Abstract
Type 1 Diabetes mellitus is a multi-factorial metabolic disorder in which insulin secretion is completely disturbed. An autoimmune destruction of the pancreatic β-cells that produce insulin creates this disturbance. This disease is the cause of premature mortality and several other health risks. The increased prevalence of this disease in children and adolescents is a cause of concern. These factors encourage research towards the understanding of the pathogenesis of this disease. Research has identified three different types of factors that can either contribute alone or in combination, towards the pathogenesis of the diseases. These factors have been identified to be environmental factors, genetic factors and abnormal functioning of the immune system. Out of the several genetic factors, the contribution of Human Leukocyte Antigen (HLA) class II genes towards the pathogenesis of the diseases is considered to be very high. A variation in these genes hampers the regulated immune responses and promotes anti-self-reactivity. The discovery of autoantigens has helped to place this disease under the pathogenetic category of autoimmunity. Environmental factors like reduced concentration of vitamin D, early introduction of cow’s milk to the infants and use of certain drugs have been associated with an increase in the incidences of type 1 diabetes mellitus. A clear understanding of the role of various factors and better diagnostic methods that can identify the disease in its initial stages can help in reducing the incidence of type 1 diabetes mellitus to a significant extent.
Table of Contents
1. Introduction to Diabetes Mellitus
2. Different Forms of Diabetes
3. Physiology of Glucose Regulation
5. Symptoms and Effects of Type 1 Diabetes Mellitus
6. Pathogenesis of type 1 Diabetes Mellitus
7. Genetic Factors and Pathogenesis of type 1 Diabetes Mellitus
8. Autoimmunity and Pathogenesis of Type 1 Diabetes Mellitus
9. Role of Environmental Factors in the Pathogenesis of the Disease
10. Combined effect Of All the Three Types of Factors
List of Figures
Figure 1: Physiology of Glucose Regulation
Figure 2: Mechanism of Pathogenesis of Type 1 DM
Figure 3: Role of autoantibodies in Type 1 DM
Pathogenesis of Type I Diabetes Mellitus
1. Introduction to Diabetes Mellitus
The word “Diabetes Mellitus (DM)” refers to a group of metabolic disorders in which the fuel metabolism in the human body is disturbed. These disorders are mainly caused by defective insulin action, insulin secretion, or both, leading to a hyperglycemic condition and dyslipidemia. DM is a chronic disease currently affecting people of all the age groups. DM is a major cause of heart diseases and stroke, hence increasing the rate of morbidity and mortality. Under chronic situations, DM leads to damage and abnormal functioning of the various organs of the body like, kidneys, eyes, nerves, brain, heart and limbs. Unfortunately, the incidence of diabetes is increasing at an alarming rate, almost reaching epidemic proportions. According to predictions made by the World Health Organization (WHO) in 2003, a 64% rise in the number of people suffering from diabetes is expected by 2025. The number of adults suffering from diabetes across the world in 2010 was 285 million, and it is expected that, by 2030, this number would rise to around 439 million (Ozougwu et al. 47) (Pittas). Apart from being a major health risk, DM also affects the economy to a significant extent as it demands huge medical expenditure. According to the economic data provided in 2007, the direct medical costs due to DM in the form of medicines and hospitalization expenditure is expected to be around $116 billion, and indirect medical expenditure due to disability, work loss, premature mortality is expected to be around $58 billion. Thus, this disease proves to be a huge burden for individuals and the economy of any country as a whole (Triplitt 1) (Holt s55). The asymptomatic nature of the disease and the subtle onset with many harmful effects creates an impediment in the detection of the disease at an early stage. This puts many people at risk of developing vascular complications that can also prove to be life threatening (Holt s55). An understanding about the different forms of DM, their pathophysiology and the factors that enhance the rate of this disease can help in reducing the frequency of this disease.
