Genetic Basis of Diabetes - Report Example

Running head: Diabetes Genetic Basis of Diabetes of the disease Diabetes is known to be a heterogeneous disorder which has characteristics of persistent hyperglycemia. There are two major types of diabetes that include type 1 diabetes previously referred to as insulin-dependent diabetes and type 2 diabetes previously referred to as non insulin-dependent diabetes. These types of diabetes are known to be caused by a combination of environmental and genetical risk factors. However, we have other diabetes rare forms that are seen to be inherited directly. They include diabetes that result from mutations in the mitochondrial DNA and ‘‘maturity onset diabetes in the young’’ (MODY). All diabetes forms are known to have a drastic impact on health besides the effects related to abnormal glucose metabolism (e.g., protein glycosylation, hyperlipidemia). A number of diabetes related complications which are long term do exist. They include renal, ocular, peripheral vascular and neurologic cardiovascular abnormalities, and they are associated to premature death, disability and morbidity in young adults. More so, the disease is linked to reproductive complications that have an effect on both the mothers together with their children. Despite improved glycemic control that is able to reduce the risk of developing complications such as these; diabetes is still seen to be a very significant cause of psychological, financial and social burdens globally (Bell and Polonsky 2001). History of the disease Diabetes has been recognized for over 2000 years for being a deadly and devastating disease. In the 1st century A.D. Aretaeus, a Greek described the destructive nature of the disease whereby he named it as ‘‘diabetes.’’ This was from a Greek word ‘‘siphon’’ (Bell and Polonsky 2001). In the ancient times, physicians such as Aretaeus, recognized the diabetes symptoms but never had the capacity of treating it effectively. In this case, Aretaeus had to recommend roses’ oil, gruel, raw quinces and dates. Also as late as 17th centuary, doctors were seen to prescribe broken red coral, gelly of vipers flesh, fresh blind nettles flowers and sweet almonds (Bell and Polonsky 2001). Molecular biology of the genes involved and biology of the gene products Type 2 diabetes genetic basis is known to be complicated to resolve. On the other hand, type 1 diabetes is associated with an autoimmune process. In this case, type 2 diabetes is a relative disease but not insulin deficiency. In this regard, the pancreatic β cells progressively changes to a level that they won’t secrete enough insulin that will be able to maintain normal lipid and carbohydrate homeostasis (Bell and Polonsky 2001). In addition, insulin resistance is experienced and is coupled with obesity, the aging effects as well as reduced exercise (Saltiel and Kahn 2002). Furthermore, the genetic contribution to type 2 diabetes is seen to be less as compared to that of type 1 diabetes, which has a general genetic risk ratio that ranges from 2 -4 (Weijnen et al.,2002).Although there is a relatively low type 2 diabetes genetic risk ratio, various genome wide scans results have indicated several chromosomal regions that could harbor genes associated with the type 2 diabetes, there has been study findings on chromosomes 12q24, 2q37 and 1q21-q24 (Demenais et al.,2003). The study done to link type 2 diabetes Mexican American to chromosomes 2q37 (Demenais et al.,2003) resulted to the susceptibility variants classification in the CAPN10 gene (Ozcan et al., 2004). Various type 2 diabetes genes are known to have been identified through candidate genes investigation. Variants which influence insulin signaling via glucose homeostasis, PTPN1 and IRS-1 (Ozcan et al., 2004) tend to be frequently less. This implies that a combination of common and rare variants contribute to risk related to type 2 diabetes in various pathways observed in different population. There are hundreds of pathways that have been studied in animals with diabetes. In this case, one pathway was isolated referred to as ATP/P2X7R, which has the capacity of triggering the T-cell to attack the pancreas, making them unable to generate insulin. Through the identification of this pathway for being the early mechanism in the body which fires allo-immune response, it resulted to the finding of the root cause of diabetes. In this case, the focus could be on the treatment options. Everything that include transplant to drug therapies that need less immunosuppression is being explored. Molecular biology of the pathogenesis of the disease HNF4A ( hepatocyte nuclear factor 4- α): Mutations that occur in HNF4A gene’s coding and promoter regions results to MODY1. HNF4A is known to be expressed in most tissues that include the pancreas and liver. It has a function of regulating the expression of hepatic gene as well as influencing other MODY genes expression like HNF1A that results to MODY3. It is known to activating the expression of insulin gene directly in the pancreas beta cell. Mutations that occur in the HNF4A gene have been as well linked to the type 2 diabetes (Silander et al., 2004). HNF1A(hepatocyte nuclear factor 1- α):Mutations that occur in this HNF1A gene are known to be the significant cause of the disease(MODY3).This gene is expressed in the pancreas and the liver. This gene is as well seen to influence the expression of HNF4A.In this case; it shows a relationship between the MODY3 and MODY1.This means that the MODY transcription factors can create a regulatory network that has the capacity of maintaining the glucose homeostasis. Besides causing MODY3, mutations in the HNF1A gene have been linked to type 1 diabetes (Moller et al., 1998) as well as type 2 diabetes (Pearson et al., 2004). UIPF1 (Insulin promoter factor-1): The mutations in this gene results to MODY4, a disease known to be rare. Homozygosity for these particular mutations