Gestational Diabetes Consequences For Fetal Programming of Vascular Disease in Adulthood - Free Essay Example

Abstract Gestational Diabetes is a condition 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 due 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 adulthood Introduction Gestational 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 ß 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 car diovascular 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 pregnancy (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 re sistance 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 transport 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 Resistance Insulin 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 ß 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 ß cells increase their secretion of insulin to maintain homeostatic glucose levels (Yogev et al 2008 Chapter 10). GDM occurs 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 cause 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 resistan t 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 GDM Diagnosis 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 Diabetes There 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 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 ß 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 form 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 whic h 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 Function The 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 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 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 Development Approximately 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 emb edded 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 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 Placentation Placentation 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 that 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 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 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 endothel ium. 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 effect of hormones produced in pregnancy Pregnancy 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 (Ri zza 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 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 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 insulin resistance. Many studies suggest t hat 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 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 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 Diabetes There 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 acids 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 (Veraste hpour 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 Programming Many 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 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 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 programming The 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 plasticity and interruptions to this development may cause abnormalities in the development of certain cells which may progress to structural di fferences in organ development (Gluckman and Hanson 2004 cited in Jansson and Powell 2008 ref 16). Effects to the fetus exposed to GDM If 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 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 pr egnancy 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 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 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 offspring Exposure 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 environment of hypergly caema (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 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 2004). Oxidative stress Endothelial cells play a role in vascular disease and they function to regulate vascular tone, control the proliferation of smooth muscle and inhibit platelet function. This is achieved by Endothelium derived nitric oxide (eNOS). If there is a reduced production of NO then endothelial dysfunction can occur and this can cause inflammation, thrombosis and cause the intima layer of blood vessels to divide (FÃ ¶rstermann 2008). Oxidative stress is an imbalance between the production of reactive oxygen species (ROS) and the ability to defend against them (Jansson and Powell 2007). There is also increasing evidence that suggests that oxidative stress plays an important part in the changes that take place, both microvascular and macrovascular, in association with diabetes. Some studies have shown that the role of oxidative stress and mitochondrial dysfunction leads to intrauterine growth retardation in type 2 diabetes. In these individuals there is an increase in production of free ra dicals due to low activity of the electron chains in the mitochondria and this can lead to damage of proteins, DNA and mitochondria (Giugliano et al 1996 cited in Shah et al 2007). Oxidative stress causes a reduction in NO and reduces protection against ROS which can lead to pro-inflammatory and atherosclerotic pathways being activated (FÃ ¶rstermann 2008). There are many mechanisms in hyperglycaemia which can lead to the generation of free radicals. Hyperglycaemia causes an increase in the polyol pathway which leads to a decrease in antioxidant defence increasing the oxidative stress. Oxidative stress is also increased in the hyperglycaemia state by the increase in glucose autooxidation and increase in protein glycation which increases oxidative factors (Giugliano et al 1996). ROS that are formed from the hyperglycaemic state have been found to be involved in the progression of vascular complications (Gao and Mann 2009). In the human placenta there are many mitochondria w hich is where the electron transport chain takes place. In normal pregnancy there are more electrons leaking from this chain and able to produce reactive oxygen