type i diabetes mellitus (iddm)

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TYPE I DIABETES MELLITUS a panorama:

TYPE I DIABETES MELLITUS a panorama Belal A El- Dabour

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Diabetes mellitus is a group of metabolic diseases in which a person has high blood sugar , either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced. This high blood sugar produces the classical symptoms of polyuria (frequent urination), polydipsia (increased thirst) and polyphagia (increased hunger).

Types:

Types There are three main types of diabetes: Type 1 diabetes: results from the body's failure to produce insulin (Also referred to as insulin-dependent diabetes mellitus, IDDM for short, and juvenile diabetes.) Type 2 diabetes : results from insulin resistance (Formerly referred to as non-insulin-dependent diabetes mellitus, NIDDM for short, and adult-onset diabetes.) Gestational diabetes : is when pregnant women, who have never had diabetes before, have a high blood glucose level during pregnancy. It may precede development of type 2 DM. Other forms : congenital diabetes, which is due to genetic defects of insulin secretion, cystic fibrosis-related diabetes, steroid diabetes and several forms of monogenic diabetes. Types I & II are chronic whereas gestational D.M is not.

Numbers:

Numbers In 2000, at least 171 million people worldwide suffer from diabetes, or 2.8% of the population. Diabetes mellitus occurs throughout the world, but is more common (especially type 2) in the more developed countries. In 2010 nearly 26 million people have diabetes in the United States alone Another 57 million people are estimated to have pre-diabetes. Type 1 diabetes accounts for 5-10% of cases, affecting 1 of 400 children and adolescents. IDDM is the second most common chronic disease of childhood , increasing in prevalence from 1 in 2500 at 5 years of age to 1 in 300 at 18 years of age. The National Diabetes Information Clearinghouse estimates that diabetes costs $132 billion in the United States alone every year.

Type I Vs. Type II:

Type I Vs. Type II Type 1 diabetes Type 2 diabetes Phenotype Onset primarily in childhood and adolescence Onset predominantly after 40 years of age* Often thin or normal weight Often obese Prone to ketoacidosis No ketoacidosis Insulin administration required for survival Insulin administration not required for survival Pancreas is damaged by an autoimmune attack Pancreas is not damaged by an autoimmune attack Absolute insulin deficiency Relative insulin deficiency and/or insulin resistance Treatment: insulin injections Treatment: (1) healthy diet and increased exercise; (2) hypoglycemic tablets; (3) insulin injections Genotype Increased prevalence in relatives Increased prevalence in relatives Identical twin studies: <50% concordance Identical twin studies: usually above 70% concordance HLA association: Yes HLA association: No

Etiology:

Etiology IDDM usually results from both an inherited risk and external triggers, Infection, diet . Type 1 diabetes is an autoimmune disorder in which the body attacks its pancreatic beta cells.

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Type I diabetes requires genetic susceptibility , triggering agent and a driving factor . ( compared to celiac disease)

Evidence for the autoimmune mechanism:

Evidence for the autoimmune mechanism evidences for an autoimmune mechanism in IDDM include an increased prevalence of other autoimmune diseases, mononuclear cell infiltrates of islets, and recurrent β-cell destruction after transplantation from a monozygotic twin.

Concerning the genetic part:

Concerning the genetic part observations supporting a genetic predisposition include differences in concordance between monozygotic (33% to 50 %), and dizygotic twins (1% to 14%), familial clustering, and differences in prevalence among different populations.

Genetics…:

Genetics… About 18 regions (Loci)of the genome have been linked with influencing type 1 diabetes risk. The most well studied is IDDM1 , which contains the HLA genes that encode immune response proteins. an important genetic risk factor, but they alone do not account for the disease. IDDM2 , which includes is the insulin gene, the other non-HLA gene maps close to CTLA4 , which has a regulatory role in the immune response.

IDDM 1:

IDDM 1 The HLA region is a cluster of genes on chromosome 6. Function: help the immune system to distinguish between self and non-self. HLA alleles may increase the risk of diabetes, have no effect, or even be protective. The inheritance of particular HLA alleles can account for over half of the genetic risk of developing type 1 diabetes . Fine mapping of these regions suggests that the two alleles DQB1 and DRB1 are the most important .

