a true representation of hyperglycaemia (Redman 2001). There are several risk factors of GDM which can be classified into trine groups and help in the covert process. Low risk factors overwhelm women who are younger than 25, normal cant at conception, no known family members with diabetes and no history of glucose i ntolerance. mellowed risk factors include fleshiness of the mother, diabetes in close relatives, a history of glucose intolerance, current glycosuria and previous pregnancies with GDM (Metzger and Coustan 1998 Chapter 25).Causes of DiabetesThere are several theories as to why diabetes occurs and this has been thought to be sympathetic to the underlying instruments that cause gestational diabetes. Diabetes is a result of pancreatic beta-cell dysfunction which can present in three main ways autoimmune, a genetic cause and on top of already present insulin resistance (Buchanan and Xiang 2005). Autoimmune diabetes accounts for approximately 5-10% of all diabetic cases (American Diabetes Association 2010). There are circulating antibodies to the cells of the islet of Langerhans. In GDM, there are a small number of women who have with these antibodies present in their circulation. It is thought that these cases present with GDM due to problems with insulin secretion caused by destruc tion of the Islets by the autoantibodies (Buchanan and Xiang 2005). This form is similar to type 1 diabetes. The Islet Cell Autoantibodies (ICA) have been shown to have four major molecular targets Insulin, Glutamic paneling decarboxylase (GAD 65), Insulinoma-associated antigen-2 (IA-2) and Zinc conveyer belt 8 (ZnT8) (Tree 2010). Monogenic diabetes has 2 general forms, one where there are mutations in autosomes and the other where there are mutations in the desoxyribonucleic acid of mitochondria. The first form is publicly referred to as Maturity Onset Diabetes of the Young (MODY). In some(prenominal) cases onset tends to be at a young age and the patient doesnt present with insulin resistance or obesity (Buchanan and Xiang 2005). Mutations that cause MODY have been found in some women with GDM and commonly occur in genes coding for glucokinase, hepatocyte atomic factor and insulin takeoff rocket factor, MODY is associated with beta cell dysfunction (Weng et al 2002). Chronic insulin resistance with beta-cell dysfunction seems to be the most common cause of GDM. As mentioned before there is an increase in insulin resistance in normal pregnancy but if this develops with background insulin resistance whence there is an even greater insulin resistance which can lead to GDM. An established suggestion is that women who are unable to increase their secretion of insulin to cope with the insulin resistance developed in late pregnancy are more susceptible to developing GDM (Buchanan and Xiang 2005). but there could be various environmental processes that are winding in the underlying pathophysiology of GDM. The products of the placenta may also have a role in increasing or decreasing insulin resistance and these will be discussed later. eutherian FunctionThe placenta is an organ that has many roles during the development of the fetus. One of these functions is that it acts as a barrier to separate the maternal and fetal come a gigantics such that the syncyti otrophoblast surface exposes the placenta to the maternal circulation and the endothelium is undetermined to the fetal circulation. This position between the two circulations authority that the placenta is influenced by molecules from twain circulatory systems, including cytokines, hormones and growth factors. The placenta produces molecules which can separately affect the maternal and fetal circulation and it expresses a large number of cytokines including leptin, resistin and tumour necrosis factor. However it has been discovered that these molecules are also produced by adipocytes. All molecules that are going from the mother to the fetus have to cross the placenta. Here they are either modified, for prototype lipids or analogous glucose, they are metabolised for placental purposes (Desoye et al 2008). The placenta plays an important role in fetal growth and the regulation of pregnancy (Giachini 2008). The placenta acts to sustain normal homeostatic levels and to designate out the functions of the vital organs. It also provides an immunological defence to the fetus and allows the exchange of molecules vital to its development (Jansson and Taylor 2007).Placental DevelopmentApproximately 4-5 days after conception, the process of sectionalization causes rapid cell divisions and one of the groups of cells to form are called trophoblast cells. Further developmental processes form the blastocyte which is surrounded by an out layer of the trophoblast cells. As the pregnancy progresses, the trophoblast cells develop into the placenta while the inner parts of the blastocyte form the embryo and umbilical cord (Huppertz 2008). The blastocyte implants itself onto the epithelium of the uterus where it antitheticiates into a syncitiotrophoblast which is able to implant itself in the epithelium leading to it being embedded into the decidual part of the uterus (Huppertz 2008). After the attachment of the blastocyte, the trophoblast layer divides very quickly and changes into 2 layers the inner cytotrophoblastic layer and the outer syncytiotrophoblastic mass (Gude et al 2004).The whole implantation process takes 12 days to complete and after this the fetus is fully embedded into the endometrial layer (Huppertz 2008). The chorionic plate is the surface of the placenta that faces the fetus and this is where the umbilical cord inserts. The basal plate is the surface that faces the mother which contains many types of cells including immune cells such as macrophages and killer cells to carry out the placentas immunological function. The maternal basal plate and the fetal chorionic plate converge to form the smooth chorion which is composed of three layers (Huppertz 2008). When the trophopblast invades the endothelium there is a remodelling of the uterine spinal arteries which is necessary to ensure that the fetus and the placenta receive an adequate argument and nutrient supply and is able to remove any waste materials. This adopt supply of b lood and nutrients to the placenta can define it as being haemochorial villous organ (Gude et al 2004). After the rapid divisions of the trophoblast and development into 2 layers there are two lanes that can occur, the villous and extravillious pathways. The extravillious pathway results in the trophoblast being able to invade into the decidua and cause the remodelling of the uterine arteries to increase blood supply to the placento-fetal unit. The villious pathway has a transportation function as well as having endocrine and protective functions (Gude et al 2004).Normal PlacentationPlacentation involves the structure and function of the placenta. The process of placentation is helped by the composition and arrangement of the extracellular hyaloplasm (ECM) of the endometrium. Studies on rats bring forth with diabetes provided results that showed that diabetes has an effect on the distribution of the ECM molecules. This study by Giachini et al illust order that Types I and III col lagen as well as other molecules, such as proteoglycan molecules decorin and biglycan were distributed throughout normal and diabetic placentas. It was shown that diabetes affects the expression of fibronectin and an increase in deposition of fibronectin may cause changes to the ECM structure which could affect the transfer of molecules from the mother to the fetus. One way in which changes in the ECM can be overcome is to test blood glucose levels frequently during the pregnancy and if kept in normal ranges this can outstandingally decrease the prevalence of diseases and disorders present in the fetus (Giachini et al 2008). As the pregnancy progresses the size of the placenta increases which also means an increase in the amount of products that the placenta produces therefore increasing in the insulin resistance (Schillan-Koliopoulos and Guadagno 2006). This is because the net effect of the products of the placenta is to increase insulin resistance. The increase in size of the pla centa means that it needs an increased blood supply. disaster of the mother to increase its blood supply to the placenta can lead to placental insuffiency which if exacerbated can be attributed to be a cause of intrauterine growth labour (IUGR). This growth restriction is more related to lamentable maternal nutrition rather than to a cause of GDM. GDM have been associated with an increased fetal and placental metric weight unit (Jansson and Taylor 2007). One of the reasons why GDM and increased insulin resistance affects the fetus is that while glucose can cross the placenta, insulin is unable to. This means that the fetal pancreas has to compensate by producing more insulin to thwart high blood glucose levels. The fetal pancreas is capable of doing this and the liver responds to the higher levels of insulin by increasing its production of glucose (Schillan-Koliopoulos and Guadagno 2006). Offspring who have an increase in birth weight have been shown to be at risk of developing cardiovascular disease and diabetes later in life. The main risk factor for this is poor transfer of nutrients via the placenta (Jansson and Taylor 2007). How dramatic these changes are depends on how good the control of blood glucose levels have been during the development of the placenta, if any treatment has been accredited and if there were any periods of away from normal glucose levels (Desoye 2006).How does diabetes affect Placentation?Diabetic insults at the beginning of the pregnancy can have long last effects of the placenta. One of the roles of the placenta is that it is able to buffer pleonastic maternal glucose which can help to keep the fetal glucose levels within range However if the insult lasts longer than the placenta is able to compensate for then excessive fetal growth may occur (Desoye Mouzon 2007). In diabetes there is endothelial dysfunction which can lead to vascular disease. The endothelial cells help to control the vascular dance step of the smooth vigo ur lining the vasculature. They do this by producing substances that help to vasodilate the smooth muscle including Nitric Oxide, Prostacyclin and Endothelium-Derived Hyperpolarising Factor (EDHF). There have been several studies to suggest different mechanisms of how diabetes affects the endothelium including impaired forfeit of these vasodilating molecules, faults with signal transduction and increased release of constricting mediators of the endothelium. The dysfunction of the endothelium in diabetes is thought to be caused by activation of protein kinase C (PKC) as well as increased oxidative stress, non-enzymatic glycation and an increased activation of the polyol pathway (De Vries et al 2000).The main reason why these effects occur is thought to be due the activation of the protein kinase C pathway and the increased oxidative stress. This can cause early damage to the development of vascular vessels (Roberts and Raspollini 2008). These mechanisms will be discussed later.The e ffect of hormones produced in pregnancymaternal quality causes changes in the circulating hormones and cytokines which can all have different effects on insulin resistance and this may help explain the mechanism underlying the resistance that is found in pregnancy and in GDM. Cytokines produced in pregnancy, such as TNF-a, Adiponectin and Leptin have been found to cause an increase in the insulin resistance (Gao et al 2008). In early pregnancy, the levels of oestrogen and progesterone rise but no net effect is seen as the two have antagonistic effects. estrogen increases the