species. This extra production of ROS can lead to damaged lipids, DNA and proteins. Pregnancy is therefore a condition where there is increased possibility of there being damage from oxidative stress (Chen and Scholl 2005). ROS can activate a number of pathways that can cause damage to cells and can be linked to the complications that occur in the later stages of diabetes. One of consequences of GDM is hyperglycaemia and this is known to cause increased oxidative stress through several mechanisms (Evans et al 2003). Firstly hyperglycaemia causes the non-enzymatic glycation of proteins, called advanced glycation end products (AGEs) and these are thought to be important in the underlying pathogenesis of diabetic complications. AGEs can interfere with signal transduction, they can change the soluble levels cytokines, hormone s and free radicals and they can alter the function of the proteins that are glycated (Brownlee 1995). Secondly high blood glucose activates the protein kinase C (PKC) pathway and is associated with complications with many of the bodies systems including the cardiovascular system. There is also the possibility that free fatty acids (FFA) are involved in activating this pathway (Koya and King 1998). Finally, it has been hypothesised that hyperglycaemia activates the polyol pathway. This pathway consists of two enzyme reactions; the first being catalysed by Aldose Reductase which reduces glucose to sorbitol which is then converted to fructose by sorbitol dehydrogenase. In rats lens it was found that these two enzymes contributed to oxidative stress in a hyperglycaemic state (Chung et al 2003). From the evidence that is available it has been suggested that oxidative stress ahs a role in the pathogenesis of GDM. Other ideas are that lower levels of antioxidant defences contribute to the progression to GDM (Chen and Scholl 2005). Vascular Tone Increased oxidative stress and inflammatory mediators will affect the vascular tone of blood vessels. The blood vessels in the umbilical cord have no autonomic innervations and therefore the vascular tone of these vessels relies solely on local substances produced in the systemic circulation (Radenkovic 2009). One study showed that serotonin induces a constrictive response on the umbilical artery (Haugen and Rognerud 2001) In diabetes, there is endothelial dysfunction which umbilical artery responds differently to substances such as serotonin in GDM (Radenkovic 2009). GDM and effects on offspring The presence of GDM during pregnancy predicts metabolic problems such as Type 2 Diabetes and metabolic syndrome which are both associated with atherogenesis and vascular dysfunction later on in life (Carpenter 2006). Gestational diabetes can have many effects of the developing fetus and the effect and how severe it is depends on when the onset of diabetes occurs. GDM usually arises in the 2nd and 3rd trimesters and the effects include macrosomia, orgnomegaly, Central Nervous System (CNS) development delay, chronic hypoxemia and the possibility of still birth (Merlob and Hod 2008 Chapter 47). Insulin resistance along with central obesity and dyslipidaemia is thought to contribute to oxidative stress, endothelial dysfunction and inflammation which in turn lead to an increased risk of developing vascular disease (Carpenter 2006). GDM has effects that can cause programming changes in utero which can lead to cardiovascular diseases later on in life such as Hypertension, Atheroscle rosis, Obesity, Dyslipidaemia and Type 2 diabetes. Hypertension Diabetic pregnancy is associated with a higher rate of hypertension which is thought to be caused by insulin resistance that is present in GDM. There may also be genetic predisposition to developing high blood pressure (Bar and Hod 2008). The presence of insulin resistance and glucose intolerance in the earlier stages of pregnancy leading to the onset of gestational hypertension suggests that there is already underlying vascular problems in the mother and predicts that they will have hypertension and/or vascular problems later in life (Carpenter 2006). A study involving rats demonstrated that offspring who are exposure to maternal diabetes get a salt-sensitive hypertension which can be related to an impaired renal function in adults (Nehiri et al 2008). Studies of women who developed gestational hypertension were shown to have increased insulin resistance and the hypertension developed during the last term of pregnancy is thought to be associated with this. Insulin resistance ca uses slight inflammation, which causes an increase in inflammatory agents and higher levels of vascular resistance (Carpenter 2006). In a study of 1000 children, it was found that those that were exposed to GDM in utero were found to have increased systolic blood pressure at 3 years old as well as increased adiposity (Wright et al 2009). Atherosclerosis Atherosclerosis is a disease of the arteries where there is an accumulation of lipid deposits in the intima layer which is most common at the bifurcation of vessels (Patterson and Stouffer 2005). The biggest causes of deaths from diabetes are from cardiovascular disease including heart attacks, vascular diseases and stroke. Oxidative stress is seen to have an accelerating role in this process and patients with diabetes are known to have increased oxidative stress levels. These increased levels can lead to oxidation of low-density-lipoproteins (LDL), endothelial dysfunction and the division of smooth muscle in the blood vessels and these mechanisms lead to the generation of atherosclerotic plaques (Jay et al 2006). Oxidised LDL attracts monocytes and can also injure cells by necrotic and apoptotic pathways which can make them more prone to forming plaques. However not all of the effects of oxidised LDL lead to atherogenesis and it may play a part in the inhibition of plaques forming (Chisolm and Steinberg 2000). Studies have shown that endothelial cell dysfunction, inflammation and oxidative stress are related to the atherosclerotic