The Epidemiology, Pathogenesis, and Treatment of Type 1 Diabetes

ISHITA AGGARWAL

The Epidemiology, Pathogenesis, and Treatment of Type 1 Diabetes – A Mini-Review

Ishita Aggarwal 1

1 HBSc Candidate, Faculty of Arts and Science, University of Toronto

100 St. George Street, Toronto ON Canada M5S 3G3 i.aggarwal@mail.utoronto.ca

THE EPIDEMIOLOGY, PATHOGENESIS, AND TREATMENT OF TYPE 1 DIABETES

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Abstract

Type 1 diabetes mellitus (T1D), also known as insulin-dependent diabetes, is a chronic disease caused by autoimmune (type 1a) or spontaneous (type 1b) destruction of pancreatic beta cells, resulting in insulin deficiency. A lack of insulin causes hyperglycemia (high blood glucose levels), resulting in recurrent urination (polyuria), augmented thirst (polydipsia) and hunger (polyphagia), and weight loss. Accounting for

10% of total diabetes cases, T1D affects millions of individuals worldwide. It is generally diagnosed in children before 20 years of age. Furthermore, the Juvenile Diabetes

Research Foundation International (JDRF Int.) predicts an increase in the incidence of the disease among youth in upcoming years. Unfortunately, T1D is fatal without treatment. This review discusses the epidemiology, pathogenesis, immune system involvement, and treatment of type 1 diabetes.

Keywords: Type 1 Diabetes, Epidemiology, Genetics, Pathogenesis, Experimental

Models, Treatment

Introduction and Epidemiology

Type 1 diabetes mellitus (T1D), also known as insulin-dependent diabetes, is a chronic disease caused by autoimmune (type 1a) or spontaneous (type 1b) destruction of pancreatic beta cells, resulting in insulin deficiency (1)(2). A lack of insulin causes hyperglycemia (high blood glucose levels), resulting in recurrent urination (polyuria), augmented thirst (polydipsia) and hunger (polyphagia), and weight loss (1)(3).

Accounting for 10% of total diabetes cases, T1D affects millions of individuals worldwide

(2)(4). It is generally diagnosed in children before 20 years of age (3)(5). Furthermore, the Juvenile Diabetes Research Foundation International (JDRF Int.) predicts an


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ISHITA AGGARWAL increase in the incidence of the disease among youth in upcoming years (2).

Unfortunately, T1D is fatal without treatment (3).

Incidence and Prevalence of T1D: Multiple registry studies, including the World Health

Organization Multinational Project for Childhood Diabetes (DIAMOND Project) (6) and

SEARCH for Diabetes in Youth (SEARCH) (7)(8), have been conducted to investigate the incidence of T1D worldwide (5). Firstly, the DIAMOND Project, initiated in 1990, aimed to study the development of T1D in children. From 1990-1994, the incidence of

T1D in children (ages 14 and younger) was reported to be 4.5% of the world’s populace in the studied age group (5)(6). Furthermore, it was observed that the prevalence of the disease increased as age increased in most groups. Accordingly, the highest prevalence of T1D was seen in 10-14 year-olds (5). The DIAMOND Project reported a variation in the occurrence of the disease by country (6). The lowest prevalence of T1D

(<1/100,000 cases per year) was observed in China and South America. Conversely, the highest incidence of the disease (>20/100,000 cases per year) was reported in

Finland, Canada, and New Zealand. The investigators attributed the variation between ethnic groups to genetic and environmental differences (5)(6).

Secondly, the SEARCH for Diabetes in Youth Study investigated the incidence of T1D in Americans 20 years of age and younger (7)(8). SEARCH evaluated the onset of diabetes by age, gender, and ethnicity (7)(8). The SEARCH Study suggested that incidence rates for T1D reached a peak in age ranges 5-9 years and 10-14 years.


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Incidence of T1D was reported to be equal in females and males (7). Furthermore, prevalence of the disease was observed to be highest in Caucasian youth (3)(5).

Temporal Trends: An updated report from the DIAMOND Project investigated the prevalence of T1D in children (14 years of age and younger) from 57 countries. From

1990-1999, the average annual increase in the occurrence of the disease was 2.8%.

The authors attributed the increase to gene-environment interactions (5).