binding of insulin to its receptor whereas progesterone reduces the ability of insulin to bind (Ryan and Enns 1988). Cortisol levels in pregnancy increase so that by the end of the pregnancy the levels are three quantify that of what they were at the beginning (Gibson and Tulchinski 1980 cited in Yogev et al Chapter 10). Studies have shown that with increased amounts of cortisol there was a decrease in insulin sensitivity causing insulin resistance (Rizza et al 1982 cited in Yogev et al 2008 chapter 10). During pregnancy the levels of prolactin increase up to ten times the normal amount (Yogev et al 2008 chapter 10). Studies have shown that in a culture of pancreatic beta cells, prolactin can cause an increase in levels of secreted insulin (Sorenson et al 1993 cited in Yogev et al 2008 Chapter 10). However, high levels of prolactin are not seen to be a pathological cause of GDM (Yogev et al 2008 chapter 10). Human placental lactogen (HPL) is a hormone, and its levels rise during the second trimester of pregnancy. This causes a decrease in the phosphorylation of insulin receptor substratum (IRS1) which can lead to significant insulin resistance (Ryan and Enns 2008 cited Yogev et al 2008 ch 10). Leptin is associated with obesity and concentrations of leptin have been shown to be related to the concentration of insulin in the plasma. In pregnancy the leptin levels increase dramatically. Dur ing pregnancy the mother uses her deep stores to support fetal growth and it is thought that the leptin levels increase with the mobilisation of these fat stores. Leptin levels relate to the body mass of the individual (Sattar et al 1998). Placental Leptin is the same in structure and charge to the one produced by adipose tissue (Ashworth et al 2000). One study showed that high leptin concentrations in the umbilical cord increased the likeliness of developing fetal macrosomia (Wiznitzer et al 2000). It is also thought that leptin effects insulin sensitivity by effecting glucose metabolism in both skeletal muscle and in hepatocytes. Rats that received an external source of leptin were found to have an increase in gluconeogenesis which accounted for the majority of hepatic glucose production (Rossetti et al 1997). In GDM there is a greater secretion of TNF-alpha in response to glucose. TNF-alpha functions to regulate metabolism of glucose and lipids as well as being involved in insu lin resistance. many studies suggest that TNF-alpha is involved in the advancement to GDM. They found that an increase in glucose cause the placenta and adipose tissue to increase production of TNF-alpha in some cases up to 4 times more than non-diabetic pregnant(Coughlan et al 2001). One study showed that the increases in the levels of TNF-alpha during pregnancy increased consistently with increases in body weight (Catalano et al cited in Yogev et al 2008). Adiponectin is a protein derived from adipose tissue and its function is to regulate insulin resistance and maintains levels of glucose. During pregnancy it has been found that its levels drop and could therefore lead to the increase insulin resistance found in GDM (Gao, Yang, Zao 2008). Adiponectin has also been found to decrease the secretion of TNF-alpha which as stated above can lead to insulin resistance (Hotamisligil 1999 cited in Yogev et al Chapter 10 2008). Adiponectin may cause increased insulin sensitivity as its con centration decreases throughout the gestational period (Desoye and Mouzon 2007). Resistin is a protein that is produced by adipose tissue and is thought to be involved in insulin resistance in diabetes and is associated with obesity (Steppan and Lazar 2002) In pregnancy, resistin is secreted by the placenta and this secretion reaches its peak by the last trimester (Yura et al cited in Megia et al 2008). Studies show that TNF-alpha is an important factor in insulin resistance during pregnancy and with inputs from leptin and cortisol there is altered glucose metabolism whereas inputs from oestrogen, progesterone and prolactin had small-minded significant effects (Kirwan and Mouzon 2002). There are many hormones produced during pregnancy, mainly by the placenta and adipose tissue that have varying affects but with the overall impact being insulin resistance.Inflammation in DiabetesThere are genes in the placenta which regulate shakeup of the endothelium and inflammatory responses and in GDM these were found to be altered. The increase in leptin receptors suggests that in the placenta this can cause proinflammatory responses (Radaelli 2003). One of the current theories is that the perverted metabolic environment in GDM can lead to increased production of cytokines and inflammatory mediators. Molecules such as TNF-alpha, Resistin and Leptin increase during pregnancy and these increases in these inflammatory mediators produce metabolic changes by increasing insulin resistance (Desoye and Mouzon 2007). Leptin and TNF-alpha activate phospholipase A2 which are a family of eicosanoid precursors that go on to produce essential fatty acids such as w3 unsaturated fatty acids (Desoye Mouzon 2007). There has been a recent investigation which found that with increased adiposity at birth there has been an increase in w3 fatty acids in the placenta (Verastehpour et al 2005 cited Desoye and Mouzon 2007). As stated before, the placenta produces cytokines but it is also a site of action of the cytokines. It is the location of the receptors for these cytokines will influence if the cytokines act on the mother, the placenta or the fetus. With cytokines there is very little transfer across the placenta from mother to fetus and the origin of the cytokines in the fetus can be from either the placenta or from the fetus itself (Desoye and Mouzon 2007).fetal ProgrammingMany studies have highlighted the fact that events that occur while the fetus is developing can alter its developmental pathway and have adverse outcomes in later life. foetal programming describes how the environment can affect reliable developmental events of which the effects are permanent and can affect processes such as metabolism and the organisms physiology. Women with GDM have an increased risk of the fetus developing macrosomia (Catalano 2008 Chapter 11). The main factor that effects the growth of the fetus is the maternal environment and there is a strong tie-up with the weight and hei ght of the mother and the growth of the fetus such that mothers who are heavier and taller will produce heavy babies. (Love and Kinch 1965 cited in Catalano 2008 Chapter 11).The placenta and fetal programmingThe placenta is very important to the developmental processes of the fetus as it is able to change the quantity of signals and nutrients that the fetus receives. Deviation from normal would alter the fetal programming, thus making it more susceptible to disease in later life. Pregnancies that are complicated by GDM have excessive oxidative and nitrate stress which has been found to change the activity of certain proteins. Oxidative and nitrate stress alter the placentas function and may cause changes in the fetal programming. Nutrient transfer depends largely on the normal development of the vasculature to allow blood flow and this can be affected by GDM which can cause a decrease in the flow of substrates and is a mechanism in which fetal programming can be affected (Myatt 2006 ). Fetal programming involves a large amount of development malleability and interruptions to this development may cause abnormalities in the development of certain cells which may progress to structural differences in organ development (Gluckman and Hanson 2004 cited in Jansson and Powell 2008 ref 16). effectuate to the fetus exposed to GDMIf a fetus is exposed to a diabetic environment during pregnancy then there can be certain long term effects. These effects can be classified into three groups Anthropometric, Metabolic or Vascular and Neurological or Psychological. Anthropometric changes are concerned with the rates of growth for both height and weight and in a diabetic environment these can be excessive leading to macrosomia and obesity in later life. Metabolic and vascular changes that occur are abnormal glucose tolerance which can eventually lead to diabetes mellitus. Finally the neurological and psychological changes that can occur are usually excusable but development of psychological and intellect can sometimes be deficient (Dabelea and Pettitt 2008). Potential problems that may arise with the fetus from an picture to maternal diabetes include abnormal organ mass, altered angiogenesis and increased levels of fetal insulin (Fetita 2006). It has also been found that if there is an increase in weight during pregnancy then there is usually a higher birth weight of the fetus (Humphreys 1954 cited in Catalano 2008 Chapter 11). The developing fetus cannot synthesise glucose and is dependent on the mother to produce it where it is transported to the fetus via facilitated public exposure through the placenta (Aerts et al 1996 cited in Mello, Parretti and Hod 2008). The result of decreased insulin sensitivity is that there is more glucose available to the developing fetus which can lead to a greater birth weight (Mello, Parretti and Hod 2008). Using animal models, it has been shown that exposure to high levels of glucose in utero can lead a diminished numb er of nephrons in the offspring (Amri et al 1999 cited in Fetita 2006 ref 68). This is important as nephrogenesis only occurs in the fetus and stops after birth (Gomez, Norwood 1999). It has been shown that a reduction in the numbers of nephron may affect the rate of progression of renal disease in adults due to an inability to secrete sodium. This may later develop into salt-sensitive hypertension (Brenner et al 1988). The mechanisms of reduced organ mass, high levels of fetal insulin and defects in angiogenesis may help explain how the fetus programs abnormal glucose tolerance in adulthood as a result of exposure to GDM (Fetita 2006).Transmission of diabetes from mother to offspringExposure to gestational diabetes mellitus increases the risk of the fetus developing abnormal glucose tolerance which may develop into type 2 diabetes. (Fetita et al 2006). The association between greater incidences of the offspring having diabetes with a mother with GDM is greater than what would be pr edicted that could be passed on by maternal genetics (McLean et al 2006). One study showed that the phenotype for GDM/T2D was more common in daughters of mothers who were diabetic rather than daughters of fathers who were diabetic suggesting that the transmission is from mothers with GDM to their daughters. However there were limitations of the McLean study. Patients may not be aware of their fathers diabetes status due to men having lower inclinations to report symptoms and share illnesses with the family. One study showed that the mass of the pancreatic beta cells is comparatively fixed by the end of fetal growth and this can be influenced by an intrauterine environment of hyperglycaema (McLean et al 2006). Congenital defects are more common in babies born(p) to diabetic mothers (Farrel et al 2002 cited in Fetita et al 2006). There are many factors that can influence the prevalence of these malformations including the duration, severity and age of onset of GDM (Kousseff 1999). I f the onset of GDM is at the beginning of development then development of some organs may be affected. However as said before, the majority of GDM develops during the second trimester. This can then lead to embryopathy which includes defects such as failure of neural tube closure and malformations in the Renal, Cardiac and Gastrointestinal systems which present in childhood (Fetita 2006). In diabetes the hexosamine pathway is activated and inhibits