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Genetic Basis Of Type 1 Diabetes

Genetic Causes Of Diabetes Mellitus Type 1

Genetic Causes Of Diabetes Mellitus Type 1

At least 20 different chromosomal regions have been linked to type 1 diabetes (T1D) susceptibility in humans, using genome screening, candidate gene testing, and studies of human homologues of mouse susceptibility genes. Responsible genes[edit] The largest contribution to the pathogenesis of Type 1 Diabetes comes from a single locus called IDDM1, which comes from several genes located in the Major histocompatibility complex on the 6p21.3 chromosome. This is believed to be responsible for at least 40% of the disease's familial aggreagation. Additionally, nearly 30% of Type I Diabetes patients are heterozygous for several HLA-DQ2 (specifically HLA-DQ2/DQ8) alleles. However, the HLA-DQ6 allele (HLA-DQA1*0102–DQB1*0602), if dominant, is responsible for partially preventing an organism from developing the disease. Therefore, these genetic features can be used to determine a patient's relative risk of developing the disease. Further discussion and research of the functional genomics of the pathogenesis of Type 1 Diabetes will be necessary in future studies in this field. See also[edit] Diabetes mellitus type 1 [edit] Continue reading >>

Immunologic And Genetic Factors In Type 1 Diabetes*

Immunologic And Genetic Factors In Type 1 Diabetes*

Under normal physiologic conditions, the entry of glucose into beta cells triggers the secretion of insulin (1) (Fig.1). The released insulin is carried in the blood to peripheral tissues where it binds to insulin receptors, which are members of the receptor tyrosine kinase family. This initiates a cascade of transmembrane events resulting in the uptake of glucose by cells and its metabolism into energy or storage as glycogen (2). Figure 1 Insulin release and action. Glucose enters beta cells via the glucose transporter (GLUT2) and ATP is generated by glycolysis. This results in closure of ATP-sensitive K+ channels, depolarization of the plasma membrane, and opening of voltage-dependent Ca2+ channels. The influx of Ca2+ leads to the release of insulin (1), which is carried in the bloodstream to cells throughout the body where it binds to insulin receptors. This results in autophosphorylation of insulin receptors and phosphorylation of tyrosines on a variety of cellular proteins including members of the insulin receptor substrate (IRS) family and Cbl-CAP (2). The phosphorylated proteins provide docking sites for SH2 domains of several proteins (e.g. phosphatidylinositol 3-kinase (PI(3)K); Grb2 and SHP2; and Crk) that activate different signaling pathways (dashed lines). This results in translocation of the glucose transporter (GLUT4) and uptake of glucose by the cell; alterations in glucose, lipid, and protein metabolism; and changes in gene expression and cell growth. Defects anywhere along the beta cell-peripheral tissue pathway can result in hyperglycemia, but at the clinical level there are two major forms of diabetes: type 1 diabetes, previously known as juvenile or insulin-dependent diabetes, and type 2 diabetes, previously known as adult or non-insulin-dependent d Continue reading >>

The Genetic Architecture Of Type 1 Diabetes

The Genetic Architecture Of Type 1 Diabetes

Open Access Abstract : Type 1 diabetes (T1D) is classically characterised by the clinical need for insulin, the presence of disease-associated serum autoantibodies, and an onset in childhood. The disease, as with other autoimmune diseases, is due to the interaction of genetic and non-genetic effects, which induce a destructive process damaging insulin-secreting cells. In this review, we focus on the nature of this interaction, and how our understanding of that gene–environment interaction has changed our understanding of the nature of the disease. We discuss the early onset of the disease, the development of distinct immunogenotypes, and the declining heritability with increasing age at diagnosis. Whilst Human Leukocyte Antigens (HLA) have a major role in causing T1D, we note that some of these HLA genes have a protective role, especially in children, whilst other non-HLA genes are also important. In adult-onset T1D, the disease is often not insulin-dependent at diagnosis, and has a dissimilar immunogenotype with reduced genetic predisposition. Finally, we discuss the putative nature of the non-genetic factors and how they might interact with genetic susceptibility, including preliminary studies of the epigenome associated with T1D. 1. Introduction The aetiology of Type 1 diabetes (T1D), like most common chronic diseases, is complex and results from the interaction of genetic and environmental factors. That interplay takes place in a sequence that is true for all autoimmune diseases, and encompasses genetic susceptibility, tissue inflammation, and clinical disease [1,2]. This sequence is characterised by a diminished risk of progression at each transition, with more subjects having genetic risk (roughly 20%) than have inflammation (roughly 14%), and more having inflam Continue reading >>