Risk Factors for Development of T1D: Age, gender, ethnicity, genetics and environmental influences contribute to the development of T1D (3)(5)(9). Firstly, T1D is prevalent in youth 20 years of age and younger. The incidence rates of the disease increase from birth and peak at age 14. The prevalence of T1D decreases after puberty and stabilizes in adulthood. The occurrence of the disease is markedly lower in adults than in children (3)(5). Secondly, it has been found that female and male children are equally affected with T1D. However, certain studies have shown that males are disproportionally affected in regions with a high prevalence of T1D while females are disproportionally affected in regions with a low prevalence of the disease (5). Thirdly, in a follow-up experiment, the SEARCH Study reviewed the incidence of T1D in five ethnic groups (non-Hispanic white, African American, Hispanic, Asian and Pacific Islander, and

Navajo populations). The authors indicated that the prevalence of T1D is highest in non-

Hispanic white populations and lowest in Navajo groups. Finally, genetics and environmental factors (discussed below) influence the onset of T1D (5).


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Genetic Susceptibility Factors

Genetics contribute to the onset of T1D. In 1998, the EURODIAB Ace Study Group found that T1D is common in families with a history of the disease (10). Moreover,

Redondo et al. and Hyttinen et al. demonstrated a high (40-60%) concordance of T1D in monozygotic twins (11). Understanding the genetic factors that underlie T1D will clarify the causes and progression of the disease. Furthermore, identifying genes that confer susceptibility for T1D will aid in the establishment of prevention and treatment methods for diabetes patients (12).

The candidate gene approach and genome-wide association studies (GWAS) (9) have been used to uncover over 40 susceptibility loci in T1D, including insulin-coding genes

(E.g. INS), human leukocyte antigen (HLA), interleukin (IL)-2 receptor a (CD25), cytotoxic T lymphocyte antigen (CTLA)-4, and the tyrosine phosphatase PTPN22 (11).

The INS gene and the HLA loci, in particular, show strong associations with T1D.

Insulin Gene-Related Pathway, INS: Insulin, coded by the INS gene, is a key autoantigen targeted by autoimmune responses in T1D (12)(13). Transcription of the hormone is controlled by binding of the transcription factor Purl to the INS promoter region element called VNTR (variable number of tandem repeats) (13). Studies have found that the VNTR is a main susceptibility determinant of T1D. For instance, homozygosity for the short Class VNTR I alleles is found in 75-85% of T1D patients compared to 50-60% of the general population (13). This suggests a link between Class


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VNTR I alleles and T1D. Moreover, homozygosity for the longer Class III VNTR alleles is rarely observed in T1D patients, indicating a dominant protective effect (13).

Major T1D Susceptibility Gene, HLA: The HLA gene, also called IDDM1 (insulindependent diabetes mellitus locus), confers a strong risk for T1D in most ethnic groups.

The HLA Class II DR and DQ alleles are found in approximately 40-50% of T1D cases

(9)(11).

Differences in alleles and haplotypes of the HLA gene exist in Western and East-Asian countries. For instance, the DR3 and DR4 haplotypes confer T1D susceptibility in

Caucasian populations (11). Alternatively, the DR4 and DR9 haplotypes are correlated with the disease in most Japanese groups (11). In Lebanese populations, however, the

DR4 haplotype is neutral in T1D inception (11). Thus, the distribution of T1D susceptibility alleles and haplotypes partially explains differences in worldwide incidences of the disease (11).

The presence of HLA susceptibility alleles does not trigger the development of T1D with absolute certainty. Hence, it is likely that external factors contribute to the onset of the disease as well. For instance, the frequency of susceptibility HLA-DQ alleles is similar in children from Finland and Karelia, a region of Russia. However, the incidence of T1D is six times higher in Finland than Karelia, suggesting a non-genetic contributor (9).

Furthermore, it has been found that the incidence of T1D differs in Western and Eastern


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Germany, despite similar genetic backgrounds in both areas (9). Therefore, it is likely that a combination of genetics and environmental factors induce T1D.

Environmental Factors and Infections Contributing to Type 1 Diabetes

Environmental factors contribute to the onset of T1D. Epidemiological studies have found associations between T1D and socio-economic status (SES), dietary and nutritional habits, and pathogen exposure.

