Type 1 diabetes mellitus

PATHOGENESIS OF TYPE-1 DIABETES MELLITUS

DR. PRIYANKA BHARDWAJ

PATHOLOGY DEPARTMENT

A group of metabolic disorders sharing the common underlying feature of hyperglycemia.

Hyperglycemia in diabetes results from defects in insulin secretion, insulin action, or, most commonly, both.

Diabetes mellitus

The total number of people with diabetes

worldwide was estimated to be between 151 million and 171 million at the turn of the century, and is expected to rise to 366 million by 2030.

The prevalence of diabetes in the developing world are due to sedentary life styles, with India and China being the largest contributors to the world's diabetic load.

Epidemiology

The chronic hyperglycemia and metabolic dysregulation may be associated with secondary damage in multiple organ systems, especially the kidneys, eyes, nerves, and blood vessels.

Diabetes is the leading cause of end-stage renal disease, adult-onset blindness, and non traumatic lower extremity amputations.

DIAGNOSIS Blood glucose values are normally

maintained in a very narrow range, usually 70 to 120 mg/dl.

The diagnosis of diabetes is established by elevation of blood glucose by any one of three criteria:

1.    A random glucose concentration greater than 200 mg/dl, with classical signs and symptoms 2. A fasting glucose concentration greater than 126 mg/dl on more than one occasion.3. An abnormal oral glucose tolerance test (OGTT), in which the glucose concentration is greater than 200 mg/dl 2 hours after a standard carbohydrate load.

Individuals with fasting glucose concentrations less than 100 mg/dl, or less than 140 mg/dl following an OGTT, are considered to be euglycemic.

Fasting glucose concentrations greater than 100 mg/dl but less than 126 mg/dl, or OGTT values greater than 140 mg/dl but less than 200 mg/dl, are considered to have impaired glucose tolerance, also known as “pre-diabetes.”

It is defined as elevated blood sugar that does not reach the criterion accepted for an outright diagnosis of diabetes.

Individuals with pre-diabetes have an elevated risk for developing frank diabetes.

Pre-diabetic individuals have a significant risk of progressing to overt diabetes.

Pre-diabetics are at risk for cardiovascular disease, as a result of the abnormal carbohydrate metabolism as well as the coexistence of other risk factors such as low levels of high-density lipoprotein, hypertriglyceridemia, and increased plasminogen activator inhibitor-1 (PAI-1).

I) Type 1 DM ( IDDM ) a) Autoimmune (Type I A) b) Non autoimmune/ idiopathic (Type 1 B) II) Type 2 DM (NIDDM) III) Type 3 DM (Other specific types of DM) A) Specific defined gene mutation

a . Maturity onset diabetes of youth (MODY) i) MODY- I : Hepatic nuclear factor 4α (FINF4A) gene

mutation

Classification of Diabetes Mellitus

ii) MODY-2: Glucokinase gene mutation iii) MODY-3: Hepatic nuclear factor 1 α gene mutationiv) MODY-4: Insulin promotor factor I (IPF 1) gene

mutationv) MODY-5: Hepatic nuclear factor 1 13 HINF 1 B)

gene mutationvi)MODY-6: Neurogenic Differentiation 1 (NEURODI)

gene mutationVii) MODY-X: Unidentified gene mutation b) Insulin gene mutationc) Insulin receptor gene mutation d) Exocrine pancreatic defect

E) Diabetes associated with genetic syndromes Prader willi syndrome F) Diabetes associated with Drug therapy IV) Type 4 DM Gestational diabetes mellitus (GDM)

Introduction Type1 diabetes Insulin Dependent diabetes mellitus, or Juvenile

onset DM. Average onset is in childhood or early adulthood

(usually before 30 years of age) Due to pancreatic islet destruction predominantly

by an autoimmune process. Cell mediated response: - Type 1 diabetes is caused by a T cell mediated

autoimmune destruction of the pancreatic beta cells.

Immune mediated in over 90% of cases and idiopathic in less than 10% .

Pathogenesis of Type 1A DM is explained on the basis of 3 mutually-interlinked mechanisms:

a)Genetic susceptibility. b) Autoimmune factors. c) Certain environmental factors. Pathogenesis of Type 1B DM remains idiopathic.

Pathogenesis of Type 1 DM

Genetic susceptibility Higher concordance rates are seen in

monozygotic vs dizygotic twins. Over a dozen susceptibility loci for type 1

diabetes are now known. Most important is the HLA locus on

chromosome 6p21; the HLA locus contributes as much as 50% of the genetic susceptibility to type 1 diabetes.

The polymorphisms in the HLA molecules are located in or adjacent to the peptide-binding -

- pockets consistent with the notion that disease-associated alleles code for molecules that have particular features of antigen display.

This disease have either a HLA-DR3 OR HLA-DR4 haplotype.