Genetic And Epigenetic Factors In Etiology Of Diabetes Mellitus Type 1

Genetic And Epigenetic Factors In Etiology Of Diabetes Mellitus Type 1

Abstract Diabetes mellitus type 1 (T1D) is a complex disease resulting from the interplay of genetic, epigenetic, and environmental factors. Recent progress in understanding the genetic basis of T1D has resulted in an increased recognition of childhood diabetes heterogeneity. After the initial success of family-based linkage analyses, which uncovered the strong linkage and association between HLA gene variants and T1D, genome-wide association studies performed with high-density single-nucleotide polymorphism genotyping platforms provided evidence for a number of novel loci, although fine mapping and characterization of these new regions remains to be performed. T1D is one of the most heritable common diseases, and among autoimmune diseases it has the largest range of concordance rates in monozygotic twins. This fact, coupled with evidence of various epigenetic modifications of gene expression, provides convincing proof of the complex interplay between genetic and environmental factors. In T1D, epigenetic phenomena, such as DNA methylation, histone modifications, and microRNA dysregulation, have been associated with altered gene expression. Increasing epidemiologic and experimental evidence supports the role of genetic and epigenetic alterations in the etiopathology of diabetes. We discuss recent results related to the role of genetic and epigenetic factors involved in development of T1D. The Editorial Board of the Section on Pediatric Trainees Monthly Feature is proud to feature an article by Dr Kavitha Selvaraj, who suggests that the effects of toxic stress can be combated through the development of physician–teacher partnerships. Her article concluded our series of featured essays on the Advocacy Campaign for 2016–2017. Catherine Spaulding, MD, Editor, Pediatrics, Continue reading >>

The Genetic Basis For Type 1 Diabetes

The Genetic Basis For Type 1 Diabetes

Type 1 diabetes (T1D) is characterized by autoimmune destruction of insulin-producing β-cells in the pancreas resulting from the action of environmental factors on genetically predisposed individuals. The increasing incidence over recent decades remains unexplained, but the capacity of identifying infants at highest genetic risk has become an increasing requirement for potential therapeutic intervention trials. Literature searches on T1D and genes were carried out, and key papers since the 1970s were highlighted for inclusion in this review. Early genetic studies identified the most important region for genetic susceptibility to T1D—the human leukocyte antigen genes on chromosome 6; later shown to contribute approximately half of the genetic determination of T1D. The other half is made up of multiple genes, each having a limited individual impact on genetic susceptibility. Continue reading >>

Which Type Of Diabetes Is More Likely To Be Inherited And Why?

Which Type Of Diabetes Is More Likely To Be Inherited And Why?