the pentose shunt pathway which decreases the production of antioxidants and therefore leads to an increase in oxidative stress. This oxidative stress has been found to disrupt gene expression and may contribute to congenital defects. One example is that oxidative stress inhibits a gene called pax-3 which is needed for neural tube closure and in diabetes there is an increased risk of neural tube defects (Horal et al 20Aetiology of Gestational Diabetes MellitusAetiology of Gestational Diabetes MellitusAbstractGestational Diabetes is a con dition present in the later stages of pregnancy where the mother has insulin resistance leading to glucose intolerance. The aetiology of Gestational Diabetes Mellitus is largely unknown but several theories include autoimmune destruction of the beta cells, monogenic mutations and insulin resistance. In pregnancy it is normal for there to be some levels of insulin resistance and it is thought that the products of the placenta contribute to the state of insulin resistance as GDM usually subsides after pregnancy. GDM in pregnancy can lead to an increased risk of cardiovascular disease in the offspring such as hypertension and atherosclerosis. This is due to the increased levels of oxidative stress and inflammatory mediators present during pregnancy. The placenta is very important as it is able to control and buffer the amount of glucose that is delivered to the fetus but if this level is too high then it is out of the placentas control and the fetus may have increased rate of growth du e to this extra glucose. The current focus of research in this area seems to be into finding ways to diagnosis GDM earlier in the pregnancy and to try and reduce the amounts of oxidative stress.Gestational diabetes consequences for fetal programming of vascular disease in adulthoodIntroductionGestational Diabetes Mellitus (GDM) occurs when there is a glucose intolerance that is first detected during pregnancy. It is a form of hyperglycaemia (Buchanan and Xiang 2005). The aetiology of the condition is unknown but there have been many suggestions as to the cause of it, including autoimmune destruction of the pancreatic cells and the possibility of a genetic predisposition to the condition. Hormones that are produced in pregnancy help contribute to the insulin resistant state which characterises diabetes. In recent years, there has been an increase in the cases of Obesity and this is a risk factor for both Diabetes Mellitus and Cardiovascular Disease. The intrauterine environment can affect fetal programming and development. This essay will look into how the placenta and its products can affect the insulin resistant state and how this resistance effects programming as well as the role of oxidative stress and inflammation in making the offspring more susceptible to cardiovascular disease.Gestational Diabetes Mellitus (GDM)GDM is a state of insulin resistance which disturbs the intrauterine environment and can lead to accelerated fetal growth (Radaelli et al 2003).It effects approximately 7% of pregnant women with approximately 200,000 cases seen each year (Schillan-Koliopoulos and Guadagno 2006). The term GDM is applicable when the onset is during the second and third terms of the pregnancy, but it does not exclude the possibility that the insulin resistance was undiagnosed before the pregnancy. If this is the case and is found to occur in the earlier stages of pregnancy then the mother should be treated the same as mothers who are known to have diabetes before p regnancy (Metzger, Coustan 1998). There is a degree of insulin resistance in normal pregnancy which begins towards the middle of the pregnancy but during the later part of the second and the final trimester these can increase to levels of insulin resistance that are associated with type 2 diabetes (Yogev et al 2008 Chapter 10). Insulin resistance is when the tissues do not produce a response to insulin due to problems with the secretion of insulin or where the tissues are desensitised to insulin and therefore lack the ability to produce a response (Catalano et al 2003). In a normal pregnancy, the mother changes her metabolism to allow a constant supply of nutrients to reach the fetus to support its rapid growth. Among these nutrients is glucose, which is the main energy source used by the fetus. During the later stages of pregnancy the mother becomes hypoglycaemic and although there is increased gluconeogenesis, the hypoglycaemia still occurs because there is a high rate of transpor t of glucose to the fetus (Herrera 2000 cited in Herrera and Ortega 2008). GDM can have effects that impact the development of the fetus such as hypoglycaemia and macrosomia, which is an increase in body weight and has the possibility of leading to problems when giving birth, such as shoulder dystocia (Schillan-Koliopoulos and Guadagno 2006). During the second trimester of pregnancy there is peripheral insulin resistance but there is also the possibility that hepatic insulin sensitivity is altered in pregnancy, although few studies confirm this. By the end of the pregnancy the levels of insulin that are circulating are thought to be double those at the start (Redman 2001).Insulin ResistanceInsulin resistance in GDM can occur in two forms. The first is where it develops in late pregnancy and it has been postulated that there is a post-receptor mechanism that may influence the insulin signalling pathway which leads to a reduced glucose uptake. The second form is where there is already a degree of resistance before the pregnancy but the changes that occur in normal pregnancy aggravate this (Metznger et al 2007). The insulin resistance that develops in pregnancy is much needed to allow the flow of nutrients, from the mother, directly to the fetus to allow for growth (Radaelli 2003). Increased insulin resistance leads to an increase in insulin secretion by the pancreatic cells (Buchanan and Xiang 2005). The insulin resistance is thought to be caused by increased adiposity and as the insulin resistance usually stops after pregnancy this suggests that there is a possibility that the products of the placenta are a potential cause of the resistance. During the course of the pregnancy the actual changes in glucose levels are very small. It would be assumed that the glucose levels would rise due to the increased insulin resistance but the pancreatic cells increase their secretion of insulin to maintain homeostatic glucose levels (Yogev et al 2008 Chapter 10). GDM occur s because there is an increased demand for insulin which under normal circumstances can be met unless there are problems with the secretion of insulin leading to the development of hyperglycaemia. The majority of mothers who develop GDM have been discovered to have a degree of insulin resistance before they became pregnant. Therefore, with the insulin resistance that occurs in normal pregnancy it can be said that GDM occurs with a greater insulin resistance than normally present in gestation (Yogev et al 2008 Chapter 10). Insulin resistance causes a decreased uptake of glucose into skeletal muscle, adipose tissue and liver as well as a decreased production of hepatic glucose. (Catalano et al 2003). One suggestion for insulin resistance looks into the possible role of the mitochondria. Studies using Magnetic Resonance Spectroscopy (MRS) have shown that in normal offspring of parents with type 2 diabetes, there is an increased amount of intramyocellular lipid. This has been shown to c ause a reduced function in mitochondria which suggests that mitochondrial dysfunction may play a part in insulin resistance (Petersen et al 2004 cited in Morino et al 2005). It has been suggested that this increase in intramyocellular lipid activates a serine kinase cascade which causes an increase in the Insulin Substrate Receptor 1 (IRS-1), which inhibits insulin receptor phosphorylation on tyrosine sites. This can cause a decrease in the effects and utilisation of glucose. One study showed that in the insulin resistant offspring the mitochondrial density was reduced by just over a third to that of a normal offspring. This suggests that offspring who are insulin resistant may inherit a condition that causes a reduction in rate oxidative phosphorylation in mitochondria (Griffin et al 2009 cited in Morino et al 2005).Detection of GDMDiagnosis of GDM helps to identify pregnancies that are at risk of fetal morbidity as well as obesity and glucose intolerance in the offspring (Buchanan and Xiang 2005). GDM is hard to diagnose as it is asymptomatic. Normal diabetes could be diagnosed by glycosuria but in pregnancy the renal threshold to glucose is lowered so that glycosuria doesnt give a true representation of hyperglycaemia (Redman 2001). There are several risk factors of GDM which can be classified into three groups and help in the screening process. Low risk factors include women who are younger than 25, normal weight at conception, no known family members with diabetes and no history of glucose intolerance. High risk factors include obesity of the mother, diabetes in close relatives, a history of glucose intolerance, current glycosuria and previous pregnancies with GDM (Metzger and Coustan 1998 Chapter 25).Causes of DiabetesThere are several theories as to why diabetes occurs and this has been thought to be similar to the underlying mechanisms that cause gestational diabetes. Diabetes is a result of pancreatic beta-cell dysfunction which can present in three m ain ways autoimmune, a genetic cause and on top of already present insulin resistance (Buchanan and Xiang 2005). Autoimmune diabetes accounts for approximately 5-10% of all diabetic cases (American Diabetes Association 2010). There are circulating antibodies to the cells of the Islet of Langerhans. In GDM, there are a small number of women who have with these antibodies present in their circulation. It is thought that these cases present with GDM due to problems with insulin secretion caused by destruction of the Islets by the autoantibodies (Buchanan and Xiang 2005). This form is similar to type 1 diabetes. The Islet Cell Autoantibodies (ICA) have been shown to have four major molecular targets Insulin, Glutamic acid decarboxylase (GAD 65), Insulinoma-associated antigen-2 (IA-2) and Zinc Transporter 8 (ZnT8) (Tree 2010). Monogenic diabetes has 2 general forms, one where there are mutations in autosomes and the other where there are mutations in the DNA of mitochondria. The first f orm is commonly referred to as Maturity Onset Diabetes of the Young (MODY). In both cases onset tends to be at a young age and the patient doesnt present with insulin resistance or obesity (Buchanan and Xiang 2005). Mutations that cause MODY have been found in some women with GDM and commonly occur in genes coding for glucokinase, hepatocyte nuclear factor and insulin promoter factor, MODY is associated with beta cell dysfunction (Weng et al 2002). Chronic insulin resistance with beta-cell dysfunction seems to be the most common cause of GDM. As mentioned before there is an increase in insulin resistance in normal pregnancy but if this develops with background insulin resistance then there is an even greater insulin resistance which can lead to GDM. An established suggestion is that women who are unable to increase their secretion of insulin to cope with the insulin resistance developed in late pregnancy are more susceptible to developing GDM (Buchanan and Xiang 2005). However there could be various environmental processes that are involved in the underlying pathophysiology of GDM. The products of the placenta may also have a role in increasing or decreasing insulin resistance and these will be discussed later.Placental FunctionThe placenta is an organ that has many roles during the development