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In the general population, only half of the people inherit a copy (allele) of DR gene called DR3 and DR4, and less than 3% of the people have two alleles. However , in type 1 diabetes at least one allele of DR3 or DR4 is found in 95% of Caucasians , and individuals with both DR3 and DR4 are particularly susceptible to type 1 diabetes. Conversely , the DR2 allele is protective . this association apparently arises not because DR3 and DR4 are susceptibility alleles but because of linkage disequilibrium between DR and DQ. The DQβ1*0201 allele, which segregates with DR3, and DQβ1*0302, which segregates with DR4, appear to be the primary susceptibility alleles. In contrast , DQβ1*602, which segregates with DR2, appears to be a protective allele; that is, it negates the effect of a susceptibility allele when both are present.

What happens ?:

What happens ? Sequences in the DQB1 gene that code for an amino acid other than aspartic acid at position 57 (non-ASP57) are highly associated with type 1 diabetes. Crystal structures suggest that loss of aspartic acid at this position creates an " oxyanion hole ". This may be occupied by the T cell during the interaction between HLA and the T-cell receptor. The diabetes risk of non-ASP57 is further increased when the haplotype also contains the DRB1*0401 allele, suggesting the possible existence of at least two separate loci of susceptibility

Protective Alleles…:

Protective Alleles… A well-known marker for type 1 diabetes is the presence of islet cell autoantibodies. However, even in the presence of islet cell autoantibodies, the haplotype DQA1*0102, DQB1*0602 has a protective effect . But once the diabetes disease process begins, the mechanism that protected these individuals from diabetes is lost, suggesting that inheriting these alleles does not prevent diabetes but may somehow delay or arrest the progression of the disease

IDDM2 Contains the Insulin Gene (INS) :

IDDM2 Contains the Insulin Gene (INS) humans have a single insulin gene that is located on chromosome 11 .It has three exons (coding regions) that span about 2,200 bases. The IDDM2 locus contributes about 10% toward type 1 diabetes susceptibility. The " risk area " of this locus is localized to a region flanking the insulin gene that contains a short sequence of DNA that is repeated many times (Tandem repeats). The repeats are found 0.5 kb upstream from the site where transcription of INS begins. because the number of repeats varies between individuals, this phenomenon is called variable number tandem repeats (VNTRs). There are three classes of VNTR in the insulin gene: Class I has alleles that range from 26 to 63 repeat units. Class II has alleles that average around 80 repeat units. Class III has alleles ranging from 141 to 209 repeat units.

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The class I VNTRs are most common in Caucasians, with around 70% of alleles being in the range of 30-44 repeats, and nearly all other alleles are longer than 110 repeats (class III). The intermediate lengths (class II) are rare . Short class I alleles are associated with a higher risk of developing type 1 diabetes, whereas the longer class III alleles are protective . The presence of at least one class III allele is associated with a 3-fold reduction in the risk of type 1 diabetes, compared with common I/I homozygote genotype.

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VNTR occurs in a non-coding region. the VNTR probably affects the transcription of the insulin gene. Indeed in the pancreas, the class III alleles are associated with 15-30% lower INS mRNA. In contrast, class III alleles are associated with higher levels of INS mRNA in the thymus . Because the longer VNTRs cause more insulin to be produced in the thymus, the detection and deletion of autoreactive T cells may be more efficient. This improved immune tolerance to insulin would lessen the risk of a future onset of type 1 diabetes caused by anti-insulin antibodies.

Other Type 1 Diabetes Susceptibility Loci: IDDM3–IDDM18 :

Other Type 1 Diabetes Susceptibility Loci: IDDM3–IDDM18 The remaining type 1 diabetes susceptibility loci, IDDM3–IDDM18, were mainly discovered by genome scan linkage studies , e.g., looking for linkage between regions of the genome and disease in affected sib-pairs. The IDDM loci are found on several different chromosomes and contain many genes, many of which have now been identified. Some Loci are still not yet approved.

IDDM 4:

IDDM 4 Several potential candidate genes lie near the IDDM4 locus on chromosome 11. These include ZFM1 (zinc finger protein 162) , which encodes a transcription factor found in the pancreas, and FADD (Fas-associated death protein ). IDDM5 The region of chromosome 6 that contains the IDDM5 locus includes the SOD2 gene, which encodes mitochondrial superoxide dismutase.

IDDM6 :

IDDM6 Several candidate diabetes susceptibility genes have been identified in the IDDM6 locus . They include a gene associated with colorectal cancer (DCC) that may be linked with autoimmune disease , a gene that encodes a zinc finger DNA binding domain (ZNF236) that may be linked with diabetic kidney disease, and a molecule that opposes apoptosis (bcl-2 ) .

