Basic Computer Memory Types Essay

Random Access Memory (RAM) RAM is a location within the computer system which is responsible for stacking away data on a temporary basis, so that it can be promptly accessed by the processor. The information stored in RAM is typically loaded from the computer’s hard disk, and includes data related to the operating system and certain applications. When the system is switched off, RAM loses all the stored information. The data remains stored and can be retained only when the system is running. When the RAM gets full, the computer system is more likely to operate at a slow peed. The data can be retrieved in any random order. Generally, there are two types of RAM; namely Static RAM (SRAM) and Dynamic RAM (DRAM). When many programs are running on the computer simultaneously, the virtual memory allows the computer to search in RAM for memory portions which havent been utilized lately and copy them onto the hard drive. This action frees up RAM space and enables the system to load different programs. Read Only Memory (ROM) This type of memory is active, regardless of whether the system is turned on or is switched off. It is a kind of permanent non-volatile storage memory. As the name ‘read only’ suggests, the contents in it cannot be changed or modified. It is an integrated circuit which is pre-programmed with important data that should necessarily be present for the computer to carry out its normal functionalities. Cache Cache is a kind of RAM which a computer system can access more responsively than it can in regular RAM. The central processing unit looks up in the cache memory before searching in the central memory storage area to determine the information it requires. This rules out the need for the system to search for information in larger and bigger memory storage areas, which in turn leads to a faster extraction of data. Computer Hard Drive These devices are important data storage components that are installed in the CPL]. Their memory ranges widely, and a user may choose the memory depending on the data needed to be stored and accessed. Nowadays, hard drives having a memory capacity of 120 gigabytes to 500 gigabytes are normally used. Flash Memory This is a non-volatile kind of memory which is intended to contribute to portable torage and a convenient transfer of data from one computer to another. The data in it can be erased and re-programmed as per the user’s requirements. It only has a specific number of erase and write cycles that it can withstand, after which it creates a tendency to lose out on the stored information. Memory cards and USB flash drives These are Just the common and main computer memory types which facilitate memory and data storage. However, there are many subtypes which are sorted out according to the memory-related functionalities they perform and the requirements they serve.

Netw410 Week2

Lab Report 1. What are the business goals? (10 points) Business Goals for this project include addressing the growth of on-campus and online students. To accomplish these goals a centralized server located in new IT wing of the administration building providing online backup of all data. Replacing the PBX-based telephone system with a VoIP based system and connecting all buildings providing high-speed wired network connection for all facility offices will be implemented along with controlled wireless access for students.Wireless access for students and general population will be provided outside the building. These steps are necessary to build a solid infrastructure for the network and allow for and to plan growth. Funding has been established to purchase land 15 miles away and as the campus expands this will be the next site for expansion.The actual business goals for this project is to offer new and better services and support, open the network to key constituents, build relationsh ips and information accessibility to a new level, as a basis for the network organizational model, avoid business disruption caused by network security problems, avoid business disruption caused by natural and unnatural disaster, modernize outdated technologies and reduce telecommunications and network costs, including overhead associated with separate networks for voice, data and video. 2.What are the business constraints? (10 points) The business constraints are like all companies and they include budgets, personnel, policies and schedule. None of which have been defined in our design lab scenario. Budget costs include equipment purchases, software licensing, maintenance agreement and staff training. Personnel constraints related to the business constraints to be considered include the availability of existing trained personnel and if existing personnel must receive additional training to implement and maintain the proposed network changes.Policies of the organization must be cons idered and since this a community college determination of protocols, standards and vendor selection must be determined. The final business constraint addressed should include the schedule of the implementation as not to interfere with current operation by faculty, staff and students. 3. What are the technical goals? (10 points) Technical goals of the project include improving responsiveness and throughput of the network as many users are added along with additional applications, especially the VoIP based system.Simplifying network management is obtained by centralizing the server(s) and backup in a newly built IT wing in the administration building. By this centralization and backup improvement should be obtained to the security and reliability of applications and data along with decreased expected downtime. By offering high speed wired network connections to each faculty office and controlled wireless access for the students modernizing outdated technologies shines as one of the t echnical goals. With all these proposed improvements scalability of the network is achieved. . What are the technical constraints? (10 points) The current system equipment must coexist with the new equipment and as already discovered there must be increased bandwidth. Existing wiring should either be upgraded to accommodate upgraded speeds. The new or expanded network must not interfere with the current applications. Any new network or expanded network should also ensure IPv6 compatibility. 5. Diagram the existing network. (10 points) The actual Visio drawing is also submitted 6. Describe the existing network traffic. (10 points)Current network traffic is at 73% or more utilization based on a five minute average with sustained spikes to 100% on the Cisco FastHub 400s installed in each building. Approximately 42 students are logged into each wireless access point. This is creating lag times and most assuredly dropped packets. While dropping packets with data is troublesome it is disa strous for voice or video. According to our text there should be no shared Ethernet segments that are saturated (no more than 40% network utilization. ) The current system is working at 73% utilization. Network traffic must be improved. 7.Complete this table for all of the applications that currently run over the network. (10 points) Application Name| Type| New or Existing| Criticality| Comments| Google Apps for Education| Email / Web Site| Existing| X| | MS Office| Productivity| Existing| X| | Web Browser (IE)| Productivity| Existing| X| | Catalog / Checkout System / Library| Database| Existing| | Administration Building only| Data Share| Productivity| Existing| X| | Terminal Emulation Program (AS400) | Productivity| Existing| X| Administration Building only| Blackboard Learning | Management System (CRM)| NEW| X| Internet Connection|