of the fetus. One of these functions is that it acts as a barrier to separate the maternal and fetal surfaces such that the syncytiotrophoblast surface exposes the placenta to the maternal circulation and the endothelium is exposed to the fetal circulation. This position between the two circulations means that the placenta is influenced by molecules from both circulatory systems, including cytokines, hormones and growth factors. The placenta produces molecules which can separately affect the maternal and fetal circulation and it expresses a large number of cytokines including leptin, resistin and tumour necrosis factor. However it has been discovered that these molecule s are also produced by adipocytes. All molecules that are going from the mother to the fetus have to cross the placenta. Here they are either modified, for example lipids or like glucose, they are metabolised for placental purposes (Desoye et al 2008). The placenta plays an important role in fetal growth and the regulation of pregnancy (Giachini 2008). The placenta acts to sustain normal homeostatic levels and to carry out the functions of the vital organs. It also provides an immunological defence to the fetus and allows the exchange of molecules vital to its development (Jansson and Taylor 2007).Placental DevelopmentApproximately 4-5 days after conception, the process of cleavage causes rapid cell divisions and one of the groups of cells to form are called trophoblast cells. Further developmental processes form the blastocyte which is surrounded by an outer layer of the trophoblast cells. As the pregnancy progresses, the trophoblast cells develop into the placenta while the inner parts of the blastocyte form the embryo and umbilical cord (Huppertz 2008). The blastocyte implants itself onto the epithelium of the uterus where it differentiates into a syncitiotrophoblast which is able to implant itself in the epithelium leading to it being embedded into the decidual part of the uterus (Huppertz 2008). After the attachment of the blastocyte, the trophoblast layer divides very quickly and changes into 2 layers the inner cytotrophoblastic layer and the outer syncytiotrophoblastic mass (Gude et al 2004).The whole implantation process takes 12 days to complete and after this the fetus is fully embedded into the endometrial layer (Huppertz 2008). The chorionic plate is the surface of the placenta that faces the fetus and this is where the umbilical cord inserts. The basal plate is the surface that faces the mother which contains many types of cells including immune cells such as macrophages and killer cells to carry out the placentas immunological function. The mater nal basal plate and the fetal chorionic plate converge to form the smooth chorion which is composed of three layers (Huppertz 2008). When the trophopblast invades the endothelium there is a remodelling of the uterine spinal arteries which is necessary to ensure that the fetus and the placenta receive an adequate blood and nutrient supply and is able to remove any waste materials. This direct supply of blood and nutrients to the placenta can define it as being haemochorial villous organ (Gude et al 2004). After the rapid divisions of the trophoblast and development into 2 layers there are two pathways that can occur, the villous and extravillious pathways. The extravillious pathway results in the trophoblast being able to invade into the decidua and cause the remodelling of the uterine arteries to increase blood supply to the placento-fetal unit. The villious pathway has a transportation function as well as having endocrine and protective functions (Gude et al 2004).Normal Placentati onPlacentation involves the structure and function of the placenta. The process of placentation is helped by the composition and arrangement of the extracellular matrix (ECM) of the endometrium. Studies on rats induced with diabetes provided results that showed that diabetes has an effect on the distribution of the ECM molecules. This study by Giachini et al illustrates that Types I and III collagen as well as other molecules, such as proteoglycan molecules decorin and biglycan were distributed throughout normal and diabetic placentas. It was shown that diabetes affects the expression of fibronectin and an increase in deposition of fibronectin may cause changes to the ECM structure which could affect the transfer of molecules from the mother to the fetus. One way in which changes in the ECM can be overcome is to test blood glucose levels frequently during the pregnancy and if kept in normal ranges this can dramatically decrease the prevalence of diseases and disorders present in the fetus (Giachini et al 2008). As the pregnancy progresses the size of the placenta increases which also means an increase in the amount of products that the placenta produces therefore increasing in the insulin resistance (Schillan-Koliopoulos and Guadagno 2006). This is because the net effect of the products of the placenta is to increase insulin resistance. The increase in size of the placenta means that it needs an increased blood supply. Failure of the mother to increase its blood supply to the placenta can lead to placental insuffiency which if exacerbated can be attributed to be a cause of intrauterine growth restriction (IUGR). This growth restriction is more related to poor maternal nutrition rather than to a cause of GDM. GDM have been associated with an increased fetal and placental weight (Jansson and Taylor 2007). One of the reasons why GDM and increased insulin resistance affects the fetus is that while glucose can cross the placenta, insulin is unable to. This means th at the fetal pancreas has to compensate by producing more insulin to prevent high blood glucose levels. The fetal pancreas is capable of doing this and the liver responds to the higher levels of insulin by increasing its production of glucose (Schillan-Koliopoulos and Guadagno 2006). Offspring who have an increase in birth weight have been shown to be at risk of developing cardiovascular disease and diabetes later in life. The main risk factor for this is poor transfer of nutrients via the placenta (Jansson and Taylor 2007). How dramatic these changes are depends on how good the control of blood glucose levels have been during the development of the placenta, if any treatment has been received and if there were any periods of away from normal glucose levels (Desoye 2006).How does diabetes affect Placentation?Diabetic insults at the beginning of the pregnancy can have long last effects of the placenta. One of the roles of the placenta is that it is able to buffer excess maternal gluc ose which can help to keep the fetal glucose levels within range However if the insult lasts longer than the placenta is able to compensate for then excessive fetal growth may occur (Desoye Mouzon 2007). In diabetes there is endothelial dysfunction which can lead to vascular disease. The endothelial cells help to control the vascular tone of the smooth muscle lining the vasculature. They do this by producing substances that help to vasodilate the smooth muscle including Nitric Oxide, Prostacyclin and Endothelium-Derived Hyperpolarising Factor (EDHF). There have been several studies to suggest different mechanisms of how diabetes affects the endothelium including impaired release of these vasodilating molecules, faults with signal transduction and increased release of constricting mediators of the endothelium. The dysfunction of the endothelium in diabetes is thought to be caused by activation of protein kinase C (PKC) as well as increased oxidative stress, non-enzymatic glycation an d an increased activation of the polyol pathway (De Vries et al 2000).The main reason why these effects occur is thought to be due the activation of the protein kinase C pathway and the increased oxidative stress. This can cause early damage to the development of vascular vessels (Roberts and Raspollini 2008). These mechanisms will be discussed later.The effect of hormones produced in pregnancyPregnancy causes changes in the circulating hormones and cytokines which can all have different effects on insulin resistance and this may help explain the mechanism underlying the resistance that is found in pregnancy and in GDM. Cytokines produced in pregnancy, such as TNF-a, Adiponectin and Leptin have been found to cause an increase in the insulin resistance (Gao et al 2008). In early pregnancy, the levels of oestrogen and progesterone rise but no net effect is seen as the two have antagonistic effects. Oestrogen increases the binding of insulin to its receptor whereas progesterone reduces the ability of insulin to bind (Ryan and Enns 1988). Cortisol levels in pregnancy increase so that by the end of the pregnancy the levels are three times that of what they were at the beginning (Gibson and Tulchinski 1980 cited in Yogev et al Chapter 10). Studies have shown that with increased amounts of cortisol there was a decrease in insulin sensitivity causing insulin resistance (Rizza et al 1982 cited in Yogev et al 2008 chapter 10). During pregnancy the levels of prolactin increase up to ten times the normal amount (Yogev et al 2008 chapter 10). Studies have shown that in a culture of pancreatic beta cells, prolactin can cause an increase in levels of secreted insulin (Sorenson et al 1993 cited in Yogev et al 2008 Chapter 10). However, high levels of prolactin are not seen to be a pathological cause of GDM (Yogev et al 2008 chapter 10). Human placental lactogen (HPL) is a hormone, and its levels rise during the second trimester of pregnancy. This causes a decrease in the phos phorylation of insulin receptor substrate (IRS1) which can lead to significant insulin resistance (Ryan and Enns 2008 cited Yogev et al 2008 ch 10). Leptin is associated with obesity and concentrations of leptin have been shown to be related to the concentration of insulin in the plasma. In pregnancy the leptin levels increase dramatically. During pregnancy the mother uses her fat stores to support fetal growth and it is thought that the leptin levels increase with the mobilisation of these fat stores. Leptin levels relate to the body mass of the individual (Sattar et al 1998). Placental Leptin is the same in structure and charge to the one produced by adipose tissue (Ashworth et al 2000). One study showed that high leptin concentrations in the umbilical cord increased the likelihood of developing fetal macrosomia (Wiznitzer et al 2000). It is also thought that leptin effects insulin sensitivity by effecting glucose metabolism in both skeletal muscle and in hepatocytes. Rats that re ceived an external source of leptin were found to have an increase in gluconeogenesis which accounted for the majority of hepatic glucose production (Rossetti et al 1997). In GDM there is a greater secretion of TNF-alpha in response to glucose. TNF-alpha functions to regulate metabolism of glucose and lipids as well as being involved in insulin resistance. Many studies suggest that TNF-alpha is involved in the progression to GDM. They found that an increase in glucose cause the placenta and adipose tissue to increase production of TNF-alpha in some cases up to 4 times more than non-diabetic pregnant(Coughlan et al 2001). One study showed that the increases in the levels of TNF-alpha during pregnancy increased consistently with increases in body weight (Catalano et al cited in Yogev et al 2008). Adiponectin is a protein derived from adipose tissue and its function is to regulate insulin resistance and maintains levels of glucose. During pregnancy it has been found that its levels dro p and could therefore lead to the increase insulin resistance found in GDM (Gao, Yang, Zao 2008). Adiponectin has also been found to decrease the secretion of TNF-alpha which