2. Different Forms of Diabetes
The common characteristic of all the metabolic disorders categorized under DM is the disturbance of the delicate glucose homeostasis in the body. The levels of glucose in the blood are well regulated by the proper balance between utilization of glucose in liver, muscle and white or brown fat, and the release of glucose into the bloodstream by the liver. DM disturbs this regulation and hence the balance. Diabetes is a very old disease and the evidences of its existence can be obtained from the ancient literature of China, Egypt and India (Khardori and Pauza 106). Classic symptoms of this disease include polyuria, polydipsia, increased appetite, weight loss and blurring of vision. In acute conditions, even the growth can get impaired and the patient shows increased susceptibility to infections. Vascular damage leading to end organ failure is noticed in chronic cases of diabetes (Pittas). The American Diabetes Association classified the disease diabetes based of the etiology of the disease, into Type 1 Diabetes, Type 2 Diabetes, gestational diabetes and a fourth group consisting of other types of diabetes, Type 1 Diabetes and Type 2 Diabetes were previously known as insulin-dependent diabetes mellitus and non-insulin dependent diabetes mellitus respectively (Khardori and Pauza 106). Usually, diabetes is detected by the presence of hyperglycemia in blood. If the casual plasma glucose level is greater than or equal to 200 mg/dL and the patient complains of the classic symptoms of diabetes, a person is considered to be diabetic. Thereafter the patient is subjected to further testing to understand the etiology of the disease. Clinical findings help to differentiate between the various forms of DM. Presence of classic symptoms of diabetes along with a high concentration of ketone bodies in the blood (diabetic ketoacidosis) is observed during Type 1 DM. These patients also show low levels of HDL (High-density lipoprotein) and high levels of triglyceride rich particles (such as very-low-density lipoprotein, chylomicrons). This condition is also termed as diabetic dyslipidemia and is corrected through insulin therapy. Patients suffering from type 2 diabetes usually do not present the symptoms of severe hyperglycemia during the initial stages and are often clinically detected during screening tests for other diseases. These patients usually show impaired glucose tolerance initially, as they are resistant to the action of insulin even though they have high levels of insulin in their plasma. This form of diabetes progresses slowly and the early stages of the disease are marked by hyperinsulinemia and hyperglycemia, followed by a reduction in the levels of insulin. These patients also exhibit dyslipidemia.
3. Physiology of Glucose Regulation
Glucose is the primary source of cellular energy. It passes through various metabolic cycles to release energy in the form of ATP (adenosine triphosphate). This energy is utilized in various biochemical reactions of the cells. Glucose is obtained through food and this dietary glucose gets absorbed across the gut wall after digestion, and gets distributed to various tissues through the blood. A portion of glucose acquired from the diet enters the liver through the hepatic portal vein and is converted into glycogen by liver cells. Under normal conditions, glucose is released by the breakdown of the glycogen reserves in the liver. An increase in the concentration of blood glucose triggers the secretion of insulin. The hormone, insulin, is secreted by the β-cells of the Islets of Langerhans in pancreas and performs multiple functions in our body. It stimulates the peripheral uptake of glucose by muscles and other cells that utilize it as a source of energy or convert it into glycogen. The uptake of glucose by skeletal muscles is increased dramatically during physical exercises. The binding of insulin with the insulin receptors stimulates the cells to increase the number of glucose transporters as GLUT4. These transporters increase the transport of glucose from the blood to the cells. Apart from increasing the usage of glucose, insulin stimulates the storage of glucose in the liver through the process of glycogenesis. It also suppresses the endogenous glucose production primarily from the liver. This ultimately decreases the glucose levels in the blood. Glucagon, secreted by the alpha cells of the Islets of Langerhans, is the second hormone that helps in glucose homeostasis. The action of Glucagon is opposite to that of insulin. Glucagon is secreted as a response to hypoglycemia and increases the blood glucose levels. This hormone primarily acts on the liver and hastens the process of glycogenolysis (conversion of glycogen into glucose). It also promotes gluconeogenesis (synthesis of new glucose from lactic acid and other metabolites). Some other hormones involved in the glucose regulation are somatostatin, gastrin and cholecystokinin. The hormone, somatostatin, reduces gut motility, affecting the absorption of nutrients from the small intestines. The hormones, gastrin and cholecystokinin released by the gastrointestinal tract, stimulate the pancreas to secrete insulin (Pat and McFadden 56) (Triplitt 2). Figure 1 shows the overall physiology of glucose regulation in the body.
4. Type 1 Diabetes Mellitus
Type 1 Diabetes was previously known as either juvenile diabetes, because of the early onset of the disease, or as insulin-dependent diabetes mellitus, because of the clinical need for insulin. It is more prevalent among children and adolescents as compared to adults. The susceptibility to the disease is high in girls belonging to the age group of 10 to 12 years and boys belonging to the age group of 12 to 14 years (Pittas). However, half of the cases of this disease are also diagnosed in adults. An absolute deficiency of insulin is noticed in this disease. Almost 5% of the patients suffering from DM show Type 1 diabetes, and the incidence of this disease is increasing in all countries. This disease is not uniformly distributed across the world. The incidence rates of Type 1 DM are the highest in Scandinavia and Mediterranean islands of Sardinia in comparison to the rest of the world. The incidence rate is 40 per 100,000 people in Finland. The incidence is low in oriental and equatorial populations (0.1 per 100,000 in china) (Khardori and Pauza 106) (Holt s56). The reason behind this geographical variation is not clear. It is speculated that decreased exposure to sunlight and consequent deficiency of vitamin D might be the reason behind this unequal geographical distribution of the disease. However, high incidence of this disease in areas receiving ample amount of sunlight as Kuwait, Rico and low incidence in Lithuania contradicts this explanation (Poretsky 181).