Capstone introduction Research Paper Example | Topics and Well Written Essays - 1000 words

Capstone introduction - Research Paper Example There are a number of factors which have affected Africa’s growth and caused it to remain behind. These are as follows; Education Education is the edification of one’s mind with knowledge, skills and even wisdom. In the modern world, education usually takes both formal and informal formats with formal education being the main form of education in today’s world. Despite Africa having a great number of people, most of them young, most of these are not educated. Africa has some of the highest numbers of uneducated and completely illiterate people (Bridges, 2007). Even most of multinational businesses corporations in Africa have to depend on outside countries for experts in different countries. According to Benson, Gospel and Zhu (2013), education is an integral and vital part of the development process. Africa remain the least educated continent, even after the massive missionary work in the previous hundred years which focused on delivering education, healthcare an d religions. Education in Africa is linked with economic prosperity. Only the wealthy can access useful education and only the educated can access wealth. This has left the continent being a continent of one billion extremely poor people and ten thousand billionaires. While the gap between the wealthy and the people is a major concern in almost any economy even in developed countries such as USA and United Kingdom, Africa has the greatest rift between the rich and the poor and this gap has been caused by the education Gap (Curaj, 2012). Most rich people in Africa are those whose families were lucky enough to access education in the pre-colonial era. These were mainly families which sided with colonial masters while the freedom fighters were in the forest fighting for the emancipation of their countries. Freedom fighters and their families never had an opportunity to get education and the wealth-education-wealth cycle never got to them. This has affected the continent ever since. Pol itics Political affects the way a country develops. Good democratic structures help a country to be able to take advantage of its resources and also to be able to help in overcoming its challenges. This is why politics is directly attached to leadership structures. Politicians are at the forefronts of a country’s leadership and therefore affect the way that country is going to develop, or not develop. It goes without saying that Africa is one of the youngest, or constitutes some of the youngest democracies in the world (Obiyan & Amuwo, 2012). In fact, most countries in the African continent can rarely be regarded as democracies. This lack of good political structures perpetuates the issues discussed above. Poor politics means corruption, which will prevent the poor from being able to access resources such as education (Obiyan & Amuwo, 2012). Poor political therefore has helped in maintaining the status quo, which means the maintenance or even expansion of the gap between the rich and the poor in Africa. As Faringer (1991) argues, corruption in many governments in Africa has meant that a few African leaders are prostituting African resources to other countries which mean that African resources only benefit a few already rich African people while the majority continue to suffer. These resources are then exported to other countries where they are used to benefit foreigners. Neo-colonialism Neo-colonialism is termed as a

Motivation in the workplace Essay Example | Topics and Well Written Essays - 500 words