IDDM 7 :

IDDM 7 NEUROD1 , a transcription factor that is expressed widely in the developing brain and pancreas . NEUROD1 regulates the transcription of the insulin gene. Other genes located within the IDDM7 locus include IGRP (islet-specific glucose-6-phosphatase catalytic subunit-related protein), which encodes the beta cell-specific version of the enzyme glucose-6-phosphatase . IGRP has emerged as a major target of cell-mediated autoimmunity in type 1 diabetes.

IDDM 10:

IDDM 10 Gene for Glutamic acid decarboxylase (GAD) - catalyzes formation of the neurotransmitter GABA. Targeting of this enzyme by autoantibodies has been implicated in the pathogenesis of stiff-man syndrome and type 1 diabetes . GAD is expressed in two different isoforms : one is expressed in the central nervous system, and the other is in the beta cells. The GAD2 gene encodes GAD65, and this protein contains a 24-amino acid segment that is similar to an amino acid sequence found in the Coxsackie virus . Autoimmunity in IDDM may thus arise by "molecular mimicry" between GAD and a viral polypeptide .

Evidence that implicate this locus : :

Evidence that implicate this locus : Autoantibodies against GAD have been found in patients who have had preclinical type 1 diabetes. In the type 1 diabetes mouse, the expression of GAD by beta cells is required for the development of autoimmune diabetes. Complete suppression of beta-cell GAD expression blocks the generation of diabetogenic T cells, leading to the theory that modulation of GAD might have therapeutic value in type I diabetes.

IDDM11 :

IDDM11 ENSA gene, which encodes alpha- endosulphine . This protein is thought to be an endogenous regulator of the beta cell potassium channel (KATP channel). The KATP channels co-ordinate a rise in blood glucose with insulin secretion. As glucose levels rise, the corresponding rise in ATP shuts the channel, leading to a change in membrane polarity. Voltage-sensitive calcium channels flip open, allowing Ca 2+ ions to enter into the beta cells, triggering exocytosis of insulin. Recombinant alpha- endosulphine has been shown to reduce the flow of K + through the KATP channel, and to stimulate insulin secretion .

IDDM12 :

I DDM12 the strongest candidates encode co-stimulatory receptors on the T cell. These co-stimulatory receptors are encoded by the candidate genes for type 1 diabetes susceptibility CTLA4 , CD28, and ICOS. They play an important regulatory role in T cell activation. Loss of regulation may lead to autoimmunity.

IDDM 16:

IDDM 16 Gene for Ab heavy chain . Genetically controlled differences in the immunoglobulin heavy chain may affect an individual's immune response to self antigens and thus alter the risk of developing autoimmune diseases such as type 1 diabetes. IDDM18 A candidate diabetes susceptibility gene in the IDDM18 locus is ILB12 . In humans, variation in IL-12p40 production may influence the reactivity of T cells and initiate or protect against autoimmune diseases such as type 1 diabetes.

Inheritance risk:

Inheritance risk The risk of IDDM in the general population is approximately 1 in 300 . With one affected sibling, the risk increases to 1 in 14 (1 in 6 if HLA identical, 1 in 20 if HLA haplo -identical). The risk increases to 1 in 6 with a second affected first-degree relative in addition to an affected sibling and to 1 in 3 with an affected monozygotic twin. Children of an affected mother have a 1 in 50 to 1 in 33 risk for development of IDDM, whereas children of an affected father have a 1 in 25 to 1 in 16 risk. This paternity-related increased risk appears to be limited to fathers with an HLA DR4 allele.

Environmental factors …:

Environmental factors … A series of evidence supports a critical role of exogenous factors in the development of type 1 diabetes, such as the fact that <10% of individuals with HLA-conferred diabetes susceptibility do progress to clinical disease, a pairwise concordance of type 1 diabetes of <40% among monozygotic twins, a more than 10-fold difference in the disease incidence among Caucasians living in Europe, a several-fold increase in the incidence over the last 50 years, and migration .

Seasonal variation & Suggested triggers..:

Seasonal variation & Suggested triggers.. Most initial autoantibodies appear during the cold period in the fall and winter but rarely in the spring or in the summer. There also seems to be some variation from one year to another in the timing and height of the autoantibody peaks . Different family members get the disease at different times\ages. The triggering agent most likely to be is the enterovirus Coxsackie virus . Rubella may be implicated, too.

Driving factors ?:

Driving factors ? Diet : exposure to most dietary factors tends to be frequent , and still there is some variation in the exposure both within and across populations. diet may play a role in the development of type 1 diabetes through influencing gut flora , intestinal permeability , and immune function in the gut . wheat in particular has been shown to have a connection to the development of type 1 diabetes, although the relationship is poorly understood Bovine insulin is an attractive candidate, since an immune response initially induced by bovine insulin will cross-react and may target human insulin in the β-cell. The role of breast-feeding.

