Diabetes Type 1 - Research Paper Example

?Running Head: Diabetes Type Diabetes Type Diabetes Type Introduction One hundred seventy-six thousand and five hundred people under the age of 20 years had diabetes in 2005, which accounts for 0.22% of all disease in this age group in the United States (U.S.) (National Diabetes Statistics, 2005). Approximately one in every 400 to 600 children and adolescents currently has type 1 diabetes (T1D). Forty percent of individuals with T1D develop the disease before the age of 20 years. It appears that the incidence of T1D in youth is increasing in the U.S (American Diabetes Association, 2008). The World Health Organization (WHO) estimates that there are over 177 million cases worldwide and this number will increase to at least 370 million by 2030 (Gad et al., 2003). Further, the disease is associated with a series of secondary health complications. Diabetes Mellitus (DM) Diabetes Mellitus (DM) is characterized by persistent and variable hyperglycemia (high blood glucose levels). Type 1 Diabetes Mellitus (T1DM), also known as insulin-dependent DM, childhood DM, or juvenile-onset DM, most commonly presents in children and adolescents. The typical age of onset is less than 25 years (Pepper, 2006). Also, in contrast to T2DM, T1DM occurrence is typically in individuals who are lean rather than obese (Myers, 2005). T1DM constitutes approximately 10% of all individuals with DM and occurs mainly in populations of Europe and North America (Champe et al., 2005; Gillespie, 2006). T1DM is increasing in incidence globally at a rate of about 3% per year (Champe et al., 2005). Like all types of DM, T1DM is associated with increased risk for and a high incidence of certain complications. Hence, DM in general has been considered a syndrome of metabolic abnormalities (i.e. metabolic disorder of glucose, protein, lipids, water and electrolytes), microvascular disease (i.e. retinopathy, neuropathy, and nephropathy), and macrovascular disease (i.e. atherosclerosis) (Myers, 2005; Champe, et al., 2005). DM is the leading cause of adult blindness and amputation, and is a major cause of renal failure, heart disease, and stroke (Champe et al., 2005). Cardiovascular disease (CVD) is the main cause of premature death among people with DM - about 65% of people with DM die from heart disease or stroke (Champe et al., 2005). T1DM patients are often young at the time of diagnosis. Although the pathogenic factors are active early on, complications usually develop later as the disease progresses and are not as common during early stages. Etiology of T1DM Type 1 diabetes is the result of the loss of ? cells, which subsequently leads to insufficient secretion of insulin. It is generally accepted that Insulin-Dependent Diabetes Mellitus (IDDM) is an autoimmune disease. The exact cause or causes of the disease are still unclear, however, a combination of genetic and environmental factors seem to be involved. Evidence for a genetic susceptibility to IDDM is shown through family studies. Approximately 6% of siblings of people with T1D will also develop the disease, as compared with a prevalence of .4% in the general population (Levin and Tomer 2003; Leoni 2003). Children of diabetics also have a higher risk of acquiring diabetes: about 3-6% of diabetic offspring get diabetes, compared with .4% of the general population. Intriguingly, the gender of the diabetic parent also seems to contribute to disease transmission, with offspring of diabetic fathers being at a greater risk (about 9%) than those of diabetic mothers (about 3%). Data from twin studies (i.e. Levin and Tomer 2003; Leoni 2003) also seem to strongly suggest a genetic predisposition to IDDM. Concordance rates for monozygotic twins vary between 35 - 70%, while the concordance rates for dizygotic twins is about 11 %. These rates increase with the time since proband diagnosis; for example, concordance is 43% within 12 years of proband diagnosis, and 50% within 40 years. Age of proband diagnosis also seems to be a crucial factor: the concordance rate for twins of probands diagnosed after age 24 was only 6%, whereas the co-twin of a proband diagnosed before age 5 has a 65% risk of developing diabetes. This suggests a higher genetic component for early onset IDDM vs. late onset (Levin and Tomer 2003). It is generally agreed that at least part of the genetic susceptibility component of this disease is associated with the major histocompatibility complex (MHC) located on chromosome 6. There is a widely recognized association of IDDM