Motivation in the workplace - Essay Example A way to ensure that governmental workers do their jobs correctly is by keeping them motivated. The person responsible to ensure that public servants are motivated is the manager. Managers have to use their people skills and leadership to motivate public workers. A lack of leadership by governmental leaders can lead to disastrous results for a public agency. It is important for managers to always keep the lines of communication open. Communication in the workplace can be enhanced by providing training and development. Active listening skills are also important. A way to motivate public workers is by empowering the staff. â€Å"Empowerment is the process of increasing the capacity of individuals or groups to make choices and to transform those choices into desired actions and outcomes† (Worldbank, 2011). Empowering the employees allows the workers to make more decisions on their own without a manager harassing them over every single detail or decision. A theory of motivation that can be used by the managers of public agencies to improve the motivation of the workers is Maslow’s hierarchy of needs. Maslow’s hierarchy of needs is composed of a pyramid of lower order and higher order needs. The five needs of Maslow’s hierarchy are physiological, safety, social, esteem, and self-actualization. The physiological needs are the most basic of all human needs which include biological maintenance, need for food, water, and substance. To comply with these needs the manager of a governmental institution must provide the employees with a lunch hour and two fifteen minutes breaks, one in the morning and another in the afternoon. There should be a lunch room in the facility with a refrigerator and a water fountain. The safety need deals with the need for security, protection, and stability. This need can be met by the manager of a governmental entity by hiring a security guard to

Philosophy and Religious Belief Essay Example | Topics and Well Written Essays - 750 words

Philosophy and Religious Belief - Essay Example tion of helping humans to be able to deal with aspects of life they are not able to understand, or are afraid of and therefore not entirely necessary for meaningful human existence. There have been all types of explanations for religion. Many professional have written about. For instance, Tolstoy (58), after going through an episode of meaningless of life, concluded that only faith (or religion), can be able to explain life and that only faith can help people to understand life and thus help them have a meaningful life. This argument by Tolstoy seems to prove Freud’s (10), argument about faith; that faith and religion are used by man as a way to deal with the aspects of life they do not understand. In his book, Theism as Illusion, he argues that people ascribe to religious beliefs because it helps them deal with aspects of life they are not able to comprehend or that give them anxiety. He argues that men ascribe to the belief of life after death because they are scared of death. Death is a scary phenomenon for most people because of two main factors. First, the finality of death scares people. Death is not undoable; once it happens, the diseased is gone and gone forever. The second issue about death that may make people want to believe in a second life after death is the fact that they are do not know what happens after it There is no way to know what happens to a person after they die. This finality and unknown nature of death comes as a scare for most humans and therefore the idea of an afterlife acts as a beacon of hope, as a way to overcome death. Almost every religion there is, from the early Egyptian religion to modern Christianity to Hinduism and Islam, believe in an afterlife, even if they do not believe in the same God. The Egyptians took it a little too far by building massive pyramids for their kings in order to immortalize them and thus also immortalize themselves. This may be an indication that religion serves the purpose of assisting people to deal

Cultural Diversity in the Media Essay Example | Topics and Well Written Essays - 2250 words

Cultural Diversity in the Media - Essay Example This paper will take on two parts. The first part will reflect on the portrayal of Jews themselves in media representations of them in relation to the Holocaust, focusing on the wounds wracked by that painful chapter in world history and their responses towards it. It will essentially use history to understand emotion and identity. The second part will take on a more contemporary approach and will look at how Israel is being portrayed in the media today, under the current context of the Middle East Conflict between Israel and Palestine. It will essentially argue that not only is history per se important, but it is also important what kind of history, and there is a need to be critical of how history is framed and deployed. History as tool to understand emotion and identity in media Media representations of Jews particularly during the holocaust have always shown the Jews as filled with so much pain and tragedy. And indeed, it is difficult to understand this if one is not imbued with a historical context. To give an example, we turn to the movie â€Å"Forgiving Doctor Mengele†, which was released in 2006. ... There are four main narratives, which are also the crucial and more dramatic points of the piece: Miriam’s death and the start of Eva’s journey; the interview with Dr. Hans Munch, a former Nazi doctor; a meeting in the West Bank with Palestinian teachers; and the destruction of the museum she built in memory of her sister by neo-Nazi hate-criminals. The documentary gives us situated knowledge, a personal experience of the Holocaust and forgiveness, although its links to larger historical and social facts are diffused and fragmented. It can be said, however, that ‘Forgiving Dr. Mengele’ is a classic Holocaust documentary film, in the sense that is meant to instruct through evidence; it poses truth[s] as a moral imperative1. But what is the media representations embedded in the film? And how does history help us understand these? A core idea being forwarded – by way of providing an example of embedded representations -- is the notion of ‘forgiven ess’, its complexity and multiple dimensions. Indeed, it is noticeable how difficult is to portray what exactly is forgiveness in general, and what is the exact meaning of forgiveness for Eva, as in the debate at the Jewish center in Chicago, where she is "grilled" on the meaning of forgiveness and her right to do so, in the wake of those that continue suffering through the trauma of the acts. There is no way that we can understand the poignant meanings of this scene without having an idea of this painful history that the Jews had suffered. Representing history through film or any other media is always fraught with issues. First of all, it is the question of the limits of the language what Hanna Arendt2 calls the