plaques found in atherosclerosis (Leduc et al 2009). Studies of women who developed gestational hypertension were shown to have increased insulin resistance and the hypertension developed during the last term of pregnancy is thought to be associated with this. GDM and body weight Rats induced with diabetes in the last term of the pregnancy were found to produce offspring whose weight varied widely from microsomic to macrosomic. The macrosomic rats were produced by mothers with more severe hyperglycaemia and the microsomic rats whose mothers had less severe hyperglycaemia. It was also discovered that there were genetic differences as it was found that the male offspring developed insulin resistance by 6 months and while the females had changed vascular structure (Segar and Norris 2009). Many studies prove that a foetus who is exposed to an environment of GDM has an increased risk of developing macrosomia. This study has helped increase our knowledge in that the diabetic environment plays an important role in determining birth weight of the offspring. Obesity Many studies have looked into whether GDM can affect the chance that the offspring is more susceptible to the development of obesity in later life. GDM causes hyperglycaemia in the fetus and this can lead to increased amounts of insulin being produced as insulin. These increasing amounts of insulin can lead to insulin resistance and could predispose the individual to develop obesity in later life (Wright et al 2009). However, while GDM may cause macrosomia it is more the post-natal environmental factors that have a bigger input into the development of obesity. Obesity in offspring is important as it is a cardiovascular risk factor. Dyslipidaemia Hyperglycaemia is thought to lead to a change in concentrations of lipoproteins. Dyslipidaemia in Diabetes consists of increased triglycerides, high lipid levels after eating and low levels of high density lipoproteins (HDL). High Levels of Lipids is a risk factor for macrovascular disease (Goldberg 2001). Pima Indians development of T2D Offspring born to mothers who have been diagnosed with diabetes have a greater risk of developing type 2 diabetes and macrosomia. Studies of the Pima Indians have shown that. Figure 2 shows that offspring who are exposed to a diabetic environment have a high BMI than siblings who are not exposed to a diabetic environment proving that the environment is a more important determine factor of BMI than any genetic component (Dabelea et al 2000). A different study established a relationship between the high levels of glucose in the last trimester of pregnancy in non-diabetic mothers and the risk to the offspring of developing type 2 diabetes later in life was the study of the Pima Indians. In this study there was a strong correlation between glucose levels in the last term of the pregnancy and the offspring developing type 2 diabetes later in life. There was also evidence to suggest that higher levels of glucose in pregnancy predisposed the child to a greater risk of obesity during ch ildhood (Franks et al 2006). Treatment of GDM Once the mother has been diagnosed with GDM her blood glucose levels should be closely followed. Treatment of GDM is aimed to keep blood glucose levels as close to the normal limits as possible to prevent any risk of developing macrosomia and other problems associated with the developing fetus. The greatest insulin resistance occurs, as stated before, in the last trimester and screening for GDM takes place around 24- 28 weeks into the gestation. Diagnosis can be made with a glucose tolerance test (Cheung 2009). Dietary control is the most important and effective way to treat GDM. If dietary control does not prove to be effective and blood glucose levels are still high then treatment with insulin may be needed. Oral hypoglycaemic agents may be given if other treatment is ineffective (Cheung 2009). Effects of GDM on the mother Mothers who develop GDM have an increased risk of developing diabetes in later years. One study in Denmark followed a group of women who had gestational diabetes during their pregnancy and then approximately 6 years after giving birth 14.5% had developed type 2 diabetes, 3.7% had Type 1 diabetes and 19.5% were classed as having pre-diabetes (Damm 2009). GDM can be seen as a marker for the mother developing T2D later on in life which is useful as it allows treatment and education on how to minimise the risk of developing it. Women who present with GDM have an increased risk of developing metabolic syndrome and are more likely to develop disturbed endothelial function and increased thickness of carotid arteries (Kaaja, RÃ ¶nnemaa 2009). Conclusion and Future Research Gestational Diabetes is a condition that affects 7% of pregnant women annually. It is defined as a glucose intolerance that presents in the later stages of pregnancy. The causes are not fully known but it involves beta-cell dysfunction with the possibility of autoimmune destruction, MODY or on top of already present insulin resistance. During the pregnancy GDM can have many effects on the placenta and its products. These products usually increase the insulin resistance. GDM can alter fetal programming and make the fetus more susceptible to cardiovascular disease mainly hypertension, atherosclerosis and hyperlipidaemia which are risk factors for many other cardiovascular diseases. Oxidative stress can lead to complications by causing damage to proteins, lipids and DNA. In hyperglycaemia there is increased oxidative stress and this can activate several pathways which can be involved in vascular complications. GDM can increase the amounts of Oxidative Stress and inflammatory mediat ors produced which can lead to a decreased vascular tone. If GDM is treated successfully by diet or drugs then this can dramatically reduce the risk of developing complications. Future research should focus on screening with all pregnant women who fall into the middle and high risk categories being screened to decrease