• Credits
  • Section Writer: Dr. Om J Lakhani
  • Section Editor: Dr. Om J Lakhani

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• Q. Summarize the pathogenesis of type 1 diabetes in 1 sentence?

  • Immune-mediated destruction of beta-cell
  • Triggered by an environmental factor
  • In genetically susceptible individuals

• Q. What are the three main things in type 1 diabetes pathogenesis?

  • Genetic susceptibility
  • Immune effect
  • Environmental factors

• Q. What are type 1A and type 1B?

  • Type 1A- antibodies positive –immune-mediated beta-cell destruction
  • Type 1B – antibodies negative – non-immune-mediated beta-cell damage

• Q. Polymorphism of which gene causes type 1 diabetes?

  • HLA Dqbeta
  • HLA Dqalpha
  • HLA  DR
  • PTPN22
  • Preproinsulin
  • IL2 Receptor gene
  • CTLA-4
  • Intereron induced helicase
  • Lectin like gene
  • CCR5- emerging player

• Q. Of these genes which are involved, which are most important?

  • HLA- highest effect
  • Preproinsulin and insulin gene- 2nd
  • PTPN22- 3rd
  • CCR5- emerging star

• Q. What is the risk of type 1 diabetes in other family members if one person has it?

  • Offspring  - 6%
  • Sibling – 5%
  • Identical twin – 50%
  • All this is no family history – risk is only 0.4%

• **HLA (MHC GENES) **

• Q. HLA region of which chromosome is the culprit?

  • Chromosome 6q

• Q. What is the role of MHC?

  • MHC carry the antigen on the surface of antigen-presenting cells and activate the  T cells

• Q. Which two haplotypes of HLA  confer the highest risk of type 1 diabetes?

  • HLA DR3, DQB1*0201 – Also called HLA DR3- DQ2
  • HLA DR4, DQB1*0302 – also called HLA DR4-DQ8
  • 90% of type 1 have either of these two haplotypes
  • 30% have both!
  • The risk of type 1 diabetes if you carry either of these two haplotypes is 5% compared to 0.4 % in controls

• Q. Which HLA DR4 haplotypes protect from type 1?

  • HLADRB1*0403
  • HLADPB1*0402
  • Additionally, HLA DQB1*0602 – also protective

• **NON-MHC GENES **

• **Pearl **

  • PTPN22 is the culprit in multiple autoimmune disorders

• Q. Which cytokine is a primary culprit in causing type 1?

  • INTERFERON-GAMMA
  • Th1 cells produce interferon-gamma
  • IL12 and Interferon-gamma releasing factors increase interferon-gamma

• Q. Are Th2 cells protective?

  • Initially, it was thought that
  • Th1- is causative
  • Th2 – protective
  • But new evidence is that Th2 is not very protective and may also be a culprit

• Q. What is the role of mutation in FoxP3 and diabetes?

  • FoxP3 mutation is seen in IPEX syndrome remember
  • Autoimmune disease like diabetes is an imbalance between Pathogenic T cells and regulatory T  cells
  • CD4 and CD25 are a significant subset of regulatory T cells and require IL-7 for activation
  • They lack an IL-7 receptor, and FoxP3 induces this receptor
  • Lack of FoxP3- there is no activation of regulatory cells  diabetes

• Immunology of Type 1 Diabetes

• Q. What components of the immune system are involved in the pathogenesis of type 1 diabetes?

  • Four things characterize the role of the immune system in the pathogenesis of type 1
  • Presence of islet autoantibodies
  • Presence of T cells that proliferate in the presence of these islet proteins (antigens)
  • Cytokines produced by T cells that cause pancreatic damage
  • Presence of activated lymphocytes in the pancreas (Insulinitis)

• **Autoantibodies **

• #Clinicalpearl: Antibodies in type 1 diabetes are not responsible for damage to beta-cell – they are mere markers of type 1 diabetes

• The actual damage is done by T cells and not these antibodies

• Q. Enlist the antibodies associated with type 1 diabetes?

  • GAD 65
  • Insulinoma associated antibody – IAD-2 (also called ICA512)
  • Insulin autoantibody – IAA
  • Zinc transporter eight antibody- Znt8

• Q. Antibodies are formed against which part of GAD65?

  • Carboxy terminal of GAD65 antibody

• Q. What is the other name of Insulinoma-associated antibody 2?

  • ICA512

• Q. Tell me something about the GAD65 antibody?

  • Present in 70% of type 1 diabetics
  • Does not reduce with age- most common antibody t checked in adults
  • Slowly developing diabetes
  • HLA-DR3 associated

• Q. Enlist the differences between GAD65 and IA-2 antibodies?

  • 

• Q. Which is the main target in type 1 diabetes?

  • The main target seems to be the Beta chain of Insulin

• Q. Which is the first antibody to appear in type 1 diabetes?