Assessment Assignment Example | Topics and Well Written Essays - 750 words

Assessment - Assignment Example The NAEP has ensured a variety of adjustments in schools since its inception. To increase its scope of application, the Congress has ensured that NAEP gains popularity by providing facilities required in ensuring that it is fully operational. The National Assessment tool is the preferred tool because of its universality since it can be used to compare methods of teaching alongside comparing performance in almost all parts of the world. NAEP as an assessment tool works under the principle of random selection. When it is used, students from various schools are randomly selected within each state to be part of the assessment. The assessments are often conducted in areas such as reading, science, arts and other disciplines in the United States since it is the region which uses the method mostly. NAEP has been widely used in the United States by the Education Department since 1969 (Jay 177). The major purpose of the assessment is to enable education policy makers, parents and the media to analyze students’ progress in various subjects so that deductions can be made to improve the education system or general classroom performance. During the assessment, not all the students are engaged in the process. Only selected students are chosen for participation to act as sample. The sample of students are picked from all public schools in the US and non public schools because the major aim is to enable all students demonstrate in depth knowledge and skills learnt by performing numerous scale scores. The National Assessment of Educational Progress is probably one of the best assessment tools in the world. It reports data results for the entire country hence enables the government compare results for the states against the results of the entire country. The trend of the results which is used nationally to compare academic progress of students between the ages 9 to about 17 are often reported at the state level rather than at school or individual level in order to avoid a situation where schools are competing for grades. One advantage of using this method as an assessment tool is that biasness is reduced because of the fact that random selection is used in assessment. The random selection ensures that no state school whether public or non public gain more advantage over the other. The results are not printed for the schools or individuals. This makes the assessment tool the best method and tool in conducting assessment since it avoids biasness and eliminates rivalry due to the fact that there is no competition involved (Ryan &Shepard 227). During the process of conducting the assessment, it is not just based on short and prolonged responses; rather, other methods used also include multi choice and oral method applications. The results of the assessment tool are compiled by the Education Department in states in the entire nation to compare the results of the students in both public and private schools. Such results are compiled using tables or scalab le vector graphics stored as slides in soft copy or printed in hard copy. Other than trying to compare results for each school within one academic year, it can be used to compare changes in performance of students from one year to the other. The results can be shown or reported using maps. After the release of the results, they can as well be used when doing analytical procedures that will help in improving the