Socioeconomic Factors: In a 2001 study, Patterson et al. showed that developed countries (high SES) have a higher incidence of T1D than poorer nations (low SES)

(11). Westernized countries place a strong emphasis on cleanliness and invest in education and medical care (E.g. vaccinations and antibiotics), resulting in higher levels of hygiene than developing countries (11). High levels of hygiene limit the survival, proliferation, and spread of pathogens. According to the “Hygiene Hypothesis,” a cleaner lifestyle suppresses the natural immune system (11)(14). An untrained immune system may respond inappropriately to self, increasing the frequency of autoimmune diseases, including T1D (11)(14).

Dietary Habits/Nutritional Factors: Dietary habits can influence the development of

T1D (9)(14). Firstly, the early introduction of cow’s milk into the diet of an infant may trigger the disease. A 1999 study by Elliott et al. compared milk consumption in 14 countries. It was found that the incidence of T1D increased with increasing consumption of the milk protein β-casein (A1 and B variants) (9). Accordingly, Nordic countries with


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ISHITA AGGARWAL higher milk consumption rates had high levels of T1D while Iceland with lower milk consumption rates had low levels of T1D (9). Secondly, dietary gluten has been associated with the development of T1D. A study of 1,600 children with T1D parents found that the consumption of gluten before 3 months of age increases islet autoantibody risk (15). Finally, nutritional factors, particularly levels of sun exposure and/or Vitamin D intake, contribute to T1D inception. Vitamin D may have a protective effect against T1D due to its immunosuppressive properties (11). Hence, countries with greater levels of sunlight and enhanced Vitamin D synthesis show a lower incidence of the disease. Furthermore, it has been reported that Vitamin D supplements during pregnancy reduce the risk of T1D (5)(11).

Pathogenic Factors (Viruses and Enteroviruses): Firstly, viral infections may contribute to the development of T1D via multiple mechanisms (15). By mimicking sequence homology of a self-peptide, a pathogen-derived peptide may trigger an immune response against self-tissue in the host organism (known as molecular mimicry) (15). Furthermore, viral infections may provoke inflammation and destruction of host cells, causing release of autoantigens and activation of autoreactive T cells (called bystander activation of T cells) (15). Significant inflammation may induce stress in the endoplasmic reticulum (ER), resulting in protein denaturation and production of new autoantigens (known as antigen spreading) (15). Human viruses, including mumps and rubella, use a combination of the aforementioned mechanisms to induce T1D (15).

Secondly, human enteroviruses, including polioviruses, echoviruses, and rhinoviruses, are associated with T1D. Enteroviruses are generally transmitted through consumption


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ISHITA AGGARWAL of contaminated food and drink. The rarity of enteroviruses in most developed countries is correlated with an increase in the incidence of T1D, demons trating the “Hygiene

Hypothesis ” (16).

Pathogenesis of T1D and Immune System Involvement

The development of T1D comprises a complex set of events from the activation of antigen-presenting cells (APCs) that generate β-cell antigens to islet destruction and insulin deficiency (2). Pathogenesis of T1D can be categorized into two stages. During the first stage (called insulitis), pancreatic islets are penetrated by leukocytes (2). After a benign prelude, insulinproducing β-cells are destroyed (2).

The immune system comprises innate and adaptive immunity (2)(17). The innate immune system uses M ϕs, DCs, NK, NK T and γ δ T cells to recognize dangerous molecules and educe an immediate immune response (17)(18). Moreover, cells of the innate immune system may activate antigen-specific cells of the adaptive immune system (2)(17). Recent studies have found that the innate immune system is associated with the development of autoimmune responses in inflammatory environments (2)(19).

In healthy tissues, APCs, including M ϕs and dendritic cells (DCs), are activated in response to infected host cells (2). By presenting self-antigens to autoreactive T cells,

APCs can remove damaged cells. In inflamed tissues, however, signals that encourage

APC maturation are prematurely generated. Hence, self-antigen-specific T and B cells are activated, causing an autoimmune response (2). Innate immune cells, including

M ϕs, DCs, NK, NK T and γ δ T cells, are crucial to the progression of T1D.