with the human leukocyte antigens HLA-DR3 and HLA-DR4, and particularly with the haplotypes HLA-DR3/HLA-DQ2 and HLA-DR4/HLA-DQ8 (Levin and Tomer 2003; Leoni 2003; Bresson and von Herrath 2004). Additional data collected from five complete genome scans have identified 18 other genomic intervals that may influence the risk of T1D. In particular, Levin reports that the insulin gene region on chromosome 11, as well as the cytotoxic T -lymphocyte-associated protein 4 gene on chromosome 2 may make significant contributions to disease risk (Levin and Tomer 2003). There are also arguments that IDDM is not purely a genetic disorder; rather, it has been suggested that certain environmental factors also play an important role and may trigger or accelerate autoimmune diseases in genetically predisposed individuals. Viruses are prime candidates as environmental risk factors because they induce strong immune reactions and can infect the pancreas and ? cells, which subsequently leads to local inflammation. While a firm causal relationship between viruses and IDDM has not been established, several viruses have been associated with the disease, including enteroviruses (especially coxsackievirus B), rubella, rotavirus, and the mumps virus (Filippi and von Herrath 2005). Data from animal studies suggest that viruses may result in ?-cell destruction in 3 ways: (1) by inducing cell damage either directly or via secretion of inflammatory cytokines that specifically harm ? cells, (2) by enhancing the function of antigen presenting cells (APCs) which subsequently leads to increased presentation of autoantigens, or (3) by molecular mimicry, where immunity against viral antigens cross reacts with self-antigens that have a similar structure (Bresson and von Herrath 2004; Bach 2005). On the other hand, human data is much more inconsistent and does not provide definitive evidence for or against viral triggers. This may be because infections often occur before the clinical onset of IDDM, at which point any trace of viral infections might be gone; furthermore, IDDM might be preceded by a multitude of viruses that all exert similar effects on the diabetogenic process, making it difficult to pinpoint specific infections as causative agents (Bresson and von Herrath 2004; Filippi and von Herrath 2005). While viruses may in fact be a partial cause of T1D, an interesting observation is that viral infections can also exert a protective effect against autoimmune diseases - thus, a lack of viral or microbial stimulation may be a contributing environmental factor to autoimmune diabetes. Many epidemiological data support this controversial theory, known as the "hygiene hypothesis." Indeed, it is well known that the occurrence of autoimmune disorders such as diabetes is much higher in westernized countries versus lesser developed countries; this is thought to be due to improved hygiene and subsequent lack of exposure to infections (Bresson and von Herrath 2004; Romagnani 2004; Bach 2005). For example, it has been shown in several laboratories that non-obese diabetic (NOD) mice develop spontaneous T1D only in a sterile environment (Bresson and von Herrath 2004). Furthermore, it has been reported that the incidence of type 1 diabetes is much higher in first-born children who are not exposed to the infections of older siblings, even more so if they are not exposed to the same in other children in a day care environment (Bach 2005). Although these observations support the idea that infections may protect individuals from autoimmune diseases, the mechanisms of this protective effect are not yet well-understood. Pathogenesis of T1DM Type 1 diabetes mellitus is a T-cell mediated autoimmune disease in which the insulin producing ? cells of the pancreatic islets of Langerhans are selectively destroyed. In spite of extensive investigation, the exact cellular and molecular mechanisms that lead to the onset of IDDM have yet to be elucidated. In any case, what is clear is that both environmental and genetic factors are involved, as evidenced by the T1DM concordance rate of 50% in identical twins, as well as the variable incidence of T1DM in different countries, which is most likely due to environmental differences such as nutrition or lifestyle (Rosmalen, Leenen et al. 2002). The role of defective immune regulation in the development of T1DM is heavily documented. Numerous ? cell autoantigens have been implicated in the disease. The strongest candidate of these in both animal models and humans is glutamic acid decarboxylase (GAD), a