40% to 50% of type 1 diabetics are combined DR3/DR4 heterozygotes.

Individuals who have either DR3 or DR4 concurrently with a DQ8 haplotype (which corresponds to DQA1*0301-DQB1*0302 alleles) demonstrate one of the highest inherited risks for type 1 diabetes in siblings.

HLA-disease association reflect the ability of specific HLA molecules to present self antigens or T-cell selection and tolerance.

HLA-mediated susceptibility represents ∼50% of the genetic susceptibility to T1D.

 HLA class haplotypes have been ranked in a risk hierarchy.

 Those in the general population with the highest risk genotype DRB1*03-DQA1*0501-DQB1*0201/DRB1*0401-DQA1*0301-DQB1*0302 have a 5% absolute risk of getting diabetes by the age of 15 years.

IA2-A are associated with specific DR alleles,

GADA are associated with DR3 and IAA are associated with DR4, The recently discovered ZnT8 antibodies

are associated with a single base pair change in the SLC30A8 gene.

ZnT8 causes changes in the secretory pathway, which leads to apoptosis and thus directly reduction of β cell mass or activation of underlying autoimmunity.

The HLA contains lots of genes close together that are transferred from the parent to the child in adjacent ‘DNA chunks’ or haplotypes that are said to be in ‘linkage disequilibrium’.

The principal susceptibility markers for T1D are HLA class II DQB1*0302 on the DR4 haplotype and DQB1*0201 on the DR3 haplotype .

Several NON-HLA genes also confer susceptibility to type 1 diabetes.

The first disease-associated NON-MHC gene to be identified was insulin, with variable number of tandem repeats(VNTR’S) in the promoter region being associated with disease susceptibility.

The mechanism underlying this association is unknown.

These polymorphisms influence the level of expression of insulin in the thymus, thus altering the negative selection of insulin-reactive T cells.

A second locus linked with susceptibility to T1D: a variable number tandem repeat region(VNTR’S) in the promoter of the INS gene, which is important for regulation of INS production. Alleles in this region are divided into

three classes distinguished by the number of DNA base pair repeats.

Class I alleles have a mean of 570 base pairs,

class II alleles 1200 base pairs and class III alleles have 2200 base pairs.

INS GENE

Class I alleles are associated with higher INS expression in the pancreas when compared with class III alleles, but the opposite is true in the thymus where class I alleles are expressed at 2–3-fold lower levels.

Protection from T1D is associated with the class III allele.

This is likely to alter the selection of T cells in the thymus and may therefore influence tolerance to INS.

CTLA-4 is a surface molecule found on activated T cells that produces a negative signal for T cell activation.

The cytotoxic T-lymphocyte antigen (CTLA-4) gene encoded on chromosome 2q33 gene for T1D susceptibility.

CTLA-4 gene expression can increase T cell self-reactivity and therefore play an important role in autoimmune diseases such as T1D.

CTLA-4

 PTPN22, a gene found on chromosome 1p13 that encodes lymphoid protein tyrosine phosphatase, to be associated with susceptibility to T1D . 

An SNP contributes to susceptibility to T1D because of increased negative regulation of T cell activation.

Polymorphisms in CTLA4 and PTPN22 and autoimmune thyroiditis; linked with susceptibility to type 1 diabetes.

Both CTLA-4 and PTPN-22 inhibit T-cell responses, so polymorphisms is responsible for excessive T-cell activation.

PTPN22

The interleukin 2 receptor alpha (IL2RA) region on chromosome 10p15 associated with T1D.

IL2RA encodes the α-chain of the IL-2 receptor complex, which is responsible for binding IL-2, a key player in the proliferation of regulatory T cells.

The polymorphism reduces the activity of this receptor, which is critical for the maintenance of functional regulatory t cells.

IL2RA/CD25

The association of IL2RA with T1D and identified two SNPs associated with the increased risk of T1D.

SNP SS52580101 to be the most closely associated with T1D.

T1D-susceptible alleles are associated with decreased concentrations of IL2RA.

IFIH1 (interferon induced with helicase C domain 1) On chromosome 2q24.3 as the sixth gene to be strongly associated with T1D. The strongest association was found with RS1990760.

IFIH1 contributes to innate immune responses by releasing the cytokine interferon-gamma and inducing apoptosis of virally infected cells.

This molecule provide molecular insights that viruses and enteroviruses, in particular, contribute to the initiation of T1D,

CoxsackieB4 infection recently demonstrated in the pancreas of individuals with T1D.

IFIH1

Vitamin D has important immunomodulatory properties, and the active form vitamin D3 (1,25 dihydroxyvitamin D3) shown to inhibit T cell proliferation.

The protective effect to T1D in infancy conferred by vitamin D supplementation.

Genetic studies of vitamin D-associated genes and T1D have been complicated.