the risk of fetal complications. Blood glucose levels should be tested to keep them within range. Possible research areas include methods to control the production of hormones by the placenta in order to keep the inevitable insulin resistance to the minimum. Possible areas of research include Antioxidants such as Vitamin E which can be used to keep oxidative stress damage to a minimum. References American Diabetes Association (2010) Diagnosis and Classification of Diabetes Mellitus. Diabetes Care, Volume 33, Supplement 1: S62- S69 Ashworth C.J., Hoggard N., Thomas L., Mercer J.G., Wallace J.M., Lea R.G., (2000). Placental Leptin. Reviews of Reproduction 5: 18-24 Bar J., Hod M., (2008). Chapter 41 Hypertensive disorders and diabetic pregnancy. Textbook of diabetes and Pregnancy: 308-317 Brenner B.M., Garcia D.L., Anderson S., (1988). Glomeruli and blood pressure. Less of one, more the other? American Journal of Hypertension 1: 335-347 Brownlee M., (1995) Advanced Protein Glycosylation in Diabetes and Ageing. Annual Review of Medicine 46:223-34 Buchanan T.A., Xiang A.H., (2005) Gestational Diabetes Mellitus. Journal of Clinical Investigation 115: 485-491 Carpenter M.W., (2007) Gestational Diabetes, Pregnancy Hypertension and Late Vascular Disease. Diabetes Care Vol 30 Supplement 2: 246-250 Catalano P.M., (2008) Chapter 11 Fetal growth in Normal and Diabetic Pregnancies. Textbook of diabetes and Pregnancy: 79-85 Catalano P.M., Kirwan J.P., Haugel-de Mouzon S., King J., (2003). Gestational Diabetes and Insulin Resistance: Role in Short- and Long-Term Implications for Mother and Fetus. Journal Nutrition 133:1674S-1683S Chen X., Scholl T.O., (2005) Oxidative Stress: Changes in Pregnancy and with Gestational Diabetes Mellitus. Current Diabetes Reports 5:282-288 Cheung N.W., (2009). The management of Gestational Diabetes. Vascular Health and Risk Management 5:153-164 Chisolm G.M., Steinberg D., (2000). The oxidative modification hypothesis of atherogenesis: an overview. Free Radical Biology and Medicine 28: 1815-1826 Chung S.S.M., Ho E.C.M., Lam K.S.L., Chung S.K., (2003). Contribution of Polyol Pathway to Diabetes-Induced Oxidative Stress. Journal American Society of Nephrology 14: S233-S236, Coughlan M. T., Oliva K., Georgiou H. M., Permezel J. M. H., Rice G. E., (2001). Glucose-induced release of tumour necrosis factor-alpha from human placental and adipose tissues in gestational diabetes mellitus. Diabetic Medicine, 18, 921-927 Dabelea D., Pettitt D.J., (2008). Chapter 48 Long term implications: child and adult. Textbook of diabetes and Pregnancy: 362-371 Damm P., (2009) Future risk of diabetes in mother and child after gestational diabetes mellitus. International Journal of Gynaecology and Obstetrics 104: S25-S26 De Vriese A.S., Verbeuren T.J., Van de Voorde J., Lameire N.H., Vanhoutte P.M., (2000). Endothelial dysfunction in diabetes. British Journal of Pharmacology 130, 963-974 Desoye G., Haugel-De Mouzon S., (2007). The Human Placenta in Gestational Diabetes Mellitus- The insulin and cytokine network. Diabetes Care, Volume 30 Supplement 2: S120- 126 Desoye G., Shafrir E., Hauguel-de Mouzon S., (2008) Chapter 8 The placenta in diabetic pregnancy: Placental transfer of nutrients. Textbook of diabetes and pregnancy: 47-57 Evans J.L., Goldfine I.D., Maddux B.A., Grodsky G.M., (2003) Are Oxidative Stress Activated Signalling Pathways Mediators of Insulin Resistance and ß-Cell Dysfunction? Diabetes Volume 52: 1-8 Fetita L.S., Sobngwi E., Serradas P., Calvo F., Gautier J.F., (2006) Consequences of Fetal Exposure to Maternal Diabetes in Offspring. Journal of Clinical Endocrinology and Metabolism Vol 91, No 10: 3718-3724 FÃ ¶rstermann U., (2008) Oxidative stress in vascular disease: causes, defence mechanisms and potential therapies. National Clinical Practice Cardiovascular Medicine Volume 5, Number 6: 338-349 Franks P.W., Looker H.C., Kobes S., Touger L., Tataranni P.A., Hanson R.L., Knowler W.C., (2006). Gestational Glucose Tolerance and Risk of Type 2 Diabetes in Young Pima Indian Offspring. Diabetes Volume 55: 460-465 Gao L., Mann G.E., (2009) Vascular NAD(P)H oxidase activation in diabetes: a double-edged sword in redox signalling. Cardiovascular Research 82: 9-20 Gao X.L., Yang H.X., Zhao Y., (2008) Variations of Tumour Necrosis Factor-alpha, leptin and Adiponectin in mid-trimester of gestational diabetes mellitus. Chinese Medical Journal 121: 701-705 Giachini F. R.C., Carriel V., Capelo L.P., Tostes R.C., Carvalho M.H., Fortes Z.B., Zorn T.M., San Martin S., (2008). Maternal diabetes affects specific extracellular matrix components during placentation. Journal of Anatomy 212: p31-41. Giugliano D., Ceriello A., Paolisso G., (1996) Oxidative stress and diabetic vascular complications. Diabetes Care 19: 257-267 Godfrey M.K., (2002) The of Role of the Placenta in Fetal Programming- A review. Placenta 23: S21-27 Gomez R.A., Norwood V.F., (1999) Recent Advances in Renal Development. Current Opinion in Paediatrics 11: 135- 140 Gude N.M., Roberts C.T., Kalionis B., King R.G., (2004) Growth and function of the normal human placenta. Thrombosis Research 114: 397—407 Haugen G., Rognerud H., (2001) Doppler flow velocity waveforms and vasoactive effects of serotonin in human umbilical arteries. Gynaecologic and Obstetric Investigation 51: 22-27 Herrera E., Ortega H., (2008) Metabolism in normal Pregnancy. Textbook of Diabetes and Pregnancy:25-34 Horal M., Zhang Z., Stanton R., Virkamaki A., Loeken M.R., (2004). Activation of the Hexosamine Pathway Causes Oxidative Stress and Abnormal Embryo Gene Expression: Involvement in Diabetic Teratogenesis. Birth Defects Research (Part A) 70:519-527 Huppertz B., (2008). The anatomy of the normal Placenta. Journal Of clinical Pathology 61: 1296-1302 Jansson T., Powell T.L., (2007) Role of the placenta in fetal programming: underlying mechanisms and potential interventional approaches. Clinical Science 113: 1-13 Jay D., Hitomi H., Griendling K.K., (2006) Oxidative stress and diabetic cardiovascular