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M ϕs: M ϕs are vital for host defence. Using pattern recognition receptors (PRRs), Mϕs can recognize pathogen-associated molecular patterns (PAMPs) and can activate immune regulators (2)(20). However, they can cause extensive local damage when uncontrolled. In T1D mice, M ϕs invade pancreatic islets before NK and autoreactive T- and B-cells (2). Furthermore, M ϕs from NOD mice (T1D animal model) produce higher levels of proinflammatory cytokines (E.g. IL-12, TNF α, and IL-1α ), promoting the differentiation of diabetogenic cells (2). Finally, M ϕs have been implicated in the direct destruction of B-cells (2). Hence, M ϕs contribute to the pathogenesis of T1D.

Dendritic Cells (DCs): Dendritic cells (DCs) are crucial stimulators of the adaptive immune system (15). DCs accumulate in pancreatic islets of T1D patients and NOD mice. In NOD mice, a subset of DCs receives maturation signals (15). Mature DCs are responsible for capturing B-cell antigens from islet cells and priming diabetogenic T cells (15). Hence, DCs contribute to the onset of the disease

NK Cells: NK cells are responsible for attacking host cells that are infected by foreign microorganisms (2)(21). Furthermore, they are potent moderators of APCs, including

M ϕs and DCs (15). Interestingly, NK cells may cause or protect against T1D depending on anatomical location and chemical environment (21). Research has shown that NK cells can mediate the breakdown of pancreatic islet cells, contributing to the onset of the disease. Furthermore, reduction of NK cells in NOD mice suppresses the progression of induced T1D, suggesting that NK cells influence T1D development (2). Conversely,


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ISHITA AGGARWAL studies have indicated that NK cells protect against T1D. Impaired function of NK cells in T1D patients suggests a protective function of NK cells (15).

NK T Cells: NK T cells, a subset of T cells, are regulatory cells that have the ability to secrete IL-4 (2). NK T cells can recognize glycolipid antigens, including α galactosylceramide. NK T cells may protect against T1D (15). In NOD mice, activation of NK T cells by treatment with α -galactosylceramide provides protection against T1D

(15). Furthermore, activation of NK T cells in NOD mice prolongs the survival of transplanted pancreatic islets (15).

γδ T Cells: γ δ T cells are crucial for linking the innate and the adaptive immune systems (2). They are not MHC restricted and can recognize a broader range of antigens compared to

α β T cells. γ δ T cells can detect molecules produced by microorganisms. Furthermore, they can recognize self-antigens expressed in epithelial cells that have experienced tissue stress and damage (2). γ δ T cells are involved in the development of autoimmune diseases, including T1D. Studies have shown that

γ δ T cells are found in areas of inflammation due to autoimmune diseases (2). Furthermore, research has found that numbers of

γ δ T cells are reduced in NOD mice and T1D patients (2).

Experimental Models

Animal Models (Mice and Rats): Animal models have improved our understanding of the immunological mechanisms that underlie T1D. Moreover, animal models are crucial


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ISHITA AGGARWAL for developing therapeutic interventions for diabetes patients. Two commonly used animal models for T1D include the NOD mouse and the BioBreeding (BB) rat (2). The

NOD mouse and the BB rat develop T1D by autoreactive T cell-mediated destruction of pancreatic

ß-cells (2). The pattern of T1D in NOD mice is similar to the pattern of the disease in humans (22). However, the incidence rate of T1D in female and male NOD mice differs from the incidence rate of T1D in female and male patients (2). For example, the incidence of T1D in female NOD mice is 60-80% while the incidence of the disease in male NOD mice is 20-30% (2). In contrast, the incidence of T1D is equal in women and men (3). The pattern of T1D development in BB rats is similar to the pattern of the disease in humans. However, BB rats experience T cell lymphopenia during T1D, unlike human subjects (2).