as stated above can lead to insulin resistance (Hotamisligil 1999 cited in Yogev et al Chapter 10 2008). Adiponectin may cause increased insulin sensitivity as its concentration decreases throughout the gestational period (Desoye and Mouzon 2007). Resistin is a protein that is produced by adipose tissue and is thought to be involved in insulin resistance in diabetes and is associated with obesity (Steppan and Lazar 2002) In pregnancy, resistin is secreted by the placenta and this secretion reaches its peak by the last trimester (Yura et al cited in Megia et al 2008). Studies show that TNF-alpha is an important factor in insulin resistance during pregnancy and with inputs from leptin and cortisol there is altered glucose metabolism whereas inputs from oestrogen, progesterone and prolactin had little significant effects (Kirwan and Mouzon 2002). There are many hormones produced during pregnancy, mainly by the placenta and adipose tissue that have varying affects but with the overall impact being insulin resistance.Inflammation in DiabetesThere are genes in the placenta which regulate reorganisation of the endothelium and inflammatory responses and in GDM these were found to be altered. The increase in leptin receptors suggests that in the placenta this can cause proinflammatory responses (Radaelli 2003). One of the current theories is that the abnormal metabolic environment in GDM can lead to increased production of cytokines and inflammatory mediators. Molecules such as TNF-alpha, Resistin and Leptin increase during pregnancy and these increases in these inflammatory mediators produce metabolic changes by increasing insulin resistance (Desoye and Mouzon 2007). Leptin and TNF-alpha activate phospholipase A2 which are a family of eicosanoid precursors that go on to produce essential fatty ac ids such as w3 polyunsaturated fatty acids (Desoye Mouzon 2007). There has been a recent investigation which found that with increased adiposity at birth there has been an increase in w3 fatty acids in the placenta (Verastehpour et al 2005 cited Desoye and Mouzon 2007). As stated before, the placenta produces cytokines but it is also a site of action of the cytokines. It is the location of the receptors for these cytokines will influence if the cytokines act on the mother, the placenta or the fetus. With cytokines there is very little transfer across the placenta from mother to fetus and the origin of the cytokines in the fetus can be from either the placenta or from the fetus itself (Desoye and Mouzon 2007).Fetal ProgrammingMany studies have highlighted the fact that events that occur while the fetus is developing can alter its developmental pathway and have adverse outcomes in later life. Fetal programming describes how the environment can affect certain developmental events of wh ich the effects are permanent and can affect processes such as metabolism and the organisms physiology. Women with GDM have an increased risk of the fetus developing macrosomia (Catalano 2008 Chapter 11). The main factor that effects the growth of the fetus is the maternal environment and there is a strong association with the weight and height of the mother and the growth of the fetus such that mothers who are heavier and taller will produce heavy babies. (Love and Kinch 1965 cited in Catalano 2008 Chapter 11).The placenta and fetal programmingThe placenta is very important to the developmental processes of the fetus as it is able to change the quantity of signals and nutrients that the fetus receives. Deviation from normal would alter the fetal programming, thus making it more susceptible to disease in later life. Pregnancies that are complicated by GDM have excessive oxidative and nitrate stress which has been found to change the activity of certain proteins. Oxidative and nitrat e stress alter the placentas function and may cause changes in the fetal programming. Nutrient transfer depends largely on the normal development of the vasculature to allow blood flow and this can be affected by GDM which can cause a decrease in the flow of substrates and is a mechanism in which fetal programming can be affected (Myatt 2006). Fetal programming involves a large amount of development plasticity and interruptions to this development may cause abnormalities in the development of certain cells which may progress to structural differences in organ development (Gluckman and Hanson 2004 cited in Jansson and Powell 2008 ref 16).Effects to the fetus exposed to GDMIf a fetus is exposed to a diabetic environment during pregnancy then there can be certain long term effects. These effects can be classified into three groups Anthropometric, Metabolic or Vascular and Neurological or Psychological. Anthropometric changes are concerned with the rates of growth for both height and we ight and in a diabetic environment these can be excessive leading to macrosomia and obesity in later life. Metabolic and vascular changes that occur are abnormal glucose tolerance which can eventually lead to diabetes mellitus. Finally the neurological and psychological changes that can occur are usually minor but development of psychological and intellect can sometimes be deficient (Dabelea and Pettitt 2008). Potential problems that may arise with the fetus from an exposure to maternal diabetes include abnormal organ mass, altered angiogenesis and increased levels of fetal insulin (Fetita 2006). It has also been found that if there is an increase in weight during pregnancy then there is usually a higher birth weight of the fetus (Humphreys 1954 cited in Catalano 2008 Chapter 11). The developing fetus cannot synthesise glucose and is dependent on the mother to produce it where it is transported to the fetus via facilitated diffusion through the placenta (Aerts et al 1996 cited in Me llo, Parretti and Hod 2008). The result of decreased insulin sensitivity is that there is more glucose available to the developing fetus which can lead to a greater birth weight (Mello, Parretti and Hod 2008). Using animal models, it has been shown that exposure to high levels of glucose in utero can lead a diminished number of nephrons in the offspring (Amri et al 1999 cited in Fetita 2006 ref 68). This is important as nephrogenesis only occurs in the fetus and stops after birth (Gomez, Norwood 1999). It has been shown that a reduction in the numbers of nephron may affect the rate of progression of renal disease in adults due to an inability to secrete sodium. This may later develop into salt-sensitive hypertension (Brenner et al 1988). The mechanisms of reduced organ mass, high levels of fetal insulin and defects in angiogenesis may help explain how the fetus programs abnormal glucose tolerance in adulthood as a result of exposure to GDM (Fetita 2006).Transmission of diabetes from mother to offspringExposure to gestational diabetes mellitus increases the risk of the fetus developing abnormal glucose tolerance which may develop into type 2 diabetes. (Fetita et al 2006). The association between greater incidences of the offspring having diabetes with a mother with GDM is greater than what would be predicted that could be passed on by maternal genetics (McLean et al 2006). One study showed that the phenotype for GDM/T2D was more common in daughters of mothers who were diabetic rather than daughters of fathers who were diabetic suggesting that the transmission is from mothers with GDM to their daughters. However there were limitations of the McLean study. Patients may not be aware of their fathers diabetes status due to men having lower inclinations to report symptoms and share illnesses with the family. One study showed that the mass of the pancreatic beta cells is relatively fixed by the end of fetal growth and this can be influenced by an intrauterine environ ment of hyperglycaema (McLean et al 2006). Congenital defects are more common in babies born to diabetic mothers (Farrel et al 2002 cited in Fetita et al 2006). There are many factors that can influence the prevalence of these malformations including the duration, severity and age of onset of GDM (Kousseff 1999). If the onset of GDM is at the beginning of development then development of some organs may be affected. However as said before, the majority of GDM develops during the second trimester. This can then lead to embryopathy which includes defects such as failure of neural tube closure and malformations in the Renal, Cardiac and Gastrointestinal systems which present in childhood (Fetita 2006). In diabetes the hexosamine pathway is activated and inhibits the pentose shunt pathway which decreases the production of antioxidants and therefore leads to an increase in oxidative stress. This oxidative stress has been found to disrupt gene expression and may contribute to congenital de fects. One example is that oxidative stress inhibits a gene called pax-3 which is needed for neural tube closure and in diabetes there is an increased risk of neural tube defects (Horal et al 20

Impact of Advertising on Consumer Price Sensitivity

advert of publicise on Consumer Price SensitivitySelling things ar the focus of any business and to cover a fruit marketing is a key factor and main step to make people buy the product. In addition, the fore round thing downstairs marketing is denote, which is the only way with which you sens change the perspective of the product in peoples mind. It is actually a form of communication intended to persuade and earreach (viewers, listeners or readers) to purchase the product.The intention of actually enlightening on advertizing is to know whether publicize has any partake on consumer footing esthesia or not. It does affect the consumer and their buying air but to what extent what are the variables and how this is transactioning consumers sensitivity toward purchase a certain product is been elaborated below.H0 Advertising Have an Impact on Willingness to Pay by a ConsumerIt is relevant to my phrase beca part of using quest curve to gather the affects of announce o n consumer scathe sensitivity. In this root The Impact of Advertising on Consumer Price Sensitivity in Experienced Goods Markets written by Tullen Erdem, Michael Keane, Baohong Son (2007), four categories of consumer goods are considered to examine how TV ad and other marketing activities affect the demand curve facing a imperfection. Advertising affects consumer demand in many different ways. The authors observed in this article, that advertize is a reason to fall consumers charge sensitivity for a particular bulls eye. To understand how advertising do cost sensitivity one necessitate to fancy how it shifts the shape of the demand curve, which means estimating a demand system for all give aways. Estimation of demand among four products, resulting one had a different reply in WTP and that is because of focusing on one distinctive feature of the product. The cause of advertising on the shape of the demand curve depend on vertically or horizontally differentiated (attri butes) of the product. Advertising tenores on vertical (claims marginal consumers) and horizontal characteristics (a crisscross perceived as having an advantage) will incr liberalization WTP most for those infra-marginal consumers.A supermarket scanner data used on four product categories to examine how advertising use experience, toll, promotional activity in the de edgeination of demand. Advertising affect the footing elasticity of demand in deuce different ways Firstly, advertising affect the limits of the demand functions of individual consumers much or less value sensitive, second advertising may affect the number of the set of consumers.The in like mannerthpaste and toothbrush panels cover 157 weeks including households in Chicago and Atlanta while ketchup and detergent panels cover cxxx weeks