neuronal enzyme that converts the amino acid glutamate to the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) (Rosmalen, Leenen et al. 2002). Anti-GAD antibodies are prevalent in the pancreata of both newly diagnosed and predisposed diabetic patients. Furthermore, GAD, as compared with other autoantigens expressed by ? cells, appears to provoke the earliest T cell proliferative response (Leoni 2003). It has been proposed that the mechanism through which GAD autoimmunity is facilitated is based on the accumulation of glutamate within ? cells, which is probably caused by nutrient stress, exogenous toxins, or genetic defects. This leads to the over-expression of GAD within the ? cell itself, and later, the over ­expression of GAD at the surface of the ? cell, which provokes an autoimmune response (Esposti and Mackay 1997). A myriad of other immune components, such as the cytokines tumor necrosis factor (TNF-?), interleukin-l (IL-l), and interferons (IFN-?), as well as nuclear factor kappa-B (NF-?B) and perforin have all been linked to the progression of T1DM, although the exact mechanism by which these entities aid in the specific destruction of ? cells is unclear. In some cases, these molecules have even been reported to exert a protective effect (Lee & Chang et al. 2004). While research has largely been focused immune system deficiencies as the main contributor to the occurrence of autoimmune diabetes, abnormalities of the islets themselves may be potent contributors to this disease. For example, it has been suggested that abnormalities in the apoptosis of ?-cells might lead to an autoimmune response. Normally, apoptotic cells are rapidly cleared from tissues by macrophages and immature dendritic cells to prevent the onset of a strong inflammatory reaction. However, defective clearance of apoptotic debris from the pancreas can trigger autoimmunity through the release of immunogenic agents such as cytokines. Also, upon phagocytosis of apoptotic waste, immature dendritic cells become mature and subsequently are able to bind to autoreactive T cells, which then leads to an anti- ?-cell cytotoxic response (Rosmalen & Leenen et al. 2002; Leoni 2003). Post-natal ? cell hyperactivity has also been linked to the development of diabetes. The central idea to this theory is that the corresponding low glycemia might increase ?-cell sensitivity to immune attack, since glucose has been shown to exert a protective effect on ~ cells (Rosmalen & Leenen et al. 2002). Finally, researchers have observed the presence of a higher percentage of larger islets (termed 'mega-islets') in non-obese diabetic mice (NOD mice) vs. control strains. The infiltration of leukocytes into the pancreas of diabetic mice are preferentially situated near mega-islets. A model of this disease pathogenesis has been proposed in which the development of Type 1 Diabetes is categorized into 5 stages, which are defined by characteristic changes in metabolic and ?-cell function (Weir and Bonner-Weir 2004). The first stage, "compensation," is accompanied by higher overall as well as acute glucose stimulated insulin secretion. This is probably a result of increased ?-cell mass. Fasting plasma glucose levels rise from normal values of ~4.5 mM to slightly higher values of around 5.0 mM that cannot be clinically considered abnormal. During the second stage, called "stable adaptation", fasting blood glucose levels rise to approximately 5.0 - 7.3 mM. Acute glucose stimulated insulin secretion (GSIS) is lost. The mechanisms responsible for the loss of GSIS are unknown. Furthermore, clear changes in the ?-cell phenotype are observed, with the down regulation of genes that are normally highly expressed in ?-cell, including those for insulin, GLUT2, glucokinase, glycerol phosphate dehydrogenase, pyruvate carboxylase, and certain transcription factors; meanwhile, genes not normally expressed in ?