Public relations Essay Example | Topics and Well Written Essays - 2500 words

Public relations - Essay Example Jacquie L’Etang, the leading British theorist of PR, describes this situation in his â€Å"Public Relations and the Rhetorical Dilemma† publication. He emphasises that â€Å"public relations needs more public relations to increase public understanding of its role in society† (L’Etang 34). Public relations are seldom referred to in a positive way in the media. This concept is typically defamed as a mere propaganda and industry of spin which is busy trading in deceitful information and lies (Miller, 2003). Others publicly acknowledge the pragmatic mission of PR by saying that it is just an art of getting material into the press without paying for it, specifically, â€Å"the art of getting favourable coverage without paying for it† (â€Å"How to Get Free Publicity†). These approaches seem to be widely applied when the public needs to be manipulated against a certain governmental or corporate project. PR is announced pure propaganda and spin and the message is quickly dismissed. At the same time, while PR gets frequently referred to as spin or propaganda, this understanding of the phenomenon is one-sided and obviously lacks objective consideration. To make matters worse, this understanding is too simplistic and conceals the essential component of PR. Namely, PR is targeted not just at corporate interest advocacy, but at the advocacy of public interest, too. Apparently, the simplified interpretation of PR prevents public from realizing how PR makes up a part of normal information management practice in democracies and its role in getting public support for some practices that are beneficial for the general public as well as businesses. By drawing on contemporary critical sources on PR, our aim is to adequately examine the work of a PR practitioner, explore the sphere of PR objectives, compare the views of critics and advocates of public relations, and discuss ethical considerations in today’s PR. In addition, this pap er attempts at producing a new objective understanding of PR and its role in modern society. It has already been mentioned that critics of PR generally refer to it as propaganda or spin. Propaganda in this respect has a clearly negative connotation and gets perceived as a pejoratively loaded concept. While it was not so in the distant past (research shows that propaganda was a term used to speak about contributing much into mobilization of the general public opinion), the term propaganda started to be applied differently after the World War I. In the period of lost ideals and widespread disillusionment, propaganda began to be seen as a tool of democracy advocacy (Tye 94). For instance, Edward Bernays considered propaganda important for democracy functioning because it advocates the developments in governmental policies or some new approaches in business. In the following years, the concept of propaganda developed even more to denote psychological manipulation of the audience by the repetition of a few simple points. In this case, the audience was perceived as a passive receiver and as â€Å"a vulnerable and persuadable lot at risk from propaganda† (Brooker & Jermin 5). Understanding public relations in terms of propaganda reduces PR to â€Å"the deliberate and systematic attempt to shape perceptions, manipulate conditions, and direct the behaviour and achieve the response that furthers the desired intent of the propagandist† (Jowett & O’Donnell 4). The propagandistic underpinnings of PR were formulated by Lasswell (1995) and other scholars accepting

Hunger in Africa Research Paper Example | Topics and Well Written Essays - 1500 words

Hunger in Africa - Research Paper Example Most of the countries which are intensely affected by the hunger crisis are West Africa, South Sudan, East Africa, Mali, Burkina Faso, Niger, Mauritania, Chad, Senegal etc (â€Å"Fighting Hunger in Africa†). Currently, Africa is still suffering from this kind of crisis among its people and is still having difficulty in resolving this never ending issue. Thus, this paper aims to discuss the hunger in Africa and the major causes on why until now the countries in this continent still starve to death. However, due to the wide scope of the topic hunger in Africa, this paper only limit to the effects of hunger among children. Hunger in Africa Hunger can cause series of health problems and nutritional deficiencies if a person failed to eat sufficient amount of food intake in a daily basis. These mainly include malnutrition, stunting, underweight, undernourishment, and worst death (â€Å"Hunger†). Children are at higher risk acquiring these health conditions due to their vulner ability and low immunity. In Africa, there are about 227 million people suffering from famine and severe malnutrition. According to the New Partnership for Africa’s Development (Nepad), in every minute, 12 people die in Africa because of extreme hunger (Chiumia). Most of these hungry individuals are situated in rural areas in which their means of livelihood is agriculture and has no any alternative sources of income which made them highly vulnerable to crisis like hunger (â€Å"Hunger†). For instance, in West Africa, a number of African families had been experiencing starvation due to lack of food sources to suffice the needs of their hungry stomachs because of insufficient rainfall and failed crops. Food and even water shortage brought individuals to extreme hunger and acute malnutrition specifically children who, at their age, highly need enough food and nutrition for them to grow healthy and well-nourished. However, reports had shown that families in countries of Af rica can hardly give their family member enough food to eat everyday because of extreme poverty, high food prices, and droughts on their farms (â€Å"West Africa Child Hunger†). If not given immediate solution, malnutrition rate in Africa among individuals particularly children will grow. As a result, the immune system of children will weaken due to poor nutrition permitting them towards acquiring diseases which might kill them if treated right away. These mainly include pneumonia, malaria, and diarrhea (â€Å"Fighting Hunger in Africa†). In Niger, absenteeism rate among children in school is relatively high. Half of the class had been absent due to their intense desire to help their parents to earn a living. These children are forced to work at an early age upon seeing that their parents can no longer give them enough amount of food everyday due to poverty. Hence, they prefer to be absent in school than to let their family members starve to death. As a consequence, th ey took for granted their chances to have a better lives in the future through education and also, their right had been exploited due to child labor (â€Å"West Africa Child Hunger†). However, we cannot blame these children for their actions because what they are doing are for the benefit and survival of their families in a day to day basis. On the other hand, South Sudan is considered to have the highest child/infant mortality rate and has the