Vitamin D receptor (VDR)

The association of polymorphisms in the CYP27B1 and CYP24A1 genes involved in the activation and inactivation, respectively, of the vitamin D precursor enzyme 1α-hydroxylase in T1D.

No association identified for the CYP24A1 gene;

An association with T1D identified for the CYP27B1 gene on 12Q13.1–Q13.3, in which the C allele of RS10877012 was significantly associated with increased risk of T1D.

A potential genetic explanation for the observed effects of vitamin D in T1D has been identified, and further studies of vitamin D in T1D are ongoing.

KIAA0350, also known as CLEC 16A, is a gene of unknown function on chromosome 16p13.2.

Its structure, it has a C-type lectin-binding domain, which indicates for cell surface receptor.

It is expressed in immune cells,

particularly B lymphocytes, dendritic cells and NK T cells.

KIAA0350

Progress in the identification of T1D susceptibility alleles: the last 35 years.

Environmental Factors Environmental factors, especially viral infections,

involved in triggering islet cell destruction type 1 diabetes.

Type 1 diabetes and infection with mumps, rubella, coxsackie B, or cytomegalovirus, among others.

At least three different mechanisms have been proposed to explain the role of viruses in the induction of autoimmunity.

The first is “bystander” damage, wherein viral infections induce islet injury and inflammation, leading to the release of sequestered β-cell antigens and the activation of autoreactive T cells.

The second possibility is that the viruses produce proteins that mimic β-cell antigens, and the immune response to the viral protein cross-reacts with the self-tissue (“molecular mimicry”).

The third hypothesis suggests that “predisposing virus” might persist in the tissue of interest, and subsequent re-infection with a related virus

“Precipitating virus” that shares antigenic epitopes leads to an immune response against the infected islet cells.

These mechanisms contribute to β-cell damage, and no causative viral infection is established.

Infections may be protective; the underlying mechanisms of such a protective effect are unknown.

No causal association between childhood vaccinations and the risk of developing type 1 diabetes.

Most autoimmune diseases, the pathogenesis of type 1 diabetes represents interplay of genetic susceptibility and environmental factors.

Mechanisms of β-cell destruction Clinical onset of type 1 diabetes is often

abrupt, the autoimmune process usually starts many years before the disease becomes evident, with progressive loss of insulin reserves over time.

The classic manifestations of the disease (hyperglycemia and ketosis) occur late in its course, after more than 90% of the β cells have been destroyed.

In type 1 diabetes pathogenesis have emerged from studies of the non obese diabetic mouse model, which shares features of autoimmune islet destruction observed in the human disease.

The fundamental immune abnormality in type 1 diabetes is a failure of self-tolerance in T-cells.

This failure of tolerance may be result of some combination of defective clonal deletion of self-reactive T-cells in the thymus, as well as defects in the functions of regulatory T cells or resistance of effector T- cells to suppression by regulatory cells.

Autoreactive T-cells not only survive but are poised to respond to self-antigens.

The initial activation of these cells is thought to occur in the peri pancreatic lymph nodes, perhaps in response to antigens that are released from damaged islets.

The activated T cells then traffic to the pancreas, where they cause β cell injury.

Multiple T-cell populations have been implicated in this damage, including TH1 cells (which may injure β cells by secreted cytokines, including IFN-γ and TNF), and CD8+ CTLs (which directly kill β cells).

The islet auto-antigens that are the targets of immune attack may include insulin itself, as well as the β-cell enzyme glutamic acid decarboxylase (GAD), and islet cell autoantigen 512 (ICA512).

A role for antibodies in type 1 diabetes is suspected that autoantibodies against islet antigens are found with type 1 diabetes,

Asymptomatic family members at risk for progression to overt disease; the presence of islet cell antibodies is used as a predictive marker for the disease.

Autoantibodies are involved in causing injury or are produced as a consequence of islet injury.

Auto immune antibodies

Islet autoimmunity can be detected multiple islet autoantibodies and their characteristics.

Combinations of antibodies to insulin (IAA), glutamic acid decarboxylase (GADA) and the tyrosine phosphatase IA-2, Insulin autoantibodies (IAAs), Islet cell autoantibodies (ICAs) are found in individuals at risk or who have recently developed T1D.

The presence of antibodies in the zinc transporter (ZNT8). 

Islet autoantibodies are indicative of ongoing autoimmune β-cell destruction.

Autoimmunity would therefore require identification of infants at genetic risk of T1D.

Autoimmunity would therefore require identification of infants at genetic risk of T1D.

The autoimmune process begins early in life: islet autoantibodies are detected at the age of 5 years in T1D cases; 

By the age of 2 years, antibodies to INS (generally the first to appear) have been detected as early as 6–12 months.

Most autoimmune diseases, the pathogenesis of type 1 diabetes represents interplay of genetic susceptibility and environmental factors.

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