There are two major subtypes of Type 1 DM. Type 1A is an immune-mediated form and arises as an outcome of organ-specific autoimmune reactions. This subtype is very common and is observed in almost 95% of the cases. Type 1B is idiopathic as the cause of its origin is unknown. This non-immune mediated form is rare and presents diabetic ketoacidosis (DKA) as observed in Type 1 DM, but other characteristics match with that of type 2 DM (Vlad and Timar 67) (Pittas). The deficiency of insulin observed in type 1 DM is mainly due to the autoimmune destruction of the pancreatic β-cells that produce insulin. This disease is characterized by a prolonged subclinical prodromal phase that lasts for years together. During this phase, several immunologic abnormalities are observed that can be used to identify the individuals having a tendency to develop type 1 DM. Almost 60–80% of the β-cells are destroyed by the time of appearance of the clinical symptoms. Some of the features that help in categorizing Type 1 DM as an autoimmune disorder include, presence of autoantibodies specific to islet cells, variations in the T-cell mediated immunoregulation and being responsive to immunotherapy (Vlad and Timar 68) (Ozougwu et al. 48).
5. Symptoms and Effects of Type 1 Diabetes Mellitus
Most of the symptoms observed in patients suffering from type 1 DM are similar to that of type 2 DM as hyperglycemia is the result of both types of DM. Some of these symptoms include feeling extremely thirsty, increase in appetite, unexplained fatigue, increase in the frequency of urination, feeling lethargic, abnormal weight loss, presence of sugar in the urine, blurring of vision and numbness or tingling sensation of feet. These symptoms show an almost sudden appearance. Some people experience a sudden upsurge in the levels of blood sugar leading to diabetic ketoacidosis. These patients express a few additional symptoms that act as warning signs. These symptoms are sweet, fruity odor of breath, dryness of the skin and mouth, rapid breathing, flushing of face, nausea and vomiting (Baruchin). Children with type I DM express gastrointestinal symptoms. A gastrointestinal autoimmune problem known as celiac disease (CD) has been identified in these children. Individuals with CD are often detected with other autoimmune disorders including type 1 DM (Narula e489).
Type 1 DM causes premature mortality as it decreases the normal life span by an average of five to eight years. It also affects other organs of the body, hence increasing the complications. It has a major effect on the heart and increases the progression of atherosclerosis and blood pressure. Coronary artery disease, stroke and heart attack are observed as a secondary effect of Type 1 DM. The functioning of the nerves gets hampered, leading to a condition called neuropathy. This affects the sensation in arms and legs. This is observed in the form of tingling sensation or numbness in arms and feet. Problems related to the erection of penis leading to impotence in men are a secondary effect of neuropathy. Chances of blood vessel injury are high in people with diabetes. This leads to the damage of the tissues in the legs and feet. Even minor infections prove to be dangerous for these people as it develops into deep tissue injury. Numbness from neuropathy aggravates this problem as the patient fails to feel the injury. Diabetes is the leading cause of new cases of blindness amongst people belonging to the age group of 20 to 74. The blood vessels supplying blood to the retina are injured, leading to a condition called retinopathy. It also increases the chances of developing cataracts and certain types of glaucoma. Diabetes also impacts the normal functioning of the kidneys. Presence of hypertension, coronary artery disease along with diabetes hastens the process of kidney damage or Nephropathy. People with diabetes are at a higher risk of developing respiratory and urinary tract infections. This disease affects the brain functioning also, hence affecting the mental ability (What are the long-term complications of type 1 diabetes and how are they treated?).
6. Pathogenesis of type 1 Diabetes Mellitus
Type 1 DM is a complex multi-factorial disorder. It is an outcome of the effects of multiple genes along with environmental and lifestyle factors. Because of its polygenic nature, this disease cannot be classified under diseases caused by dominant or recessive genes. Switching on or off of a single gene is not enough for the development of the disease, rather, a complex interaction of multiple genes leads to the development of type 1 DM. This makes the identification of susceptible genes difficult. Nearly 50 loci have so far been found to be impacting susceptibility to the disease. Out of these susceptible loci, the contribution of Human Leukocyte Antigen (HLA) complex towards the overall genetic susceptibility is very high (~60%). Out of the three classes of HLA genes, class II genes encoding for molecules that participate in antigen presentation are strongly associated with the development of the disease. A variation in these genes increases the risk of type 1 DM, as the presentation of β-cell antigens is altered. This alteration in presentation is triggered by the failure to impart regulated immune responses, or by promotion of anti-self-reactivity (Atkinson 7). A significant discordance in monozygotic twins proves that the alteration in the genetic factors alone does not explain the etiology of the diseases. The auto-immune nature of the diseases shows that bone marrow derived elements are involved in the pathogenesis of the disease (Khardori and Pauza 106). Accumulation of T cells within affected islets has been observed in these patients. An increased expression of MHC near the sites of β-cells destruction suggests that active antigen presentation might take place within the islet tissue. These factors confirm the role of the immune mechanism in diabetes development (Khardori and Pauza 108). However, the specific mechanism behind insulin-producing β-cells damage is yet to be elucidated.