Yahoo!-ABC News Network | 2018 ABC News Internet Ventures. All rights reserved. Which Type Of Diabetes Is More Likely To Be Inherited And Why? DIRECTOR OF THE DIVISION OF ENDOCRINOLOGY, UNIVERSITY OF MARYLAND SCHOOL OF MEDICINE Question: Which type of diabetes is more likely to be inherited and why? Answer: Type 1 diabetes typically occurs in childhood, while type 2 diabetes usually develops in adults. However, some adults develop a form of diabetes that looks very similar to type 1 diabetes, and now with the huge increase in obesity, many children and adolescents are getting type 2 diabetes. Now, both type 1 and type 2 diabetes have a genetic component; that means of course, that they tend to run in families. However, we often regard diseases that develop in childhood as being more likely to be due to genetics. But this is not the case for diabetes, and in fact, studies show that type 2, which mostly commonly develops in adulthood, seems to have a greater genetic basis than the childhood form of type 1 diabetes. For example, as you know, identical twins share 100 percent of their genetic material; however, if one twin has type 1 diabetes, the chance of that the other twin will develop it is only 10 to 20 percent. In contrast, if one twin has type 2, or the adult form of diabetes, the other twin has up to a 90 percent chance of developing type 2 diabetes. In type 2 diabetes, we know that overeating and lack of physical activity are very important contributors. Meanwhile, for type 1 diabetes, it's more the exposure to toxins in the environment, possibly viruses, and other external factors that can increase risk to this form of diabetes. Continue reading >>

Genetic Discovery May Help Better Identify Children At Risk For Type 1 Diabetes

Genetic Discovery May Help Better Identify Children At Risk For Type 1 Diabetes

Follow all of ScienceDaily's latest research news and top science headlines ! Genetic discovery may help better identify children at risk for type 1 diabetes Medical College of Georgia at Augusta University Six novel chromosomal regions identified by scientists leading a large, prospective study of children at risk for type 1 diabetes will enable the discovery of more genes that cause the disease and more targets for treating or even preventing it. Six novel chromosomal regions identified by scientists leading a large, prospective study of children at risk for type 1 diabetes will enable the discovery of more genes that cause the disease and more targets for treating or even preventing it. The TEDDY study's international research team has identified the new gene regions in young people who have already developed type 1 diabetes or who have started making antibodies against their insulin-producing cells, often a precursor state to the full-blown disease that leads to a lifetime of insulin therapy. Their analysis of 5,806 individuals published in the Journal of Autoimmunity also confirmed three regions already associated with one of those related conditions. "We want to build a more precise profile of who will get this disease and when," says Dr. Jin-Xiong She, director of the Center for Biotechnology and Genomic Medicine at the Medical College of Georgia at Augusta University, principal investigator of TEDDY's Georgia/Florida site and the study's corresponding author. In keeping with their theory that two subtypes of type 1 diabetes will become clear from longitudinal studies of those at risk, the international TEDDY team also found different chromosomal regions were associated with which autoantibody shows up first in a patient, a sign his immune system is turning on h Continue reading >>

11111 Fact Sheet 48|diabetes Types 1 And 2 And Inherited Predisposition

11111 Fact Sheet 48|diabetes Types 1 And 2 And Inherited Predisposition

 WHAT IS DIABETES? Diabetes mellitus (commonly known as diabetes) refers to a group of conditions which cause high levels of glucose (a form of sugar) in the blood. Glucose provides the energy that cells need to function. The level of glucose in an individual’s blood is carefully regulated by the hormone insulin. Insulin is produced in the pancreas and its role is to keep the levels of glucose balanced - not too high and not too low - as both extremes are dangerous and can disrupt the body’s chemical processes. There are two major forms of diabetes:  Type 1 (insulin dependent diabetes mellitus: IDDM)  Type 2 (non-insulin dependent diabetes mellitus: NIDDM). There is also another rarer type of diabetes called mature onset diabetes of the young (MODY). All of these forms of diabetes have different symptoms and a different genetic basis. Type 1 diabetes (IDDM) Type 1 diabetes is a chronic autoimmune disease, where the immune system destroys the insulin- producing cells of the pancreas. About 10% to 15% of people with diabetes in Australia have type 1 diabetes. The general population risk for developing type 1 diabetes is around 1 in 1000. The condition is usually first seen in childhood or adolescence and so is sometimes called juvenile diabetes. The risk of type 1 diabetes in 0-14 year olds around 1 in 750. It can, however, occur at any age and onset after the age of 20 years occurs in 50% of cases. Symptoms include:  thirst  frequent urination  weight loss  fatigue  blurred vision  sugar in the urine Insulin medication (usually by injection) is necessary to provide the body with insulin, and thus type 1 diabetes is described as insulin- dependent diabetes (IDDM). In about 90% of cases, individua Continue reading >>