included households in Sioux Falls, South Dakota and Springfield. Weekly advertising ardor strides gross saving points for each disfigurement in the market and 60% of househo lds linked to TV ads for last 51 weeks restricted only who bought 3 times over the period. The toothpaste panel contains 345 households who make 2880 purchases, toothbrush panel contains 167 households who made 621 purchases detergent panels contains 581 households who made 3419 purchase and ketchup panel contains 135 households who made 1045 purchases. Advertising provides more than than soft information in the ketchup menage (differentiated horizontally e.g. thickness in Heinz) and more hard information (vertically differentiated like quality, such as cavity fighting power in toothpaste, removal of plaque in toothbrush and cleansing power in detergent) and is obvious that nature of ad varies according to product. Advertising is more likely to join on expense sensitivity and lead to more pro- warring effects when the hard information is in advertising (e.g. relative quality information) rather than soft (e.g. image oriented). All products observed by different brands of sel fsame(prenominal) category by market share, mean scathe, ad frequency, display frequency, feature frequency and mean coupon availability. The statistics are in this way that there are three kinds of variables, like percentage of purchases (covers brand commitment), ad viewing habits, and willingness to pay with reference to wrongs that offered.For all 18 brands, advertising reduces price sensitive but cast ups the prices. Advertising is not profitable because it lowers the elasticity of demand, but lifts the level of demand. The more the noisy signs of product attributes in advertisings devote lower variance alternative and set out greater WTP while non-risky consumers have higher variance even for the same features. This unites to the view that non-price advertising affect differently due to consumers diverse tastes. Advertising raises the level of demand by increasing the equilibrium price elasticity and decreasing the equilibrium price. Price advertising and non-price adv ertising affects the demand curves by be of gaining information colligate to price, types of consumers and consumers tastes that visits the stores. People who are less sensitive to price are uncertain about attributes. Price advertising affects stores demand curves differently if consumers have different costs of acquiring price information, and different types of consumers visit each store. It means that advertising is complimentary to consumption and is consistent with models where advertising increases WTP for a brand by producing arranged differentiation and conveying information about brand attributesVariables fool natural selection, Information and market power, Quality of the brand, Existence of the brand, Heterogeneity of consumers tastes, Attributes of the brand, Awareness of substitutes, Ad design, grass differentiation, Barriers to launch and Experience.H0 consumer price sensitivity moderated by brand crediblenessThis article How Advertising Influences daub Credi bility and Consumer Price Sensitivity written by Tulin Erdem, Joffre Swait, Jordan Louviere (2001), connects with my topic in this way that it explains the implication brand credibility of an advertised brand on consumer price sensitivity. Every brand has different affects on consumers on various stages on their decision of choices of a brand. It passes through different utility functions. The root word enlightens the fact, brand effects with information economics depth to analyze whether consumer price sensitivity, consumer valuation of a products overall attractiveness or utility, has an impact by brand credibility, by and by making a choice of a brand by advertising. The impact of brand credibility on consumer price sensitivity across class that absorbs different levels of consumer ambiguity, four different types of products utility analyzed which are Frozen concentrated juice (Dole, Minute Maid, Sunkist, Tropicana and Welshs) Jeans (Calvin Klein, Gap, Lee, Levis, Wranglers) Shampoos (Clairol, Herbal Essence, Pantene Pro- V, Pert Plus, Salon Selective) and Personal computers (Apple, Compaq, Dell, Gateway, IBM)Two types of data relevant the guessing firstly, confirmatory factor analysis (CFA) to obtain brand credibility of the most advertised brands at individual level in each of the four categories and secondly, by price manipulations of the same brand to know the credibility. Subjects rated all quin brands individually to estimate the credibility by them and completed a simple pricing choice experiment involving 17 choice sets in each of two product categories in addition to this, there was a distracter task that includes questions regarding their personal places to minimize the chances of linking two tasks. These four products chosen subjects could relate to them.They asked to assess how sure-footed they would feel measuring new products in 21 different product categories before trial, after one trial and after a year of use (using 7- point agree/d isagree scales)These results suggested that, as a group, the subjects viewed frozen juice concentrate more as a search good, jeans and shampoo as more short- to fair-term experience goods, and a PC as a longer-term experience good. Subjects in the pre-test (n = 31), main and supplementary (n = 170) fall outs were undergraduate students at two major(ip) North American universities. Final sample sizes for the main survey were, respectively, 221, 232, 217 and 198 for juice, jeans, shampoo and PCs. The main survey took approximately 35-40 minutes to complete.Brand credibility decreases price sensitivity but the zeal of the consumers choices differs with products. The emphasis is on the product category factors that could affect the impact of brand credibility on price sensitivity. Consumer characteristics similarly might determine the level of impact of brand credibility and price sensitivity. Observed results suggest that the interaction amongst brand price and credibility is hete rogeneous, which suggests that it is likely to be associated with consumer specific characteristics and the level of advertising occur in certain period.These types differ in consumer uncertainty about product attributes plus in specific features in categories that affect sensitivity to uncertainty. It argues on the impact of price on consumption of a credible brand when there is asymmetric information through advertising. Economic framework suggests that brand credibility moderates price sensitivity under uncertainty. In high latent risk and high social function categories, in which consumer purchase decisions may be quite complicated, the predicted effect was bigger. Price effects strongly recommend that credibility offer number of consumer benefits, which decreases price sensitivity.Variables Brand credibility (trustworthiness, expertise, usage), Brand choice, Product category, Product attributes, Brand line and Consumer benefits.H0 online medium effects consumer price sensiti vity more than offline mediumTo see the impact of online advertisement on advertising price sensitivity is the reason tail assembly choosing this article. According to article The online medium and consumer price sensitivity written by Venkatesh Shankar, Arvind Rangaswamy, Michael Pusater (1999), paper explains a logical framework regarding the assumption that internet increases price sensitivity and intensify price competition and factors characterizing the online medium, consumers and intermediaries to explain the main reasonable effects of the online medium in price sensitivity. The articles inspect two main aspects of price sensitivity, the intensity of customer attaches to price relative to other attributes (Price sizeableness and price search).About 1/4th of revenues in online shopping industry come from travel services, data set 1comprises of both medium but specified only to Marriott international and a same with data set 2 for making different hotel booking but for any h otel chose by the respondent with same questionnaires. They asked questions regarding most recent online reservation and most recent offline reservations. Investigation in data set 1extends from the brand level to the product category level and overcomes problems due to self- selection bias in data set 1, to reduce impartiality, the differences in the frequency of shopping amidst the samples accounted for analysis.For data set 1 primary data collected for the customers of Marriott international and comparing the attitudes and behavior demographically to the population that differ in the medium usage, examine the online medium moderation on price sensitivity and lastly stresses the effects of website factors on price sensitivity. For offline medium consumers questionnaires mailed to customers through Marriott international customers data while for online customers, the survey posted on Marriotts website with a new tag. Only 214 form online and 306 from offline usable recipients (15% ) enabled to respond.Data set 2 had to go through a test provided by hospitality sales and marketing connective international and customers chose on the basis of using both online and offline medium, Receiving 144 responses from a sample of 2000 customers randomly selected from the list, who chose hotel both online and offline (a response rate of 7.2%)Talking about online medium factors interactivity and perceived depth of the message suspensors dampen price importance but at the same time ease of price search increases price importance, content and information interactivity does not give any significant result. Using an intermediary and product/price bundling increases price comparison and price importance. Brand loyalty and time value reduces online price search. Looking at offline medium, the perceived range of option does not diminish price importance or price search but price search reduce because of product/price bundling by an intermediary. Price comparisons using intermedi aries has a much stronger impact on price search offline than online. For both sets, the result is consistent as the online and offline models are similar. Online medium effects price importance more becauseHighlights the range of product options and price bundling by an intermediary to diminish the price importance then it put emphasis on brand loyalty which decreases price search and the effect of price comparison by an intermediary and lastly it is easier to search for price information which reduces the search cost and time as well. Price/product bundling proves to be a strategic advantage for the firms, more online than offline. The price comparison using intermediaries will be more upright if online intermediaries are used and provide proper service/ good description with prices and get it linked to the other sites as well.Variables Price search, Price importance, Price information, Non-pricing advertising, Web-site design, Targeting distribution, Brand loyalty, value of time, frequency of shopping, Alliance strategies, Online attributes price importance influence by medium- product category, demographics.H0 Advertising Effects Evaluates In Three-Dimensional Space of Product (Experience, Affect, Cognition)This paper named How Advertising Works written Demetrios Vakratsas, Tim Ambler (1999) by related to my topic in this way that it talks about the impacts of advertising on consumers which helps observe what features of ads influences consumer behavior or changing their buying behavior. The authors gather the information about how advertising affects the consumer. Advertising effects classified into intermediate effects, for example, on consumer beliefs and attitudes, and behavioral