The rise in the global incidence of this disease, variation in geographical distribution and rapid upsurge in the disease incidence rates when individuals migrate from low- to high-incidence countries, suggest that environmental factors also have the potency to develop type 1 DM. Various environmental factors that contribute towards the development of the disease include the attack by microbes (bacteria and viruses), early weaning off breast milk, introduction of cow's milk proteins, low serum concentrations of vitamin D and association with toxic nitrosamine compounds. The combined effect of the trio (environmental factors, genetic factors along with the immune system) is responsible for the development of type 1 DM (Atkinson 11).
7. Genetic Factors and Pathogenesis of type 1 Diabetes Mellitus
The incidence of type 1 DM is 15 times more in siblings, suggesting that genetic factors and family history play a strong role in the development of the disease. This disease does not adopt simple inheritance patterns as observed with the diseases involving single gene defects. The involvement of single gene defects in the development of the disease is extremely rare, but not unknown. IPEX (immune dysfunction, polyendocrinopathy, enteropathy, X-linked) and APS-1 (autoimmune polyendocrinopathy syndrome type 1) are two rare syndromes that involve single gene defects and increase the susceptibility to type 1 DM. FOXP3 gene is mutated in IPEX syndrome affecting the major population of regulatory T lymphocytes. This favors overwhelming autoimmunity that leads to the development of type 1 DM. AIRE (autoimmune regulatory gene) is mutated in APS-1 syndrome and affects the expression of the peripheral antigens in thymus. The ultimate effect of this mutation is enhanced autoimmunity (Poretsky 185).
The human histocompatibility (HLA) complex is located on the short arm of the chromosome 6 and influences the risk of the development of the diseases to a great extent. This complex is divided into three main regions: class I, class II and class III. These regions harbor genes involved in the regulation of immune response and antigen presentation. Several loci located within the HLA complex independently contribute towards the development of diabetes. These loci are usually inherited together in the form of extended haplotypes. Hence, these loci function as multi-gene susceptibility locus. HLA-A*0101, HLA-B39 and HLAA*3002 are the HLA class I alleles that are independently associated with a susceptibility to the disease. An allele of HLA-A24 gene influences the rate of destruction of β-cells and the age of onset of the disease. Hence, this allele increases the risk to the disease (Pugliese 102).
Further, research has shown that out of the various regions of HLA complex, HLA-DQ and HLA-DR class II alleles are strongly associated with the development of the disease. The majority of type 1 DM patients carry HLA-DR3 or -DR4 class II antigens and some of them (30–50%) are DR3/DR4 heterozygotes. The heterozygotes are at a higher risk (1 in every 15 individuals) of developing this disease in comparison to the individuals without this genotype (I in every 300 individuals). The heterozygous individuals are followed by DR4 and DR3 homozygous individuals in terms of risk (Pugliese 102). HLA-DQ8 and HLA-DQ2 heterodimers are considered to be the main susceptibility determinants amongst the HLA class II genes. Both, class I and class II antigens, of HLA complex are involved in the antigen presentation. Thus, allelic variation at the HLA- DR and -DQ loci of class II, and HLA- A and –B loci of class I will effect the presentation of islet peptide antigens to CD4 and CD8 T lymphocyte cells. Ultimately, the effect of the modulation of antigen presentation is observed on the T cell tolerance and the activation of the immune response. Individuals with type 1 DM were detected with the presence of alanine instead of aspartic acid at the 57th position of the beta chain in HLA class II molecules. This alteration in the amino acid along with other residues provides structural and functional distinctiveness to these molecules. As a result, these molecules favor the escape of the autoreactive Tcells from negative selection (Khardori and Pauza 107) (Pugliese 103).
There are certain HLA haplotypes as DR2DQ6 that are associated with the resistance to the disease. Presence of these haplotypes decreases the risk of development of the diseases even in the presence of high-risk HLA alleles. These haplotypes encode certain protective HLA molecules that show an increased affinity towards some islet autoantigen peptides. As a result, presentation of autoantigens is enhanced in thymus, leading to effective deletion of autoreactive Tcells (Khardori and Pauza 106) (Pugliese 103).