-cell, such as glucose-6- phosphatase, fructose-l,6-bisphosphatase, lactate dehydrogenase, and hexokinase, are upregulated. Stage 3, or "unstable early decompensation," is a transient phase during which fasting glucose levels rise rapidly from ~7.3 mM to stage 4 levels of 16 - 20 mM. This swift transition occurs in type 1 diabetes when ? cell mass becomes inadequate at some critical point - as mentioned previously, about 70% percent of ? cells are destroyed before normal pancreatic function is lost. Stage 4, called "stable decompensation," patients typically have enough insulin secretion to keep from progressing to ketoacidosis - however, if left untreated, the rapid destruction of ? cells can lead to this very quickly. Patients with islet transplants can typically remain in stage 4 for considerable periods of time if immunosuppressive therapy can sufficiently maintain viable ? cells. Stage 5, "severe decompensation," is characterized by a considerable loss in ? ell mass. At this stage, blood glucose levels are >22 mM, and patients develop ketoacidosis. Without insulin treatment, this condition leads to death (Weir and Bonner-Weir 2004). Diagnosis of T1DM DM is a disease of hyperglycemia and diagnosis of both T1DM and T2DM rely on demonstrating either a fasting or postmeal hyperglycemia (Champe, 2005). Normal blood glucose is typically less than 6.0 mmol/L in a fasting state. A fasting plasma glucose level ? 7.0 mmol/L (126 mg/dL); a random plasma glucose ? 11.1 mmol/L (200 mg/dL); or a glucose value ? 11.1 mmol/L (200 mg/dL) two hours after a 75g oral glucose load on more than one occasion are diagnostic criteria for DM. These diagnostic criteria are defined based on risk for diabetic retinopathy (Englegau, 1997). Individuals with levels of glycemia that are intermediate between normal levels and levels that are consistent with DM are categorized as being in a prediabetic state and are at risk of developing DM later on (Champe, 2005). Treatment of T1DM The control of T1DM involves both lifestyle adjustments and medical treatments. Insulin replacement is the cornerstone of therapy for T1DM (Talreja, 2005). The optimal treatment regimens involve nutritious diet and exercise, which allow the patient to maintain a healthy, active lifestyle. Maintaining glycemic control is accomplished by therapeutic use of insulin and can prevent or minimize long-term microvascular complications of DM. Insulin must be administrated by subcutaneous injection. Many different insulin treatment regimes are used to control blood glucose levels. These vary in the speed and duration of a therapeutic effect and are variously referred to as rapid acting, short-acting, intermediate acting and long acting (Talreja, 2005). The best option depends upon a variety of individual factors (Habermann, 2006) and must be tempered with caution to avoid hypoglycemia. Conventional (standard) insulin treatment and intensive insulin treatment are the two main types of insulin treatment plans. These differ in the types and dose of insulin used and the frequency of injections. In general, intensive insulin therapy involves more frequent insulin injections or use of an insulin pump. Intensive insulin treatment also requires more frequent monitoring of blood glucose. This type of therapy aims to more closely mimic insulin secretion by the pancreas and usually offers greater control of glycemia, (Habermann, 2006), lower glycated hemoglobin (A1C), and therefore lower risk for complications (Habermann, 2006). Conventional insulin treatment is an older regimen only recommended for selected patients (McCulloch, 2007). Conclusion T1D is an autoimmune disorder. It is a chronic disease characterized by the destruction of pancreatic ?-cells leading to complete insulin deficiency. In the past, the need for insulin determined whether an individual was classified as T1D. Now, the classification is determined by degree of insulin deficiency, with further classification distinguishing between autoimmune (type 1 a) and not immune-­mediated (type 1 b). Type 1 a is the more common form in youth. People with T1D must have insulin delivered by injection or a pump to survive. They face many complications that can lead to blindness, kidney damage, heart disease and lower-limb amputation. As these individuals become adults they face the additional disease burden of greater susceptibility to many chronic illnesses. Despite research efforts, progress has been slow in identifying what causes T1D. Some believe genetics are solely responsible for T1D, while others believe environment plays a role. Most likely T1D is caused by interactions between genetic and environmental factors. References American Diabetes Association (2008). Standards of Medical Care in Diabetes: 2008, Diabetes Care 31 (1) pp. S12–S54. Bach, J. F. (2005). Six questions about the hygiene hypothesis. Cellular Immunology 233(2): 158-61. Bresson, D. and M. von Herrath (2004). Mechanisms underlying type 1 diabetes. Drug Discovery Today: Disease Mechanisms 1(3): 321-327. Champe P., Harvey R., and Ferrier D. (2005) Lippincott's Illustrated Reviews: Biochemistry, 3rd Edition,; 25: 335-346. 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