complications. Free Radical Biology and Medicine 40: 183-192 Kaaja R., RÃ ¶nnemaa T., (2009) Gestational Diabetes: Pathogenesis and Consequences to Mother and Offspring. The Review of Diabetic Studies 5: 194-202 King J.C., (2006) Maternal Obesity, Metabolism and Pregnancy Outcomes. Annual Review of Nutrition 26: 271-291 Kirwan J.P., Hauguel-De Mouzon S., Lepercq J., Challier J.C., Huston-Presley L., Friefman J.E., Kalhan S.C., Catalano P.M., and (2002) TNF-alpha is a Predictor of Insulin Resistance in Human Pregnancy. Diabetes Vol 52: 2207-2213 Kouseff B.G., (1999) Diabetic Embryopathy. Current Opinion in Paediatrics 11: 348-352 Koya D., King G.L., (1998) Protein Kinase C Activation and the Development of Diabetic Complications. Diabetes Volume 47: 859-866 Leduc L., Levy E., Bouity-Voubou M., Delvin E., (2010). Fetal Programming of Atherosclerosis: Possible role of the mitochondria. European journal of Obstetrics and Gynaecology and Reproductive Biology 149: 127-130 McLean M., Chipps D., Wah Cheung N., (2006). Mother to child transmission of diabetes mellitus: does gestational diabetes program Type 2 Diabetes in the next generation? Diabetic Medicine 23: 1213-1215 Megia A., Vendrell J., Gutierrez C., Sabate M., Broch M., Fernandez-Real J.M., Simon I., (2008) Insulin sensitivity and resistin levels in gestational diabetes mellitus and after parturition. European Journal of Endocrinology (2008) 173-178 Megia A., Vendrell J., Gutierrez C., Sabate M., Fernandez-Real J.M., Simon L., (2008). Insulin sensitivity and resistin levels in gestational diabetes mellitus and after parturition. European Journal of Endocrinology 158: 173-178 Mello G., Parretti E., Hod M., (2008). Chapter 28 Prevention of Fetal Macrosomia. Textbook of diabetes and Pregnancy: 291-296 Merlob P., Hod M., (2008) Chapter 47 Short term implications: the neonate. Textbook of diabetes and Pregnancy: 352- 261 Metzger B.E., Buchanan T.A., Coustan D.R., De Leiva A., Dunger D.B., Hadden D.R., Hod M., Kitzmiller J.L., Kjos S.L., Oats J.N., Pettitt D.J., Sacks D.A., Zoupas C,.(2007). Summary and recommendations of the Fifth International Workshop-Conference on Gestational Diabetes Mellitus. Diabetes Care Jul;30:S251-60 Metzger B.E., Coustan D.R., (1998). Summary and Recommendations of the Fourth International Workshop-Conference on Gestational Diabetes Mellitus. Diabetes Care Aug;21 Supplement 2:B161-7 Morino K., Petersen K.F., Dufour S., Befroy D., Frattini J., Shatzkes N., Neschen S., White M.F., Bilz S., Sono S., Pypaert M., Shulman G.I., (2005) Reduced mitochondrial density and increased IRS-1 serine phosphorylation in muscle of insulin-resistant offspring of type 2 diabetic parents. The Journal Of Clinical Investigation Volume 115, No.12: 3587-3593 Myatt L., (2006) Placental adaptive responses and fetal programming Journal Physiology 572: 25-30 Myatt L., Kossenjans W., Sahay R., Eis A., Brockman D., (2000) Oxidative Stress Causes Vascular Dysfunction in the Placenta. The Journal of Maternal-Fetal Medicine 9:79-82 Nehiri T., Duong Van Huyen J.P., Viltard M., Fassot C., Heudes D., Freund N., Deschenes G., Houillier P., Bruneval P., Lelievre-Prgorier M., (2008) Exposure to Maternal Diabetes Induces Salt-Sensitive Hypertension and Impairs Renal Function in Adult Rat Offspring. Diabetes Volume 57: 2167- 2175 Patterson C., Stouffer G.A., (2005). Atherosclerosis. Encyclopaedia of Life Sciences. https://mrw.interscience.wiley.com/emrw/9780470015902/els/article/a0005998/current/abstract?hd=All,Atherosclerosis Radaelli T., Varastehpour A., Catalano P., Hauguel-de Mouzon S., (2003) Gestational Diabetes Induces Placental Genes for Chronic Stress and Inflammatory Pathways. Radenkovic M., Radunovic N., Momcilov P., Grbovic L., (2009) Altered Response of Human Umilical artery to 5-HT in Gestational Diabetic Pregnancy. Pharmacological reports 61: 520-528 Redman C., (2001) Pregnancy: Maternal Disorders ELS Roberts D.J., Raspollini M.R., (2008) Chapter 7 Histopathology of the Placenta. Textbook of diabetes and pregnancy:41-46 Rossetti L., Massillon D., Barzilai N., Vuguin P., Chen W., Hawkins M., Wu J., Wang J., (1997) Short Term Effects of Leptin on Hepatic Gluconeogenesis and in Vivo Insulin Action. The Journal of Biological Chemistry volume 272: 27758-27763 Ryan E.A., Enns L., (1988) Role of gestational hormones in the induction of insulin resistance. Journal Clinical Endocrinology and Metabolism 67(2):341-7 Sattar N., Greer I.A., Pirwain I., Gibson J., Wallace A.M., (1998). Leptin levels in pregnancy: marker for fat accumulation and mobilization? Acta Obstetricia et Gynecologica Scandinavica 77: 278-283 Schillan-Koliopoulos M., Guadagno S., Walker E.A., (YEAR) Gestational Diabetes Management: Guidelines to a Healthy Pregnancy. The Nurse Practitioner Vol 31 No 6: 14-23 Segar E.M., Norris A.W., Yao J.R., Hu S., Koppenhafer S.L., Roghair R.D., Segar J.L., Scholz T.D, (2009) Programme of growth, Insulin resistance and vascular dysfunction in offspring of late gestation diabetic rats. Clinical Science 117: 129-138 Shah S., Iqbal M., Karam J., Salifu M., McFarlane S.I., (2007) Oxidative stress, Glucose Metabolism and the prevention of Type 2 Diabetes: Pathophysiological Insights. Antioxidants and Redox Signalling Vol 9, No. 7: 911-929 Steppan C.M., Lazar M.A., (2002). Resistin and obesity-associated insulin resistance. Trends in Endocrinology and Metabolism Volume 13 Issue 1: 18-23 Thornburg K.L., Otierney P.F., and Louey S., (2010) Review: The Placenta is a Programming Agent for Cardiovascular Disease. Placenta 31, Supplement A, Trophoblast Research Vol 24: S54-59 Tree T., (2010) The pathogenesis of type 1 diabetes Lecture Weng J., Ekelund M., Lehto M., Li H., Erkbery G., Frid A., Aberg A., Groop L., Berntorp K (2002). Screening for MODY Mutations, GAD Antibodies, and Type 1 Diabetes-Associated HLA Genotypes in Women With Gestational Diabetes Mellitus. Diabetes Care 25:68-71 Wiznitzer A., Furman B., Zuili I., Shany S., Reece E.A., Mazor M., (2000). Cord leptin level and fetal macrosomia. Obstetrics and Gynaecology 96: 707-713 Wright C.S., Rifas-Shiman S.L., Rich-Edwards J.W., Taveras E.M., Gillman M.W., Oken E., (2009) Intrauterine Exposure to Gestational Diabetes, Child Adiposity, and Blood Pressure. Am Journal Hypertensive. 2009 February ; 22(2): 215-220 Yogev Y., Ben-Haroush A., Hod M., (2008) Pathogenesis of gestational diabetes mellitus. Textbook of Diabetes and Pregnancy: 71-79 Goldberg I.J., Diabetic Dyslipidaemia: Causes and Consequences. Journal of Clinical Endocrinology and Metabolism. Volume 86: 965-971 Dabelea D., Hanson R.L., Lindsay R.S., Pettitt D.J., Imperatore G., Gabir M.M., Roumain J., Bennett P.H., Knowler W.C., (2000). Intrauterine Exposure to Diabetes Conveys Risks for Type 2 Diabetes and Obesity A Study of Discordant Sibships. Diabetes Volume 49: 2208-2211