effects, which relate to purchasing behavior, for example, on brand choice. The authors propose that advertising effects studied in a space, with affect, cognition, and experience as the three dimensions. The EAC Space adjusted according to the context of use product category , competitive environment, other marketing mix components, stage of the product life cycle, and target audience. The article has reviewed former research of intermediate and behavioral effects of advertising using models from market response. Advertising can be estimate in a three-dimensional space using the dimensions of experience, affect, and cognition (the EAC Space). The coordinates of the three dimensions can verify the importance of a specific advertising promotion.The article have classified and reconsider preceding research of intermediate and behavioral effects of advertising using a arrangement of models preliminary from market response and ending with integrative and nonhierarchical models. The principal overview concerned the persuasive hierarchy (CA) category of models of advertising effects. Although such models dynamically engaged for 100 years but still flawed on two bases the concept of hierarchy on which its origin cannot by trial and wrongdoing sustained, and h ave eliminated experience effects.The article suggest that behavioral (brand choice, market share) and cognitive and affective (beliefs, attitudes, awareness) directed industry to analyze the edge of context, intermediate effects, and long- and short-term behavior. In this attempt, determination of affective reactions from cognitive partiality evaluated and this is especially important for low-involvement products for which habit and affect are much more important than cognition. On the contrary, it is safe to give tongue to that effects of advertising can calculated by (EAC) space of any product but the dimensions can vary from product to product and hence the importance of dimensions as well.Variables Consumers beliefs, Consumers attitudes, Purchasing behavior, Brand choice, Ads goal diversity, Product category, Competition, Stage of product cycle, Target market, Market share and AwarenessH0 Price Advertising Positioning tactical manoeuvre Increases Brand Equity, Price Importanc e and Consumer Price SensitivityH1 Non-Price Advertising Positioning Tactics Decreases Brand Equity, Price Importance and Consumer Price SensitivityThe article The impact of advertising positioning strategies on consumer price sensitivity written by Ajay Kalra and Ronald C. Goodstein (1998) examines the relationship of brands positioning strategies through advertising with consumer price sensitivity. The authors examine the link between advertising and price effects and that this bond depends on the definite advertising positioning strategies. The advertising has different objective, depending on the competitive perspective of the brand and others positioned to pin down the supposed difference between brands. The authors recognize that price- oriented advertising raises sensitivity while non-price oriented advertising decreases sensitivity.Non-price advertising examines two tactics that fail to increase brand price equity value-oriented positioning, attribute (meaningless) differen tiation, while comparative tactics increase price importance and sensitivity at the category level.In addition, findings confer about that advertising effectiveness measured at both the brand and category levels. The hypothesis tested in two experiments transversely different product categories, entailing that advertising effectiveness must extend other than brand rate related to attitude. Testing of how non-price advertising positioning strategies affect brand equity, price importance, and category price sensitivity. Opposing to the accepted vision, numerous types of non-price positioning tactics can diminish equity and increase price sensitivity.Ninety graduate students at a major west coast university volunteered to contribute in experiment carry out in one of four experimental surroundings and as an bonus for $100 lottery given. They asked to analyze a rough advertisement for a new product and under high-involvement, circumstances and advertising positioning varied without the revision in the brand attribute information in the advertising copy. The experiment designed within one factor and four level of advertisement positioning.An advertisement can have particularly dissimilar effects at each level like at comparative level will be skillful for minor brands but not for premium brands, because it will increase price sensitivity for whole product category.The results also suggest that brand equity and advertising effects must assess in terms of both attitudes and behavioral manifestation. Pricing effects happen because of advertising, when attitudes extracted from the analysis. Nevertheless, the case is different in low involvement where meaningless attribute positioning and celebrity endorsements could significantly affect brand equity and category price sensitivity. Emotional appeals and fear appeals as attitudinal effects also influence advertisements in a cognitive manner.On this note, the conclusion made that non-price advertising positioning strate gies affect brand equity, price importance, and price sensitivity and promotional price advertising increases price sensitivity, whereas non-price advertising decreases price sensitivity. Several types of non-price positioning tactics can decrease equity and increase price sensitivity and brand equity measures extend beyond attitudes and include the ability to demand a premium price.Variables Advertising- positioning strategies, Brand equity, Celebrity endorses positioning, Meaningless attribute differentiation, unique features positioning, Brand comparison and Value positioningH0 Price Sensitivity is MeasureableThe paper Price Sensitivity Measurement written by Robert C. Lewis and Stowe Shoemaker (1997) elaborates on the measurement of price sensitivity through hospitality industry, to see the determinants of price sensitivity are the reason of choosing this article. Instead of using price methods on trial basis and error to determine the right price for products or services, a hot el or restaurant operator can use a relatively simple survey scape to measure customers price sensitivity. The prices for services faces at least three complicating factors Customers often have inaccurate or limited reference prices (i.e. right prices) for services, they use price as a key signal for quality and monetary price is the only cost for service customers. Reference prices have complicated the different needs of customers in two ways The interpretation of price (value based) on the buyers view and the relationship between price and value. A price sensitivity measurement determines how consumers perceptions of the value affected by the interaction of price and quantity. A study conducted in which consumers asked to state the highest and lowest prices to which they purchase selected inexpensive items, showed that price act as a quality indication but not an absolute barrier to purchase. Actually, the price sensitivity measurement examines price perceptions by determining le vels of customers resistance as they relate to perceived quality and the market range of acceptable prices for a specific product or services.Authors examined the application of the price sensitivity measurement model (PSM) to the association meeting market. The five components of our hypothesis are as follows firstly, a point at which hotel room rates considered cheap or expensive the price considered too cheap and quality questioned no matter what the quality and price is, it is too expensive and purchase is beyond consideration and lastly a way to measure the above points. In addition, these are the questions to analyze the value of a product or service. The last two questions are actually to measure the optimal price point. Room rates are a definite factor in the meeting planners purchase decision. The hypothetical situation considered was to plan an annual convention for shaping to hold in Des Monte with expected attendance of 300- 500 attendance, which will last four days, an d hosted in first class hotel. Rooms iodine occupied and participants will stay at the same hotel and the chosen (four) hotels without any prior experience. Final decision based on four questions and the design made with two objectives in mind to minimize the intervening variables that might enter into the situation, thereby affecting their respondents and expect respondents to projects their associations needs and into the situation. Survey to send to a random sample of 443 association-meeting planners and received 115 usable responses (constituting 33% response rate).The study has indicated the existence of a range of acceptable prices for meeting planners. it can be accommodating in determining to compare the perception of specific brands, the competition and variables within a product line. The result showed that the price sensitivity measurement technique could most likely apply to the hotel industry though there is no basis for interpreting the results. It could give the ind ifferent point, an indifference percentage, and an optimum pricing point, a stress level and a range of acceptable prices on lodging industry benchmarks with which to compare those values. In addition, the conclusion made that some meeting planners have in mind threshold prices outside of which price will inhibit their decisions to purchase. The degree to which they are price sensitive (respondents) is difficult to determine.Variables Quality, Product features, and consumers perception of valueH0 An increase in non-price advertising leads to lower price sensitivity among consumersH1 The use of price advertising leads to lower pricesH2 An increase in price advertising leads to higher price sensitivity among consumersThe paper Empirical Generalizations about the Impact of Advertising on Price Sensitivity and Pricewritten by Anil Kaul and Dick R. Wittink (1995), is linked to my topic in this way that this paper have made generalization statements which works as a medium for measuring t he impact of advertising on consumer price sensitivity. The term empirical generalizations suggest the same results comes out in different circumstances and are gathered on outcomes from varied marketing strategies and the result will help estimating the price insensitivities and making a strategic decision about market segmentation, price-marketing activities and competitive market strategies. Two types of advertising are Non-price advertising (national advertising) gives the information about the brand positioning and its intentions to communicate about the characteristics (unique) of the brand and Price advertising (local characteristics) gives the information related to price and availability of the brand. A change in price sensitivity is measured either by Researchers employing experiments (interaction between advertising and price) or by econometric researchers (use price elasticity). It generates a set of three empirical generalizations after studying the previous marketing m ethodsThe approach is to analyze the characteristics and results of previous studies providing explanations on the relevance of these generalizations means the relationship between advertising and price sensitivity observed by an overview of 18 studies. The observations made from a large set of products e.g., new products, shape up products, consumer (non-durables) and durables, services with identification the type of product, the number of brands, the type of advertising, the measure of advertising and price sensitivity, and the type of interaction (result). Three implications considered