Social Illness - Islam Is the Best Solution Essay Example for Free

Social Illness Islam Is the Best Solution Essay If Maher Zain stands on the stage to praise the Almighty in his song , If Datuk Dr. Fadzillah Kamsah gives his powerful words to motivate us but me , will deliver you a nice speech as it is also a good reminder to us entitled ‘Islam as the best solution for social illness’. First and foremost , I bid you Assalamu Alaikum Warahmatullahi Wabarakatuh to the honourable judges , the punctual timekeeper , teachers and fellow friends . Please lend me your ears on this delightful morning . Let me define first the meaning of social and illness . According to Oxford Dictionary defines social as activities in which people meet other for pleasure . While , illness is the state of being physically or mentally ill. So, social illness can be noted as the illness or the problems created by the human kind in the society related to the immoral behaviour. Members of the floor , On the 4th June 1981 people throughtout the world have been surprised with the presence of new virus which is known as HIV . Althought the virus has killed about millions of people in this world , scientist still cannot find any vaccine to treat this problem . However , how many of us are trying to find the vaccine for the virus of social ills, although it has been spread widely since hundred years ago ? It is possible if we have found the vaccine for social ills before the black day , 4th June 1981 ; the HIV may not spread throughout this world . This is because the HIV virus had been firstly detected from a couple of homosexual in America . A popular saying goes . , ‘’ it is as well to know which ways the winds blows ‘’ , as it is better to know first the cause of the social illness before we eagerly take precautions steps . For my view, lack of religious education among Malaysians is the underlying factor for this problem as we knew that none of the religions in this world ask their follower to be a bad person . It is important to gives religious education to our children as early as 3 or 4 years old as there goes a saying ‘‘ spare the rod and spoil the child ’’, the children who are never been disciplined will grow up to be bad . It is definitely wrong if modernism parents think that religious education is not important in order to create a shining future for their children as religious education is like a barrier in their heart to prevent them from doing something bad such as playing truant . Members of the floor , Other that that, it is believed that family crisis is one of the main factors for the disease . The children will be so depressed with the problem and they will do ‘something’ to release their tension . Majority parents from this kind of family are usually not taking care much on their children’s situation as they are more preferring to solve their own problems . The children felt free to do anything without parental concerned sich as clubbing and racing . This is not good for them as they may meet more bad companies that can lead them to worst social problems . Last but not least , this problem is also caused by the peer factor. In 24 hours a day , the children spent their time more with their peers than with others and that is why peers have great influence in their children’s behavior . As teenagers are too young , sometimes they cannot consider their decision correctly . They will follow all their peers’ behavior even they know their peers are not good ones as they think that their peers will exclude them if they do not follow what their peers do. To round off , the social ills in Malaysia are getting worse to worst nowadays. As you can see here , I keep focusing on their children and teenagers in Malaysia as the number of social ills gradually increasing among them . We , as the future leader of our mother land should take all the necessary steps to solve this problem. It is our responsibility to produce the free-social-ills-next-generation . Remember , ‘’preventing is better than cure ’’. With that I end my speech with Wa billahi Taufiq Wal hidayah Wassalamu Alaikum wbt . Thank you .