Genetics Of Diabetes And Its Complications

Genetics Of Diabetes And Its Complications

Genetics of Diabetes Type 1 diabetes is the third most prevalent chronic disease of childhood, affecting up to 0.4% of children in some populations by age 30 yr, with an overall lifetime risk of nearly 1% (1,2). It is believed that a large proportion of cases of type 1 diabetes result from the autoimmune destruction of the pancreatic β cells, leading to complete dependence on exogenous insulin to regulate blood glucose levels (3). Type 1 diabetes is strongly clustered in families with an overall genetic risk ratio (the prevalence in siblings of a proband relative to the population prevalence, λS) of approximately 15 (4). (This compares with the less familial but more prevalent type 2 diabetes with λS of approximately 2). At least one locus that contributes strongly to this familial clustering resides within the MHC on chromosome 6p21, which accounts for nearly 40% of the observed familial clustering of type 1 diabetes, with a locus-specific genetic risk ratio (λS) of approximately 3 (5). In a recent analysis of data from three previous genomewide scans (United States, United Kingdom, and Scandinavia) as well as new families collected for the Type 1 Diabetes Genetics Consortium (1435 multiplex families provided evidence for linkage of type 1 diabetes to the MHC (IDDM1), insulin (INS, IDDM2), a region that contains several genes, including CTLA4 (2q31-q33 [IDDM12 and IDDM7]) and seven other chromosome regions (6). The genetic basis for type 2 diabetes has been difficult to resolve. Unlike type 1 diabetes, in which there seems to be an autoimmune process, type 2 diabetes is a disease of relative rather than absolute insulin deficiency. In type 2 diabetes, the pancreatic β cells become progressively less able to secrete sufficient insulin to maintain normal carbohydrat Continue reading >>

Genetics Of Type 1 Diabetes

Genetics Of Type 1 Diabetes

1. Introduction Type 1 diabetes (T1D) is an autoimmune disease characterized by immune destruction of insulin-producing pancreatic β cells. This leads to dysfunctional regulation of blood glucose levels in T1D patients. The destruction of β cells of Langerhans islets is caused by infiltration of dendritic cells, macrophages and T lymphocytes. The destruction of β cells starts with an autoimmune process that is followed by massive destruction of β cells later on. Autoantibodies against T1D-specific antigens are present in serum and can be detected in the early stage of the disease (Ounisis-Benkalha & Polychronakos, 2008). There are several main types of T1D autoantibodies: islet antibodies, antibodies to insulin (IAA), glutamic acid decarboxilase (GADA) and tyrosine phosphatise IA-2. In the last few years antibodies to zinc transporter (ZnT8) have been added to this group (Mehers & Gillespie, 2008). It is generally accepted that T1D occurs as a result of genetic and environmental factors when presence of many alleles combined with effects of numerous environmental factors lead to disease development (Pociot et al., 2010). Research of T1D genetic basis and environmental factors has increased dramatically in the last two decades. Today it is considered that beside HLA region on chromosome 6q21 that contributes approximately with 40% to T1D development, more than 50 non-HLA genes significantly increase the risk of T1D occurrence (MacFarlane et al., 2009, Ziegler et al., 2010, Concannon et al., 2010). The final aim of genetic research is integration with clinical practice, which is expected once the main understanding of genetic etiology of T1D is achieved. Translation to clinics includes development of genetic-based diagnostic tests, population screening methods and pre Continue reading >>