Clinical Trials and Clinical Research: Clinical trials are a crucial research tool used to advance medical knowledge about T1D (3). They can be used to investigate T1D under different conditions. By studying the effects of different environmental factors on the development of T1D, researchers can attain a stronger understanding of the underlying mechanisms of the disease. They may then investigate therapies that diminish the effects of T1D (3). In 2002, a clinical trial tested the glycaemic control of patients who use continuous subcutaneous insulin infusion and patients who use intensive insulin injections (9). It was found that glycaemic control was higher in patients who used continuous subcutaneous insulin infusion compared to patients who used intensive insulin injections. Furthermore, it was discovered that less insulin was needed to achieve a strict control level in patients who used continuous subcutaneous insulin


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ISHITA AGGARWAL infusion (9). Furthermore, an ongoing clinical trial is evaluating the risk of cardiovascular disease in adults with T1D (11). Patients with T1D (40 years of age and older) will be followed for three years. The treatment group will receive metformin while the control group will receive a placebo. Researchers will monitor the thickness of arteries in their neck to determine risk of heart disease (11). It is clear that clinical trials are frequently used to investigate multiple aspects of T1D.

Treatment and Prevention

PAST THERAPIES

Immunosuppressive Therapies for Treatment of T1D: In the mid1980’s,

Cyclosporine A was the first large-scale immunosuppressive to be studied (15).

Cyclosporine A reduced the activity of the immune system, decreasing autoimmune responses and lowering the incidence of T1D (15). However, renal toxicity was a common side-effect and cyclosporine A testing ceased (15).

PRESENT THERAPIES

Insulin Injections/Pumps and Glucose Monitors: Common treatments for T1D include frequent injections of rapid-acting insulin with meals combined with daily basal insulin (16)(23). Moreover, insulin pumps are widely used to treat youth with the disease

(23). In the 1990’s, pediatric diabetologists were cautious when using insulin pumps for children (5)(16). They observed a three-fold increase in severe hypoglycemia in subjects who were extensively treated with insulin pumps during the Diabetes Control and Complications Trial (DCCT). However, developments in our understanding of


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ISHITA AGGARWAL insulin

’s mechanism and advancements in pump features have reduced the caution generated by hypoglycemia (5).

The development of continuous glucose monitors (CGMs) has improved glycemic outcomes in T1D patients (1)(5). CGMs were evaluated in a JDRF clinical trial. The clinical trial compared T1D adults with glycated haemoglobin (A1c) levels over 7% who were using CGMs to controls (5). A large reduction in A1c levels was observed in adults

25 years of age or older. In contrast, A1c levels rose in controls (5).

Antigen Specific Therapies for Treatment and Prevention of T1D: Antigen specific therapies are safer than immunosuppressive therapies (15). Hence, antigen specific therapies are crucial intervention techniques for T1D patients (4). The most thoroughly studied antigens to date include insulin and HAD65 (15). Antigen specific therapies use target autoantigens to eradicate pathogenic T cells and activate T regulatory cells at the target organ (15). Trialnet/Diabetes Prevention Trial (DPT) conducted two studies to determine insulin

’s potential in preventing the development of diabetes in T1D patients

(15). Insulin was administered parenterally and orally. The study found that parenteral insulin did not decrease progression of the disease. Similarly, oral insulin did not alter overall progression of diabetes (15). However, in subset of patients with high levels of insulin autoantibodies, delay in progression of T1D was observed (15).

Environmental Therapy for the Prevention of Islet Autoimmunity: Early exposure to foodstuffs may confer susceptibility to T1D (24).

The Trial to Reduce IDDM in the


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Genetically at Risk (TRIGR) documented the rates of autoantibody development and the incidence of T1D in children, ages 10 and younger (25). Infants who had a firstdegree relative with T1D and possessed high risk HLA alleles were given a highly hydrolyzed formula (treatment group) or conv entional cow’s milk formula (control group)

(25). Children who received the hydrolyzed casein-based formula had less autoantibody positivity campared to the control group (25), suggesting that environmental therapies may benefit T1D patients.

FUTURE DIRECTIONS FOR TREATMENT: Stronger knowledge of T cell structures will aid in the discovery of a cure for T1D in humans.

Acknowledgements

The author thanks Drs. Jennifer Gommerman, Dana Philpott, and Liliana Clemenza for their feedback, comments, and assistance. This work would not have been possible without the support of the Immunology Department at the University of Toronto.

Conflict of Interest

The author reports no conflict of interest.

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The Epidemiology, Pathogenesis, and Treatment of Type 1 Diabetes

The Epidemiology, Pathogenesis, and Treatment of Type 1 Diabetes – A Mini-Review

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