Developmental of behaviorism - Free Essay Example

Sample details Pages: 4 Words: 1128 Downloads: 5 Date added: 2019/03/22 Category Psychology Essay Level High school Tags: Behavior Essay Did you like this example? Researchers Jacqueline Trouillas and Patrick Mertens have written in the article about four common stages they experimented in the brain development of a sensorimotor stage child. I am only going to be talking about Maturation of the central cerebral regions which is stage four. Stage four is mostly about seeing the individuality of a child when growing. Don’t waste time! Our writers will create an original "Developmental of behaviorism" essay for you Create order On how smart one is without their parents helping at all. (Afif, A., Trouillas, J., Mertens, P. 2015) When I was reading towards what the characteristics for a two-year-old should be I came upon: pointing to things, knowing names of people, says sentences two to four words, understands instructions, names pictures in books, kicks ball, and can hop one leg at a time. When I was observing the two-year-old, he seems to be in peace. He does not ask for mom only auntie and nana. He seems to copy everything his brother does. His older brother is his role model for what I have seen. He loves to play outside and to talk a lot even though we cannot seem to understand very good what he is trying to say. He is a very loving kid that loves hugging and if you say stop or trying to make him understand he is doing wrong he understands and cries. I think it has been a month since I have seen him. He left with his dad to home in Grand Junction and left his older brother back at grandmas. My parents went to go visit him last weekend and he is so big and smart. He talks, and we can understand everything he says. I had read that kids at age two get hit with their vocabulary suddenly and can be understood to what theyre trying to say. In this article the researchers experiment was for them to see the attachment of a child and his mother and how they would react for them leaving. If they would cry and hug them when they would come back it meant they are attached to them, and if not, they had insecure attachment. From what the researchers have experimented was with 17 children. 16 of them were concrete stage graduates and only 1 was not. They said that it was common with many other groups and same backgrounds. Many had the same scores except the one with bad environmental experiences. What I mean by scores is by same behaviorism score they did while overviewing these children. Over time of reviewing many other groups, the numbers kept going down from 17 to only 5 people in a group. They were just trying to figure out the same type of answer of some specific children. (Southard, M., Pasnak, R., 1997) The child that I am observing is with the grandmother yells and says, Why dont you love me? to his grandmother. When his step father came out of jail, he took care of the two boys while the mother was not at home to take care of them herself. After a month of taking care of them he decides to head back home. He left both the children with the grandmother. The five-year-old is constantly only looking at the tv if not he is mad, sad, confused. He constantly cries for his mother wanting to know when she is coming home. One day when I picked him up at day care he was real upset about something and did not want to go home with me. I asked, what is the matter? He responded with I thought you were my mom, I just miss her, it broke my heart hearing him say this. He is always had his grandma and his brother with him, but ever since his mom left and then his step dad left, he felt empty. A month after his step dad had left his little brother left with his father back home and he stayed with his grandma. I would understand why he feels so lonely. Everyone has left without saying anything. We have tried getting him help with a counselor, but without any parent here the counselor will not accept to help him. The reason towards I decided to research the behavior of a five-year-old and a two-year-old is because of these two brothers. I have known them since they were born, and I am so sad on how I discovered so much about them. When I started this class, the professor told me about a research paper. I instantly thought about these two boys. These two boys have been through a lot and Ive noticed that the oldest one was more affected towards the separation of his parent then the smaller one did. About a week ago now the small one was with my mother, so they facetimed the older brother and he seemed to be happy to see his brother, but the only thing he wanted to know when the step dad was going to go visit him and take him with him. He was so upset that we wanted him to go get him and take him with him. It didnt matter if he was with his nana all he wanted was one of his parents. I have no idea exactly why it didnt affect the smaller one as much as it did to the oldest. I always thought it would affect the smaller one more than the oldest, but it all was backwards. Both children are with a permanent guardian. The 5-year-old is with his Nana; he has been with her for over a month now. The young one is with his dad