Genetic Basis For Type 1 Diabetes | British Medical Bulletin | Oxford Academic

Genetic Basis For Type 1 Diabetes | British Medical Bulletin | Oxford Academic

Type 1 diabetes (T1D) is characterized by autoimmune destruction of insulin-producing -cells in the pancreas resulting from the action of environmental factors on genetically predisposed individuals. The increasing incidence over recent decades remains unexplained, but the capacity of identifying infants at highest genetic risk has become an increasing requirement for potential therapeutic intervention trials. Literature searches on T1D and genes were carried out, and key papers since the 1970s were highlighted for inclusion in this review. Early genetic studies identified the most important region for genetic susceptibility to T1Dthe human leukocyte antigen genes on chromosome 6; later shown to contribute approximately half of the genetic determination of T1D. The other half is made up of multiple genes, each having a limited individual impact on genetic susceptibility. Historically, there have been many controversial genetic associations with T1D, mostly caused by underpowered casecontrol studies but these are now decreasing in frequency. The functional effect of each gene associated with T1D must be investigated to determine its usefulness both in risk assessment and as a potential therapeutic target. Recently identified copy number variants in DNA and epigenetic modifications (heritable changes not associated with changes in the DNA sequence) are also likely to play a role in genetic susceptibility to T1D. type 1 diabetes , genes , HLA class II , islet autoantibodies The immune system protects by being able to specifically differentiate between host cells and infectious agents. In autoimmunity, however, this system breaks down: for instance, in type 1 diabetes (T1D), insulin-producing -cells are subjects to specific attack by the host immune system. T1D is often co Continue reading >>

Common Genetic Basis Between Type 1 And Type 2 Diabetes Mellitus Indicated By Interview-based Assessment Of Family History

Common Genetic Basis Between Type 1 And Type 2 Diabetes Mellitus Indicated By Interview-based Assessment Of Family History

Volume 66, Supplement , December 2004, Pages S91-S95 Common genetic basis between type 1 and type 2 diabetes mellitus indicated by interview-based assessment of family history Author links open overlay panel TomomiFujisawa HiroshiIkegami Get rights and content To investigate the intrafamilial clustering of type 1 and type 2 diabetes, an interview-based assessment of family history of diabetes was conducted. Outpatients with either type 1 (n = 23) or type 2 diabetes (n = 124), and non-diabetic subjects (n = 118) received an interview regarding the diabetic status of each of their family members. In patients with type 1 diabetes, 22% (5 out of 23) had a parental history of diabetes, and diabetes in these 5 parents was assessed as type 2 diabetes mellitus. The prevalence of parental diabetes in the type 1 diabetic probands (22%) was significantly higher (P < 0.05) than that in non-diabetic probands (7%, 8 out of 118). In probands with type 2 diabetes, the prevalence of parental diabetes was 39% (48 out of 124), which was significantly higher (P < 0.0005) than that in the non-diabetic probands (7%). In the type 2 diabetic probands, no significant difference was noted in the prevalence between paternal (19%, 23 out of 124) and maternal diabetes (23%, 28 out of 124), suggesting no preferential inheritance of maternal diabetes in this population. The present interview-based assessment of family history of diabetes suggested a common genetic basis between type 1 and type 2 diabetes. Continue reading >>

The Genetic Basis Of Type 1 Diabetes Autoimmunity Noble, Janelle A. Children's Hospital & Res Ctr At Oakland, Oakland, Ca, United States

The Genetic Basis Of Type 1 Diabetes Autoimmunity Noble, Janelle A. Children's Hospital & Res Ctr At Oakland, Oakland, Ca, United States

The genetic basis of type 1 diabetes autoimmunity Type 1 diabetes (T1DM) is a chronic autoimmune disorder with a complex genetic susceptibility component; however, only about 10% of cases have a family history. Thus, a thorough understanding of the genetic factors that control susceptibility is crucial to prediction of, and subsequent intervention in, disease in the general population. The highest risk genetic marker identified to date (the HLA-DR3/DR4-DQB1*0302 genotype) only predicts an approximately 1 in 15 risk of disease in Caucasians, as compared to the general population risk of about 1 in 300. HLA genetic risk is even less well understood in non-Caucasian groups, and the spectrum of non-HLA genetic risk factors for all groups is just beginning to be elucidated. The autoimmune process that results in clinical onset of type 1 diabetes begins months to years before diagnosis and has complex etiology. Measurement of autoantibodies directed against insulin, glutamic acid decarboxylase (GAD65), and the tyrosine phosphatase-like protein IA-2 can give useful information about the progression of autoimmunity; however, these assays are not practical at the population level. In addition, autoantibodies are variable among prediabetic individuals and new-onset patients. Some ethnic groups, particularly African- Americans, exhibit clinical disease which differs from that in Caucasians; thus, thorough understanding of the genetics of true type 1 diabetes should aid in the diagnostic distinction of different forms of diabetes. This proposal aims to use a unique set of resources, which include state-of-the-art genotyping technology and access to sample sets from numerous ethnic groups as well as to the ethnically-diverse pediatric patient population at Children's Hospital Oakla Continue reading >>