A genome-wide analysis was carried out on large datasets from several populations across the world to identify additional susceptibility loci. Apart from HLA, almost 20 non-HLA loci were found to make a significant contribution towards the disease. These loci include CTLA-4, PTPN22, insulin (INS), IL2RA and IFIH1. Amongst them, INS that maps to the chromosome 11p5.5 contributed significantly towards the disease. Variations in the VNTR (variable number of tandem repeats) located upstream to the INS gene modulated the levels of insulin mRNA in thymus. The number of these repeats is directly associated with the increased thymic expression of insulin. Class III VNTRs are large and associated with high levels of expression of mRNA. Hence, they are considered to be protective alleles. Polymorphisms in the T-cell regulatory gene CTLA-4 located on the chromosome 2q22 were also found to be associated with type 1 DM in several studies, but not in all populations. Due the expression of CTLA-4 in activated Tcells and its association with several autoimmune diseases like thyroid disease, it is expected that CTLA-4 could also be associated with type1 DM. The normal function of CTLA-4 is to down regulate the T cell responses. Polymorphisms in CTLA-4 decrease the synthesis of an alternatively spliced transcript that translates into a soluble form of CTLA4 (sCTLA4). The reduced levels of sCTLA4 disturb the immune regulation, thereby promoting the autoimmunity (Pugliese 104).
The gene PTPN22 encodes Lyp protein that negatively regulates the T cell receptor (TCR) signals. The binding of Lyp with the signaling molecule Csk, down-regulates the TCR signaling. A change in arginine to tryptophan at position 620 of Lyp protein due to missense mutation suppresses TCR signaling and favors the survival of autoreactive Tcells. The genetic basis of the disease is multi-factorial. Hence, a correct understanding about the genetics of the diseases can improve the diagnosis and treatment of the diseases significantly (Pugliese 105).
8. Autoimmunity and Pathogenesis of Type 1 Diabetes Mellitus
Type 1 DM is characterized by insulitis or inflammation of the islet cells and autoimmune destruction of the insulin producing pancreatic β-cells. Many theories have been postulated to explain the specific β-cell autoimmunity. One such theory is molecular mimicry. According to this theory, the sharing of the antigenic properties between β-cells and environmental agents like viruses leads to an alteration in self-antigens that triggers autoimmunity (Atkinson 8). The direct evidence for the role of autoimmunity was obtained when the sera from type 1 diabetic patients was incubated with the pancreas tissue sections obtained from normal patients. A group of antibodies known as islet cell autoantibodies (ICAs) were identified in the sera of type 1 DM patients with polyendocrine disease in 1976. These antibodies were used to study the clinical course and pathogenesis. Further, these antibodies also helped in the discovery of islet autoantigens (Notkins and Lernmark 1248) (Roep and Peakman 1).
The two principal autoantigens recognized with the help of ICAs were glutamic acid decarboxylase (GAD65) and protein tyrosine phosphatase–like molecule (IA-2). Insulin was the third antigen to be recognized. The auto-antibodies are targeted to the B chain of human proinsulin or insulin. IA-2 is a member of PTP (protein tyrosine phosphatase) family that is expressed in both α and β-cells of the pancreatic islets. Certain other autoantigens recognized were carboxypeptidase H and IA-2β (also termed phogrin). The intracellular domains of IA-2 and IA-2β are the targets for autoantibodies. IGRP (islet-specific glucose-6-phosphatase catalytic subunit-related protein) and imogen-38 are targets of CD4 T-cells, and also act as β-cell autoantigens in type 1 DM. The identification of the β-cell autoantigens through cell biological strategy also confirmed the involvement of IA-2, IA-2ß, imogen-38 and IGRP in the immunopathogenesis of type 1 diabetes. In addition, zinc transporter 8 (ZnT8) and ICA69 were also identified as novel autoantigens (Roep and Peakman 2).
Usually, the T cells reactive to the self-antigens die by the process of apoptosis in the thymus. This process is also known as central tolerance. Some self-reactive T cells that escape this process are eliminated by the peripheral tolerance. Under peripheral tolerance, the autoreactivity is regulated by certain naturally occurring, autoantigen-specific regulatory T cells. The factors involved in the loss of tolerance to β-cell antigens are unclear. However, the auto-reactive CD4 T cells and β-cell-specific CD8+ T cells have been found to play a key role in regulating the immune attack on the β cell. That is why this disease is also known as T cell mediated organ specific autoimmune disorder. The insulin producing β-cells of the pancreas are targeted by activated cytotoxic T-lymphocytes (CTLs). The release of the cytokines triggered by the CTL activity stimulates the proliferation of the activated macrophages and autoantibodies. These autoantibodies get attracted to the site of immune activation (inflammation) and trigger the process of complement-mediated lysis. This is responsible for the overall destruction of the pancreatic tissue (Type I Diabetes: Insulin Dependent Diabetes Mellitus).