up in Grand Junction and we can see him whenever and seems to be happy to be with him. The mom is now in an addiction clinic up in Denver and cant see her children until they know she is doing better. Towards this paper Ive realized that many teens/ adults struggle with life because they have grown up in an unstable home. When kids grow up like this they always seem to be depressed or cant trust anyone. Every time the 5 years old Nana goes to work, he cries when she comes back because he thinks that hes going to abandon him like everyone else has. I am glad I had the opportunity to write about them. This is a hard topic for many people, but I was able to talk to my aunt about it and she agreed for me to write this about her daughters struggle. My aunt has cried through it all and shes just glad everything is falling in place and was glad I was there to help with any type of problem. I was there to observe the childrens behaviors and was able to participate for them to feel loved and cared for.

Essay on The First Industrial Revolution Progressing Society

The First Industrial Revolution: Progressing Society The First Industrial Revolution modified every aspect of daily life. According to Princeton University â€Å"Economic historians are in agreement that the onset of the Industrial Revolution is the most important event in the history of humanity since the domestication of animals and plants† (Princeton par. 6). The First Industrial Revolution brought along machines, a capitalist economy, and trade expansion. Machines increased productivity, capitalist economies boomed with inventions, and trade expansion accelerated transportation with innovations. Sources from BBC History to Lewis Hackett concur that the First Industrial Revolution changed human life forever by industrializing countries.†¦show more content†¦(U.S. History par. 2) Great Britain did not want incidents such as Slater’s to happen again, as royal documents from the late 18th century show they did not let factory workers or architects leave the cou ntry at the time. Slater started his own factory in the states which had machines that greatly increased the production speed of yarn, thus others followed him in the path of industrialization. Soon, new systems came about. These new systems included the Outwork system which allocated small parts of a large production, and the Factory system which did large-scale projects in one location. New systems and factories led to more work opportunities, and thus more workers which operated factory machines. Those factories were powered by two sources: steam engine(s) or water mill(s). The commercial steam engine is nicked the â€Å"foundation† of the First Industrial Revolution and was invented by Thomas Newcomen with James Watt. The steam engine worked by turning water and fire into steam which built up pressure and in turn moved a valve and piston. (Lemson Center pars. 1-9) Oliver Evans later improved on the commercial steam engine’s design in New England. 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Predicting the future of human cloning at present is indeed futile as it will only yield more needless speculations. As much as I recognize the dangers of human cloning, I see the hoo- ha of human cloning a matter of perspective and time frame. All the attention given it is a passing phase. Ever since the advent of the industrial revolution, mankind has demonstrated his unquenchable thirst for discoveryRead MoreEssay History Marketing1353 Words   |  6 Pagesb) You should then discuss in what ways this context has changed and how the marketing discipline has changed amp; needs to change further in order to adapt to the current and future needs of firms, consumers/customers; perhaps even alluding to society in general. According to Marketing Association (1985, as cited D. Hall and R. Jones 2010: 48) Marketing is the process of planning and executing the conception, pricing, promotion and distribution of ideas, goods and services to create exchange

Report E-Catalog Database

Question: Describe about the eCatlog database? Answer: Introduction This is a report for the eCatalog database. In this report different phases of building the database will be discussed. For this database, Microsoft Visio, Excel, Access has been used. Requirement Analysis To understand the entities, relationships and attributes of the database are needed to be understood before designing or developing the database itself. For that purpose, some eCatalogs available online, have been studies thoroughly. After understanding how data is stored, what attributes are there, what real world entities are present etc. It then moves to the next phase of designing the logical data model for the eCatalog database. Data Modeling Data modeling is the first stage of database design and development. The business rules identified from the requirement analysis are, There may be two types of documents Books and Journal articles. Each should be uniquely identifiable. A book may have more than one edition from same or different publishers. However, this is not true for journal articles. A journal article will be published on a specific journal by a journal publisher once. There are authors who can write journal article or book. Each book will have one or more chapters. A chapter will belong to one book only. There are two types of publishers, journal publishers and book publishers. A book or journal article may be written by one or more authors. ER diagram for the eCatalog database having entities like Author, Book, Journal, Journal Publisher, Book Publisher, Chapter etc. , relationships among the entities and attributes of the same, is, There are one to one relationship between Chapter and Book, Journal Publisher and Journal etc. These are represented using foreign keys from one side to many side. There are many to many relationships, both binary and ternary. For example, binary many to many relationship Journal Publication, ternary many to many relationship Book Publication. These