Role of Obesity :

Role of Obesity Type I diabetes is rising in developed countries, so is obesity .

Why should we care ?:

Why should we care ? The identification of exogenous factors triggering and driving β-cell destruction offers potential means for intervention aimed at the prevention of type 1 diabetes.

Disease progression:

Disease progression Loss of insulin reserve occurs during a few to many years. The earliest sign of abnormality is the development of islet autoantibodie s when blood glucose concentrations, glucose tolerance (ability to maintain normal blood glucose levels after ingestion of sugar), and insulin responses to glucose are normal. This period is followed by a phase of decreased glucose tolerance but normal fasting blood glucose concentration .

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With continued loss of β cells, fasting hyperglycemia eventually develops but sufficient insulin is still produced to prevent ketosis ; during this period, patients have non-insulin-dependent diabetes mellitus.

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Eventually, insulin production falls below a critical threshold, and patients become dependent on exogenous insulin supplements and have a propensity to ketoacidosis . Younger patients generally progress through these phases more rapidly than do older patients. Retinopathy , neuropathy develops & approximately 50% of patients eventually die of renal failure.

Signs and symptoms :

Signs and symptoms The classical symptoms of type 1 diabetes include: polyuria (frequent urination ), polydipsia (increased thirst), polyphagia (increased hunger), fatigue , and weight loss . Patient may suffer diabetic ketoacidosis episodes which are sometimes fatal, especially in children.

Diagnosis (WHO criteria) :

Diagnosis (WHO criteria) Fasting plasma glucose level at or above 7.0 mmol /L ( 126 mg/ dL ). Plasma glucose at or above 11.1 mmol /L ( 200 mg/ dL ) two hours after a 75 g oral glucose load as in a glucose tolerance test . Pre-diabetes Symptoms of hyperglycemia and casual plasma glucose at or above 11.1 mmol /L (200 mg/ dL ). Glycated hemoglobin (hemoglobin A1C) at or above 6.5.

autoantibodies:

autoantibodies The appearance of diabetes-related autoantibodies has been shown to be able to predict the appearance of diabetes type 1 before any hyperglycemia arises, the main ones being islet cell autoantibodies, insulin autoantibodies, autoantibodies targeting the 65 kDa isoform of glutamic acid decarboxylase (GAD) and autoantibodies tergeting the phosphatase-related IA-2 molecule. Per definition, the diagnosis of diabetes type 1 can be made first at the appearance of clinical symptoms and/or signs, but the emergence of autoantibodies may itself be termed latent autoimmune diabetes.

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Not everyone with autoantibodies progress to diabetes type 1, but the risk increases with the number of antibody types, with three to four antibody types giving a risk of progressing to diabetes type 1 of 60%-100 %. The time interval from emergence of autoantibodies to frank diabetes type 1 can be a few months in infants and young children, but in some people it may take years - in some cases more than 10 years.

Management :

Management Insulin therapy. Rigorous control of blood glucose levels reduces the risk of complications by 35% to 75%. The development of islet autoantibodies several years before the onset of IDDM has led to the development of studies to predict and prevent IDDM. The administration of insulin or nicotinamide appears to delay the development of IDDM in some patients. Pancreas transplantation generally only used together with or some time after a kidney transplant. Islet cell transplantation Not fully developed , requires immunosuppression.

Case study:

Case study F.C., a 45-year-old father with late-onset diabetes mellitus, was referred to the endocrinology clinic for counseling regarding his children's risk for diabetes. F.C . developed glucose intolerance at the age of 39 years and fasting hyperglycemia at 45 years. He did not have a history of other medical or surgical problems. He had five children by two different partners; a child from each relationship had developed insulin-dependent diabetes mellitus ( IDDM ) before 10 years of age. His sister developed IDDM as a child and died during adolescence from diabetic ketoacidosis.

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The geneticist explained that given his family history, F.C. might have a late-onset form of IDDM and that his current non-insulin-dependent diabetes mellitus was probably an antecedent to development of IDDM . After discussing the possible causes of and prognostic factors for the development of IDDM, F.C. elected to enroll himself and his children, who are all minors, in a research protocol studying the prevention of IDDM. As part of that study, he and his children were tested for anti-islet antibodies. Both he and an unaffected daughter had a high titer of anti-islet antibodies; the daughter also had an abnormal glucose tolerance test result but not fasting hyperglycemia. As part of the study protocol, F.C. and his daughter were prescribed low-dose insulin injections.

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