These T lymphocytes not only promote the destruction of β-cells but also contribute to insulitis to a significant extent (Mona). It is suggested that the abnormal immunogenicity of β-cells arises as an outcome of viral infection or endoplasmic reticulum (ER) stress. Sometimes, even direct damage to the β-cells stimulates autoimmunity. Under these conditions that act as danger signals, a hyper expression of HLA class I is triggered. This leads to the expression of the cytokines and chemokines. Interferon-α, a cytokine whose expression is triggered by a viral infection and chemokine CXCL10 attract immune cells into the islet microenvironment. The net result is the infiltration of leukocytes (insulitis), which is the first observed abnormality in pancreatic islets. After the presentation of particular islet antigens to the immune system, a set of additional T cells having different islet antigen specificities become activated. The exact islet antigen that leads to the pathogenic autoreactivity is not known. Macrophages also invade the islet cells and produce Interleukin 1 (IL-1) and tumor necrosis factor (TNFa). These cytokines induce structural changes in the β-cells and suppress their insulin releasing capacity (Mona). Figure 2 depicts the general mechanism of the pathogenesis of type 1 DM.
Autoantibodies against β-cells are being studied in laboratories across the world, as they help in the diagnosis of the disease several years before the onset of the actual clinical symptoms. They help in the prediction of the risk of the development of the diseases. For example, antibodies against GAD, IA-2, T8Zn are found to be significantly associated with clinical cases of type 1 DM (Mona) (Vlad and Timar 68). Islet specific autoantibodies are produced by even normal individuals. Hence, the screening test for the autoantibodies is limited to first degree relatives of a proband. If two or more distinct antibody specificities are detected in this group, the prediction of future type 1 diabetes is confirmed. Studies have shown that the presence of GAD65 and IA-2 autoantibodies together increase the risk of developing type 1 DM by 50% within 5 years. The presence of GAD65 and IA-2 autoantibodies along with the antibodies against insulin increases the chances of developing this disease by 70%. Figure 3 represents the effect of multiple autoantibodies on the risk of developing type 1 DM. Further, autoantibody screening along with HLA typing can also be used for the prediction of the diseases in the general population (Khardori and Pauza 108).
The nature of autoantibodies and their specificities depends on a variety of factors like age of onset of disease, duration of the disease and even the ethnic groups. Usually, the antibodies against GAD65 tend to remain stable throughout the disease. On the other hand, IA-2 autoantibodies tend to decrease with the progress of the disease (Notkins and Lernmark 1248).
Studies have shown that autoreactive T cells can be easily suppressed. Hence, local inflammation triggered by monocytes and antigen-presenting cells (APCs) might be essential for the initiation and maintenance of auto aggression. This finding has helped to streamline the research towards the understanding of the role of APCs in triggering autoimmunity in type 1 DM patients. Studies in animal models have shown that APCs drive the local inflammatory process that is necessary for the activation of the autoreactive T cells. After the initial destruction of some islet cells, the β-cell antigens are presented at a higher rate by the local APCs. This leads to the epitope spreading to the non-tolerant T cells. Further, the autoreactive lymphocytes cannot cause chronic inflammation and disease without the presence of activated APC. Both animal and human studies have shown that a general immune dysregulation might be an underlying cause of type 1 DM. Both environment and genetic factors might aggravate this dysregulation (Vlad and Timar 69).
9. Role of Environmental Factors in the Pathogenesis of the Disease
It has been observed that only a small proportion of genetically susceptible individuals actually develop the disease. Studies conducted on monozygotic twins have shown that, in only 13%–33% of individuals, a pair-wise match is observed for type 1 DM. The geographical distribution of the disease also varies in the different parts of the world. Moreover, the recent increase in the incidence rates among children cannot be due to increase of the genetic susceptibility to the disease in the population. Rather, this change can be attributed to the changes in the lifestyle habits and environmental factors. Many hypothetical theories also point out that certain environmental stresses accelerate the rate of prognosis of the disease. These studies imply that there are certain additional factors that trigger and impel the disease process in genetically susceptible individuals. These additional factors have been identified to be the environmental factors that trigger and accelerate the prognosis of type 1 DM (Knip and Akerblom 2).