Aetiology of Gestational Diabetes Mellitus

Aetiology of Gestational Diabetes Mellitus 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 cardi ovascular 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 resista nce 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 th e 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. (Catala no 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 resistant may inher it 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 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 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 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 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, th e 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 fe tus (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 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 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 (Rizza et a l 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 supp ort 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 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 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 (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 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 differe nces 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 pregnan cy 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 l ater 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 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 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 20 Aetiology of Gestational Diabetes Mellitus Aetiology of Gestational Diabetes Mellitus 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 cardi ovascular 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 resista nce 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 th e 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. (Catala no 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 resistant may inher it 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 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 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 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 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, th e 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 fe tus (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 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 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 (Rizza et a l 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 supp ort 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 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 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 (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 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 differe nces 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 pregnan cy 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 l ater 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 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 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 20

The Underground Railroad :: essays research papers

The Underground Railroad One of the most shameful periods in history was the institution of slavery in the nineteenth century 2. Slavery was a divided issue in the 1800’s. Most slaves brought to America were known as low class people who could bring no good, but history fails to state that many of the slaves who came were people of many trades, ambitions, as well as determinations. The Underground Railroad had its earliest beginnings with runaway slaves fleeing from the Southern United States into Canada. By confronting human bondage without direct demands or violence, the Underground Railroad played a definite role in the destruction of slavery. The Underground Railroad was a term used to describe a network of people who helped escaped slaves on their way to freedom. Supposedly, the term Underground Railroad originated when an enslaved runaway, Tice Davids, fled from Kentucky and may have taken refuge with John Rankin, a White abolitionist, in Ripley, Ohio. Determined to retrieve his property, the owner chased Davids to the Ohio River, but Davids suddenly disappeared without a trace, leaving his owner confused and wondering if the slave had "gone off on some underground road." The Railroad was begun as a result of the Fugitive Slave Act of 1850 2. The Fugitive Slave Act demanded that if an escaped slave was sighted, he or she must be turned in and sent back to the rightful owner 2. The Nation grew divided on the slavery question. The Fugitive Slave Law called for the return of bonded and indentured runaways, as well as freed African Americans. This threatened the protection of the freed slaves. Many North American indentured slaves were freed after they had served their time after five to seven years 6. Most runaways were males, however women and children did escape. Their numbers were smaller because they were more likely to be captured. Yet, The Underground Railroad became the most dramatic protest action against slavery in United States history 2. The Railroad helped escaped slaves make their way from the Southern states through the northern states, into freedom. The Underground Railroad was operating in America, yet it was not a railroad and was not underground. This â€Å"railroad† was for blacks escaping from slavery in the South. They were escaping to the free North, and to Canada where there was no slavery at all. The Underground Railroad lacked in formal organization, relying on individuals or various groups. The Underground Railroad :: essays research papers The Underground Railroad One of the most shameful periods in history was the institution of slavery in the nineteenth century 2. Slavery was a divided issue in the 1800’s. Most slaves brought to America were known as low class people who could bring no good, but history fails to state that many of the slaves who came were people of many trades, ambitions, as well as determinations. The Underground Railroad had its earliest beginnings with runaway slaves fleeing from the Southern United States into Canada. By confronting human bondage without direct demands or violence, the Underground Railroad played a definite role in the destruction of slavery. The Underground Railroad was a term used to describe a network of people who helped escaped slaves on their way to freedom. Supposedly, the term Underground Railroad originated when an enslaved runaway, Tice Davids, fled from Kentucky and may have taken refuge with John Rankin, a White abolitionist, in Ripley, Ohio. Determined to retrieve his property, the owner chased Davids to the Ohio River, but Davids suddenly disappeared without a trace, leaving his owner confused and wondering if the slave had "gone off on some underground road." The Railroad was begun as a result of the Fugitive Slave Act of 1850 2. The Fugitive Slave Act demanded that if an escaped slave was sighted, he or she must be turned in and sent back to the rightful owner 2. The Nation grew divided on the slavery question. The Fugitive Slave Law called for the return of bonded and indentured runaways, as well as freed African Americans. This threatened the protection of the freed slaves. Many North American indentured slaves were freed after they had served their time after five to seven years 6. Most runaways were males, however women and children did escape. Their numbers were smaller because they were more likely to be captured. Yet, The Underground Railroad became the most dramatic protest action against slavery in United States history 2. The Railroad helped escaped slaves make their way from the Southern states through the northern states, into freedom. The Underground Railroad was operating in America, yet it was not a railroad and was not underground. This â€Å"railroad† was for blacks escaping from slavery in the South. They were escaping to the free North, and to Canada where there was no slavery at all. The Underground Railroad lacked in formal organization, relying on individuals or various groups.