information about entities, relationships etc. will be transformed into implementation of the database in Microsoft Access. Relational Database Design in Microsoft Access In this phase there will be a table for each many to many relationship and entities from the ER diagram. The attributes of each will be also there. Using Create table option these tables will be created. Then the attributes and data types will be set. The primary key and foreign keys will also be set. After building the database in Access and saving it, each table will be exported into HTML web pages. The Structures of the tables will be shown in HTML web pages. The Access Database contains different tables, like Author It describes the details of each author. Including their unique ID, name, and contact details. Book It describes the details of each book, like unique ID, title, publication details, number of pages, edition etc. the composite primary key is BookID and Edition. BookPublication It describes the publication of an edition of a book by a publisher. BookPublisher It describes the details of book publisher. There are fields like unique identification for each book publisher, name, contact address etc. Chapter Each book will have one or more chapters. So there is a composite key including BookId and chapter no. Chapter no will uniquely identify each chapter in a book. There are other fields like name of the chapter, additional details etc. Journal A journal will be identified by journal ID. There are other fields like name, year of publication etc. JournalPublication There will be publication details of each journal in this table. There will be detailed date of publication, city etc. along with the unique ID. JournalPublisher There will be details about each journal publisher. Each publisher will have their name, website, email, contact details etc. The Access database is, Data Dictionary A data dictionary provides information about the data in the database. That is, it will provide information about the tables, attributes, primary keys, foreign keys etc. For that purpose an Excel based data dictionary has been developed. Where description from each attribute of each table has been described. The data dictionary descriptions are, Author Attribute Name Description Comment AuthorID This is the primary key field and uniquely identifies each record in the Author table. Name Author It represents the name of the author. Email ID It represents the email id of the author. Contact Number It represents the contact number of the author. Book Attribute Name Description Comment Book ID This is one of the key field and unique for each book. The composite primary key BookID and Edition uniquely identifies a Book Edition This is one of the key field. Book Name This is the name of a book. Date Publication This is the date of publication of an edition of a book. Number Pages This is the number of pages in an edition of a book Book Publication Attribute Name Description Comment Book ID This is a key field and a foreign key to the Book Table. The composite primary key contains all these four attributes. It uniquely identifies each record in Book Publication Table Author ID This is a key field and a foreign key to the Author Table. Edition This is a key field and a foreign key to the Book Table. Book Publisher ID This is a key field and a foreign key to the BookPublisher Table. BookPublisher Attribute Name Description Comment Book Publisher ID This is the primary key and uniquely identifies each record in the BookPublisher table. Name This is the name of a book publication company. Address This is the contact address of a book publishing company. Chapter Attribute Name Description Comment Chapter No This is a key field. It represents the chapter in some Book These three fields constitute the primary key of the table Chapter Book ID This is a key field. It represents the book to which the chapter belongs to. This is also a foreign key to Book table. Edition This is a key field and foreign key to Book table. Name This is the title of a chapter. Details This is an optional field for describing some details associated with a chapter. Journal Attribute Name Description Comment Journal ID This is the primary key field for Journal table. Journal Name This is the name of a journal. Volume This is the volume of a journal. Issue This is the issue number of a journal. Year Of Publication This is the year of publication of a journal. Journal Publisher This is a foreign key to the table Journal Publisher. It represents the reference to the publisher of a journal. Journal Publisher Attribute Name Description Comment Journal Publisher ID This is a key field. It is also a foreign key referencing to the Journal Publisher table. Name This is the name of the Journal Publishing organisation. Email This is the email of the Journal Publishing organisation. Website This is the website (URL) of the Journal Publishing organisation. Address This is the address of the Journal Publishing organisation. Journal Publication Attribute Name Description Comment Author ID This is a key field in the Journal Publication table. This is also a foreign key referencing to the Author table. These two fields constitute the primary key of the table. Journal ID This is a key field in the Journal Publication table. This is also a foreign key referencing to the Journal table. Date Publication This field gives the Date of the publication of some journal. City This is the publication city of a journal. Conclusion In this report, the phases of designing and developing the eCatalog database have been described. There are discussions on designing the logical schema, building the database and creating the data dictionary. References Garcia-Molina, H., Ullman, J. D., Widom, J. (2011). Database Systems: The Complete Book. Pearson. Lambert, J., Cox, J. (2013). Microsoft Access 2013 Step by Step. Pearson Education. Silberschatz, A., Korth, H., Sudarshan, S. (2010). Database System Concepts (6th ed.). McGraw-Hill Education.