Infectious microbial agents are considered to be very strong environmental influencers of type 1 DM. There are no direct evidences to prove the role of infectious agents in the pathogenesis of the disease. However, the association of enteroviral infections and β-cell autoimmunity can be ascertained through indirect evidences obtained from seroepidemiological human studies. There are two mechanisms through which viruses can trigger the disease. Viruses can either trigger a direct cytolytic effect or trigger an autoimmune process leading to a gradual destruction of β-cell. The structural homology between β-cell antigens and viral structures has further ascertained the role of molecular mimicry in the pathogenesis of the disease (Knip and Akerblom 4).
Enteroviruses (EV) are a group of small non-enveloped RNA containing viruses that cause many common human diseases. Infections by these viruses are very common in new -born babies and young infants. Studies have shown a close association between first diabetes-associated autoantibodies and enteroviral infections. Moreover, these autoantibodies are also detected to be at high levels during the fall of winter when the chances of infection by enteroviruses are very high. These observations suggest that a diabetogenic EV infection can mostly trigger β-cell autoimmunity in a majority of cases. Neutralizing antibodies were used to analyze which virus had better chances of triggering autoimmunity. CBV1 (Coxsackie virus B1) showed high chances of triggering β-cell autoimmunity thereby leading to the clinical manifestations of type 1 DM. Some other viruses that can be associated with this disease include mumps, rubella, rotavirus, cytomegalovirus, retroviruses and Ljunganvirus. A molecular homology between VP7 protein of rotavirus and T-cell epitopes of the autoantigens like 65 kD isoform of GAD and IA-2 molecule has been detected by researchers. The significant rise in the rotavirus antibodies was associated with diabetes-associated autoantibodies in genetically predisposed infants. This indicates that an infection by rotaviruses can induce β-cell autoimmunity in infants showing genetic susceptibility. Further research is required to ascertain the role of other viruses in the pathogenesis of the disease. Animal studies have shown that the natural gut microbiome can protect from the development of type 1 DM as they promote intestinal homeostasis (Knip and Akerblom 3).
Observations from the birth cohort studies indicate that the early signs of β-cell autoimmunity make their appearance during the first year of life. In the majority of clinical cases of childhood type 1 DM, autoimmunity was observed before the age of 3 years. These observations indicate that the environmental risk factors for type 1 DM or β-cell autoimmunity should be present during the stages of early nutrition itself. Even though prolonged breast feeding might not inhibit the development of type 1 DM, breast feeding for a short period might trigger the emergence of β-cell autoimmunity. Early weaning from breast feed and introduction of cow’s milk (infant formula) has been observed to be closely associated with an increased risk for developing β-cell autoimmunity and subsequent clinical disease. Introduction of foreign foods to the babies varies amongst the different parts of the world. The foods provided to the infants during the early stages are of different types like cereals, extensively hydrolyzed formulas or pure milk formulas. Hence, ascertaining the clear association between the introduction of cow’s milk and the pathogenesis of the disease becomes difficult. The exact molecular mechanism behind this association is yet unknown. However, there are multiple reports suggesting the role of a variety of constituents of cow’s milk such as casein, bovine insulin and bovine serum albumin (BSA) in the development of type 1 DM (Atkinson13).
As the incidence of type 1 DM is found to be very high in northern Europe where sunshine is limited, low serum concentrations of vitamin D (sunshine vitamin) was suspected to be associated with the pathogenesis this disease. Various studies were conducted to understand this association. It was observed that supplementation of vitamin D during infancy played a protective role against this disease as it reduced the risk of developing this disease. Recent studies have also correlated the polymorphisms in the vitamin D metabolism gene with the disorder (Atkinson 13) (Knip and Akerblom 9).
Some other environmental factors that influence the pathogenesis of the disease include toxins, food constituents and drugs. Toxic doses of N-nitroso derivatives trigger the generation of free radicals that cause diabetes. Certain factors like an accelerated linear growth, overeating and weight gain increase the work load on β-cell. They get activated to match the insulin secretion required by the body. Cytokine induced damage is noticed more in the active β-cells rather than in the resting β-cells. This increases the chances of developing insulin resistance, further leading to both type 1 and type 2 DM. Obesity during the early childhood life puts one at a greater risk of developing the disease. Hence, modifications in the lifestyle habits through diet control and physical activity can reduce the risk to a certain extent (Knip and Akerblom 10) (Atkinson 14). Research has suggested that Interferon-alpha, which is normally used as an injectable drug to cure hepatitis C, has a tendency to initiate type 1 DM. Normally, interferon-alpha fights against different viruses and some forms of cancer. The mechanism behind its association with type 1 DM is the upregulation of the genes that are under its control (Digitale).