has been linked to neonatal diabetes as well as to newborn pancreatic genesis. In this regard, infants with such mutations seem to be small for gestational age. People who have MODY4 could as well develop type 2 diabetes (Cockburn et al., 2004).IPF1 is known to regulate the expression of insulin, glucokinase as well as other genes that are involved in the metabolism of glucose. UHNF1B(hepatocyte nuclear factor 1- β).Mutations in this gene results to MODY5,a disease that has been with MODY1 due to this gene normally regulate HNF4α.MODY5 is also known to be linked with renal cysts, renal failure and proteinuria Current Treatments Currently, it is not possible to prevent type 1 diabetes. Insulin injections that are life-long are seen to be the only treatment available for the disease. Hence, currently, genetics doesn’t play any role in the prevention or treatment of type 1 diabetes. Despite a cure for type 1 diabetes is not available currently; there are various big multi-national investigations that have been designed in order to evaluate various secondary and primary disease interventions (Devendra et al., 2004).The interventions which have been tested include prophylactic nasal insulin. It is highly expected that through genetic testing, people with high chances of getting the disease, type 1 diabetes would be identified before the onset of the disease; in this case, there could be the administering of primary prevention strategies safely. It is most likely that such predictive genetic testing would be offered to families with an affected individual before it is made available to the general population. Unlike type 1 diabetes, type 2 diabetes can basically be prevented through physical activity as well as maintaining an appropriate body weight. Despite the messages from public health that puts more emphasis on regular physical activity and a nutritious diet to be adopted, there has not been an impact in relation to the prevention of the disease. In relation to the recent epidemic of obesity, it is clearly evident that the current intervention strategies are not being taken into consideration by most people in the general population. Future Treatment The prediction made by the concerned parties of Human Genomic Project is that the genetic tests could be available for several common disorders in the first 21st century. This could allow people to be able to know their susceptibility to the disease and be able to take corrective measures to reduce the risks related to the disease (Collins and McKusick, 2001). Furthermore, we have several companies providing genetic susceptibility testing, which could be ordered online by any person having problems like obesity and cardiovascular disease (Khoury et al., 2004). Before the drug makers managed to manufacture human insulin, they were using insulin from cows and pigs in the treatment of diabetes. For instance, scientists from Washington University, School of medicine opted to know if pancreatic cells from pigs could manufacture insulin when transplanted in humans. In their experiment, they transplanted the pig’s cells to monkeys. The conclusion made was that despite it never cured diabetes in the monkey, they believed that more cells transplant could actually provide cure. The most unique aspect of this diabetes treatment research was that cell transplantation required no immune suppression drugs needed together with the transplant of the whole organism. Research on humans is in the planning stage. This is one of the several diabetes cure and treatment project underway. Everything that include transplant to drug therapies that need less immunosuppression is being explored (Lee etal., 2000). In regard to gene therapy (insulin), it can be taken into consideration just like any other approach that involves foreign gene introduction into the cells of the body. In this case insulin could be produced. The introduced gene might be insulin gene itself, and probably under the control promoters that are tissue specific (Lee etal., 2000) This can allow the expression of insulin in a non-beta cells types or a gene that encodes a factor that is able to activate the insulin gene. Therefore, this will allow the production of ectopic insulin. The stem cell differentiation induction into the beta cells through molecular intervention could be included in such gene therapy (Demeterco et al., 2001) Bibliography Bell GI, Polonsky KS(200). Diabetes mellitus and genetically programmed defects in beta-cell function. Nature 414: 788 –791 Cockburn, B.N., Bermano, G., Boodram, L.-L.G., et al.(2004). Insulin promoter factor-1 mutation and diabetes in Trinidad: identification of a novel diabetes-associated mutation (E224K) in an Indo-Trinidadian family. J Clin Endocrinol Metab,. 89: 971-978. Collins, F.S., McKusick, V.A. (2001). Implications of the Human Genome Project for medical science. 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Mutations in the hepatocyte nuclear factor-1a gene in Caucasian families originally classified as having type 1 diabetes. Diabetologia,. 41: 1528-1531. Ozcan U, Cao Q, Yilmaz E, Lee AH, Iwakoshi NN, Ozdelen E, Tuncman G, Gorgun C, Glimcher LH, Hotamisligil GS(2004). Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 306 : 457 –461 Pearson, E.R., Badman, M.K., Lockwood, C., et al (2004). Contrasting diabetes phenotypes associated with hepatocyte nuclear factor-1a and -1B mutations. Diabetes Care,. 27: 1102-1107. Saltiel AR, Kahn CR (2002). Insulin signalling and the regulation of glucose and lipid metabolism. Nature 414 : 799 –806 Silander, K., Mohlke, K.L., Scott, L.J., et al (2004). Genetic variation near the hepatocyte nuclear factor-4a gene predicts susceptibility to type 2 diabetes. Diabetes,. 53: 1141-1149. Weijnen CF, Rich SS, Meigs JB, Krolewski AS, Warram JS(2002).Risk of diabetes in siblings of index cases with type 2 diabetes: Implications for genetic studies. Diabet Med 19 : 41 –50 Read More