to assess the link between advertising and price sensitivity Firstly, the difference between price sensitivity of authorized consumers from additional consumers attracted by increased advertising. Secondly, the measurement of price sensitivity whether aggregate (price elasticity) or disaggregate (brand choice to price) data. Third consideration is about target market. If market were exceedingly price-sensitive, then the ceiling effect would be a partial effect of price advertising on sensitivity but if it is of price-insensitive, non-price advertising will moderately influence the price receptiveness. The results specify that in nine studies price sensitivity increases with higher advertising, in seven studies it decreases with higher advertising, and in two cases both effects are attained. Considering only those cases where at least three studies have provided the same result.Focus is on the area of price advertising as moderators such as market share, similarity of brands characteristics or benefits, product life cycle, and the number of competitors, in affecting this relationship and is large enough to alter the brand choice. Moreover, creates variation on price sensitivity due to increase advertising from 20% to 180%. Considering this fact that product-related and other factors that affect the amount of change in price sensitivity in such situations, the conclusion i s that non-price advertising reduces the price sensitivity( accepts H0 ) and falsifies H1 and H2.Variables Brand positioning, Product information, Product differentiation, Brand loyalty, Brand choice, Product market level, Type of product (new products, mature products, consumer nondurables and durables, services), Advertising content, Market share, Similarity of brands characteristics or benefits, Product life cycle and Number of competitors.H0 Advertising Builds Market PowerSimilar to above article this article Price Sensitivity and Television Exposures written by Vinay Kanetkar, Charles B. Weinberg, Doyle L. Weiss (1992) elaborates the contradictory findings with regard to increases in brand advertising activities lead to increase /decrease in price sensitivity. Mentioning the lack of data to measure the revelation of ones households to advertisements and to restrain competitive activities has been a major limitation to date. This paper finds in high-level of publicity of the pro duct, house- holds brands choice and price sensitivity can decrease for two frequently purchased products though it says that increased advertising linked with increase households brand choice and price sensitivity as well. For a number of decades researchers have been attempting to understand the impact of marketing mix variables (price and advertising) on sales (or market share) of purchased goods. However, the interaction of price and advertising has not altogether measured. Set of models designed to examine the effects of advertisings on price sensitivity.Dry dog food accounts for about 60% of total consumer expenditures and eighteen of the 39 brands have large differences in advertising intensity with only one brand had a market share greater than 10%, there were 186 unique brand available to consumers. Because of so many brand choices, minor brands combined into aggregate brand categories. In addition, brand-sizes ignored for three reasons. First, television advertising focus es on brand benefits and does not deal with packet size. Second, the package size decision is likely, not a purchase-to-purchase decision. Finally, for the sample households, more than 70% of the dog food purchases were for a package size of five pounds. To reduce the number of alternatives to a manageable size, brands grouped into aggregate categories according to the size of their market share of 5% and brands advertised and not advertised, so the number of alternative comes down to 11. All brands attributes compared to each other as alternative of others. A similar procedure applied to the aluminum pamper data. The aluminum foil market (in the test city) was aggregated to consist of three brands or choice alternatives, one major brand, private brands, and generic brands. Only the major brand advertised on television and the results were similar of that dog food.The results are steady with the point of view that increased advertising is associated with increased brand choice and price sensitivity. In light of the effect of advertising on sales, several points noted. Firstly, the purchases vary in buying behavior of households and reflect only short operate on effects for advertising and the other mix variables. Price sensitivity effects are generally short-lived. In addition, results show that the indirect effects of advertising have an important effect on price sensitivity usually that the immediate impact of advertising is still low as compared to that of other variables.In turn, the hypothesis is constant with the confirmation that the information conveyed to consumers may not be underpinned the distinct traits and attributes of a brand. Rather, advertising may be increasing consumers brand awareness, strengthen likeness with other brands, and increasing price competition at the retail level. The interpretation of this means that good advertising that builds market power is difficult to develop and maintain.Variables Brand choice, Market share, prefer red brands, Direct competition, Awareness among consumers, Search costs, Brand equity, Display activities, and Brand loyalty.H0 Advertising diminishes the effect of Consumer Price Sensitivity

Napoleon Essay -- European History Military Generals Essays

snooze I live only for posterity, death is nonhing, but to live without glory is to die every day (Lefebvre 43). Napoleon was driven by his desire for glory and ambition and his ascension was tremendous. Born in Corsica, his family moved to France, in Marseilles, when he was only a child. From the province of a lieutenant, at the age of sixteen, to the one of emperor in 1804, till reigning over the European continent after his conquest of Prussia, his ascension was not only due to the events that occurred during his life, but was also due to his ambition and his tremendous genius. His genius was both military and political. Napoleon was a military genius because of his life history rapidity. He went to the School of Officers in Paris. At the age of sixteen he was already a lieutenant. At Toulon, this battle en adaptedd him to climb quickly the echelons in the military. As Chandler states, Napoleon gave military orders to produce a large number of guns. Thes e guns and mortars provided Napoleon the possibility to attack the different forts situated in vests that were overlooking the harbor. Because of this production, Napoleon was able to produce enough guns to attack the place without having a great loss in his army. Horne declared the recapture of the port became possible because the previous attacks enabled Napoleon to place a number of guns and mortars in good position to fire the British fleet commanded by Hood (17). By the success of his capture, the British fleet go forth the harbor and Napoleon gained great recognition by the military and was soon after promoted to the rank of gneral de brigade. Napoleons military genius is perceive through the new division of the army. Gates state... ..., Georges. A Romantic Tempered by Realpolitik. Kafker & Laux. Napoleon and his Times Selected Interpretations. Malabar Florida Robert E. Krieger Pub. Co., 1989. Napoleonic Europe 1812. Map. Atlas of European History. By Barthol omew, Edinburgh. New York HarperCollins, 1994. 148-49Rothenberg, Gunther. Military Affairs. Kafker & Laux. Napoleon and his Times Selected Interpretations. Malabar, Florida Robert E. Krieger Pub. Co., 1989.Rowe, Michael. Debate Napoleon and the Post-Revolutionary Management of Sovereignty. Modern and Contemporary France 8.4 (2000) 510-13. Academic Search Premiere. EBSCO. Roesch Library, Dayton. 04 Nov. 2002 Vandal, Albert. The Restoration of Order and National Unity. Kafker & Laux. Napoleon and his Times Selected Interpretations. Malabar Florida Robert E. Krieger Pub. Co., 1989.

The History Of Arts And Crafts Essay -- essays research papers

The distinction between Craft and Design can be at times problematic explain what you understand these terms to mean, and illustrate their application in relationship to the work of one practitioner.The definition for craft is, the reservation of decorative or functional objects, generally by hand. Hand and power tools may be used, however, in making some craft items. The term crafts besides refers to the objects made. The function of crafts is generally concerned with crafts as creative hobbies, practiced primarily in the home with a minimum of specialized equipment. Crafts as so defined, form certain functions. In a world that is becoming increasingly mechanized and standardized, they give people the opportunity to work with their hands and to express their individuality. Crafts also be often used in occupational therapy for example, a patient might be taught a craft to develop weakened muscles or to help in gaining use of an dodgeificial limb. An emotionally disturbed person might be taught a craft that would serve as an outlet for feelings. Craftwork also provides the disabled with purposive activity that diverts attention from their handicaps. Many hobbyists find themselves going into business. A craftsperson who perhaps has at first sold craft items only to friends or at topical anaesthetic bazaars may find that increased demand leads to a wider clientele and sales by mail order, at crafts fairs, or through a shop. There is a fine line of distinction between crafts produced by amateur hobbyists for their personal satisfaction and crafts that in the hands of gifted artisans approach or can be considered art forms, generally made with a view toward the use and enjoyment of others. The difference between hobby-produced crafts and formal decorative art objects lies in the degree of trigger in form and technique and in the intention of the artisan. Crafts can be grouped by technique or medium. Under the headings that follow are drawing descriptions o f some of those crafts most popular with hobbyists today, with indications of the degree of skill and basic equipment required.The type of craft that I will be studying is known as handicraft. rigorously speaking, handicrafts are occupations that involve making usable or decorative products by hand. Before the Industrial Revolution all such products were handmade, often in the home. The fester of... ...anization and mass production. It had its basis in the ideas of Pugin and Ruskin, the most influential of the writers who deplored the effects of industrialization, but it was left to William Morris to translate their ideas into practical activity. His hand-made products (books, furniture, textiles, wall-paper, and so on) were successful aesthetically, but his ideal of producing art for the masses failed. Nevertheless, he influenced craftsmen, teachers, and propagandists (such as C. R. Ashbee, who founded the Guild of Handicraft in 1888), and in the early years of the 20th century t he ideals of the humanities and Crafts Movement spread abroad, notably to Germany, Austria, the Low Countries, and Scandinavia, where the Danish silver designer George Jensen was one of the key figures. After World War I the movement was transformed by the acceptance of unexampled industrial methods, but it has had an enduring legacy on 20th-century design.AcknowledgementsCNN, Arts Report 1987 summaryBritannia, Oxford, and Comptons Interactive EncyclopaediasThe Book of Art Design The Modern Arts MovementWWW.Encarta.ComThe Essential William MorrisThe Industrial Design Guide 1992Crafts and Designs Today