10. Combined effect Of All the Three Types of Factors
The three essential prerequisites of the pathogenesis of type 1 DM are activation of β cell-reactive T cells, proinflammatory response and failure of immune regulation of autoreactive responses. Extensive studies have shown that a collaborated action of the trio, that is, genetic factors, environmental factors and autoimmunity, decide the pathogenesis of the disease. Various environmental factors act on the developing immune system. This action can begin from the womb and continue throughout childhood. These factors can also effect in adulthood, bringing changes as immunosuppression, allergic responses, inflammation and autoimmunity. Such disturbances in the immune reaction during the early childhood usually get suppressed in a normal person. But individuals who are genetically more susceptible, for example, those having polymorphisms in HLA class II genes or those who show mutations in FOXP3 gene and ARE gene, fail to suppress this autoimmune reaction. Non-tolerant lymphocytes are produced in the peripheral lymphoid organs due to the autoimmune reaction. The thymic negative selection that suppresses the autoreactive T lymphocytes fails and the lymphocytes bearing the T cell receptors starts reacting with the islet antigens. Certain local intra-pancreatic events also contribute towards the systemic activation of the autoreactive T lymphocytes. Maternal antibodies, viral infections or APC dysfunction can play the role of a local precipitator that triggers systemic activation. These factors can act either alone or along with a genetic predisposition. Once the APCs driving the autoreactive lymphocytes reach a particular level in the islet cells, the development of type 1 DM begins its course. More antigens get targeted as the islet cell destruction progresses. This appears in the form of increased level of autoantibodies. Some factors that are detrimental to β-cells include cytotoxic T cells, tumor necrosis factor α, type 2 interferon, Interleukin -1β and nitric oxide. Even though the exact etiology might not be confirmed during many cases, the current research has helped to ascertain the crucial effector pathways of islet destruction.
11. Summary
There are several hurdles in the pathway of identifying the pathogenesis of type 1 DM disease. Some of these hurdles include difficulty in biopsying the pancreas, identification of the proportional contribution of the environmental factors and other predisposing factors like genes, etc. Out of the several factors contributing towards the development of type 1 DM, environmental factors offer a potential means for intervention. As these factors are exogenous, they can be targeted to prevent the disease from spreading at an epidemic rate in many parts of the world. Primary prevention targets new born children in those areas where type 1 DM is more prevalent. The effect of increasing the duration of the breast milk, along with the delay in the introduction of the cow’s milk or cereals is being currently tested under various clinical trials. Supplementation of vitamin D, omega 3 fatty acids and cod liver oil to the infants and pregnant women is also being tested. The secondary prevention of the disease aims to stop the destructive autoimmune process after the initial diagnosis. This can be achieved with the help of certain drugs like immunosuppressants. Depending on the age of diagnosis (ranging between 10-20 years) a portion of β-cells may remain unaffected and intact. These unaffected cells have shown chances of survival even after 30 years of initial diagnosis. Immunosuppressants like cyclosporine can arrest the autoimmune destruction, hence preserving the unaffected β-cells. These drugs can help in prolonging the life of an individual, but are associated with many side effects (Poretsky 196). Identification of the autoantigens (β-cell proteins) was a breakthrough achievement, as it helped in the understanding of the role of autoimmunity in the pathogenesis of the disease. All autoreactive lymphocytes do not trigger the destruction of the β-cells. In fact, certain cytokines like IL-4 or IL-10 show positive effects when they are expressed in correct quantities at the right time. For example, their introduction prior to the massive loss of the islet cells can help to prevent the disease to some extent. Hence, an ideal intervention program aiming at augmentation of regulatory responses and control of aggressive anti-islet activities can help to arrest the β-cell destruction. Systemic modulators like vitamin D3 analogs and islet-antigen specific DNA vaccines that increase the concentration of the regulatory T lymphocytes are being tested in this line. However, further research is required to define the contribution of environmental factors and the interaction of the environmental factors with the predisposing genes or protective genes. This research would provide a holistic picture of the development of type 1 DM.
Figure 1: Physiology of Glucose Regulation
An image showing overall physiology of glucose regulation (Clinical Pathophysiology Of The Endocrine System).
Figure 2: Mechanism of Pathogenesis of Type 1 DM
This image shows the role of environmental factors, genetic susceptibility and ineffective immune response in the pathogenesis of type 1 DM (Ozougwu et al. 49).
Figure 3: Role of autoantibodies in Type 1 DM
This figure represents the effect of multiple autoantibodies on the risk of developing type 1 DM. The effects of GAD65, IA-2, or insulin autoantibodies were tested. It shows that the risk of developing diabetes increases with the increase in the autoantibody types (Notkins and Lernmark 1249).
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