Defining The Genetic Contribution Of Type 2 Diabetes Mellitus

Defining The Genetic Contribution Of Type 2 Diabetes Mellitus

Diabetes mellitus (DM) affects over 150 million people world wide, with a prevalence that varies markedly from population to population.1 Estimates predict that almost 300 million people will suffer from DM by 2025 (fig 1) with the vast majority being cases of diabetes mellitus type 2. Many risk factors have been identified which influence the prevalence (total number of cases as a percentage of the total population) or incidence (total number of new cases per year as a percentage of the total population). Factors of particular importance are a family history of diabetes mellitus, age, overweight, increased abdominal fat, hypertension, lack of physical exercise, and ethnic background. Several biochemical markers have also been identified as risk factors, including fasting hyperinsulinaemia, increased fasting proinsulin, and decreased HDL cholesterol.2 Both diabetes mellitus types 1 and 2 show a familial predisposition, which is a strong indication for the involvement of genes in people's susceptibility to the disease. However, the aetiology underlying types 1 and 2 is different and different genes are likely to be involved in each type of diabetes mellitus. The following discussion focuses on a genetic dissection of type 2 diabetes mellitus. The two most common forms of diabetes mellitus, type 1 and type 2, are both characterised by raised plasma glucose levels. Normal glucose homeostasis depends on the balance between glucose production by the liver and kidneys and glucose uptake by the brain, kidneys, muscles, and adipose tissue. Insulin, the predominant anabolic hormone involved, increases the uptake of glucose from the blood, enhances its conversion to glycogen and triglyceride, and also increases glucose oxidation. Plasma glucose levels are normally kept within a s Continue reading >>

Type 1 Diabetes

Type 1 Diabetes

Type 1 diabetes is a disorder characterized by abnormally high blood sugar levels. In this form of diabetes, specialized cells in the pancreas called beta cells stop producing insulin. Insulin controls how much glucose (a type of sugar) is passed from the blood into cells for conversion to energy. Lack of insulin results in the inability to use glucose for energy or to control the amount of sugar in the blood. Type 1 diabetes can occur at any age; however, it usually develops by early adulthood, most often starting in adolescence. The first signs and symptoms of the disorder are caused by high blood sugar and may include frequent urination (polyuria), excessive thirst (polydipsia), fatigue, blurred vision, tingling or loss of feeling in the hands and feet, and weight loss. These symptoms may recur during the course of the disorder if blood sugar is not well controlled by insulin replacement therapy. Improper control can also cause blood sugar levels to become too low (hypoglycemia). This may occur when the body's needs change, such as during exercise or if eating is delayed. Hypoglycemia can cause headache, dizziness, hunger, shaking, sweating, weakness, and agitation. Uncontrolled type 1 diabetes can lead to a life-threatening complication called diabetic ketoacidosis. Without insulin, cells cannot take in glucose. A lack of glucose in cells prompts the liver to try to compensate by releasing more glucose into the blood, and blood sugar can become extremely high. The cells, unable to use the glucose in the blood for energy, respond by using fats instead. Breaking down fats to obtain energy produces waste products called ketones, which can build up to toxic levels in people with type 1 diabetes, resulting in diabetic ketoacidosis. Affected individuals may begin breathin Continue reading >>

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