  • IAA- insulin autoantibody is the first to appear

• Q.  If IAA is the first to appear, why does it not have more importance compared to GAD65, etc.?

  • Any person given insulin can develop IAA antibody
  • Hence measurement of antibody anytime after two weeks after insulin injection will give a positive result

• Q. Which is often the last antibody to appear?

  • Znt8
  • It also disappears first
  • IAA first,  then GAD → , then IA2 → Last ZnT8

• Q. Summarize the prevalence of various antibodies in type 1 diabetes?

  • IAA – almost 100% - but not a reliable marker
  • GAD65- 70%
  • IA-2 – 68%
  • Znt8 – 60-80%

• Q. Apart from the fantastic four, which other antibodies are proposed?

  • Antibodies against
  • IGRP
  • ICA69
  • Chromogranin A

• #Clinicalpearl

  • Antibodies of type 1 diabetes also affect the nervous system!

• Q. What do Indian studies say about Antibodies in type 1?

  • South Indian study – GAD65 was present in 70% - just like the west
  • Cuttack Study- ICA512 was more common – in 43%
  • GAD65 only in 7%

• **Role of cell-mediated immunity **

• Q. Which is the most commonly used animal model for type 1 diabetes?

  • NOD mice

• Q. Which cells are responsible for type 1  -  T cell or B cell?

  • T cell

• Q. Which causes diabetes- Th1 or Th2?

  • Th1- causative
  • Th2 – protective (however, the role of Th2 as protective has been questioned)

• Q. What is the relation between Th2 and gut?

  • Gut immunity develops via Th2
  • Th2 we know is protective
  • Hence oral insulin/antigens may have a role in causing tolerance to type 1 diabetes

• Q. Which cytokines produced by Beta-cell cells are involved in the pathogenesis of type 1 diabetes?

  • Interferon-gamma – most important
  • TNF alpha
  • IL-1

• Q.. Is there molecular mimicry involved?

  • It is possible because antigens of Coxsackievirus is similar to GAD65

• Q. Are alpha cells, PP cells, Delta cells also damaged by autoimmunity in the pancreas?

  • No
  • They are spared

• Q. Do some detectable changes occur in the body in type 1 susceptible individuals even before autoimmune markers appear?

  • Yes
  • Some Metabolic changes that prepare the body for a proinflammatory response develop even before immune markers appear
  • These include:
    • Reduced serum succinate
    • Phospholipids
    • Ketoleucine
    • elevated glutamic acid

• Q. Summarize the steps in Immune events in type 1?

  • Step 0
    • Environmental triggers and genetic suspeblity set up the stage for the development of type 1 diabetes
  • Step 1a- The periphery
    • In the periphery, the environmental trigger produces a change in the system and changes the body to a proinflammatory system
    • In this proinflammatory environment,  there is an imbalance between  Pathogenic T cells and regulatory T cells – the pathogenic T cells dominate
    • Hence there is a generation of autoreactive T cells
  • Step 1b- the pancreas
    • Environmental triggers set up the immune destruction in beta cells
    • Beta cells of the pancreas, as a result, upregulate MHC class I and IFN- gamma
    • This sets them from attack by autoreactive CD8, which have specificity for islet antigens
  • Step 2
    • The destruction of beta cells produce more antigen, which is picked up by the APC present in the pancreas and taken to the lymphatic system
  • Step 3
    • These beta-cell antigens taken by the APC are transported to the periphery, where they activate CD4 T cells
    • CD 4 cells activate more autoreactive T cells and also activate B cells to produce autoantibodies
  • Step 4
    • Now, these antibodies and further T cells which are produced go to the pancreas and produce a second wave of attack
    • IFN gamma, TNF alpha, and IL-1 produced by T cell have the damage
    • This now stops the beta cell from producing insulin
    • This is called ‘Pseudoatrophy’ of beta cells
  • Step 5
    • The second wave of the attack  cycle repeats of producing more beta cell antigens and more Autoreactive T cell and autoantibodies
    • The regulatory T cells may put a brake on the process; hence there are fluctuating stages of destruction and repair
    • However, eventually, the autoreactive T cells win and lead to beta-cell destruction
  • Step 6
    • When only 10% of beta cells remain  full-blown, diabetes occurs

• **Relationship with other autoimmune diseases **

• Q. How common is TPO antibody in type 1 and autoimmune thyroid disease?

  • TPO antibody is present in 25%
  • Autoimmune hypothyroidism – present in 5%

• Q. What about Celiac disease?

  • 10% have Ttg positive
  • PTPN22 and CTL4 genes are common to diabetes and celiac

• Q. What about autoimmune adrenalitis?

  • <1 %

• Q. Which immune syndromes are associated with type 1?

  • IPEX
  • APS 2 and 1

• Role of Environmental factors in type 1 diabetes

• Q. Which environmental factors are implicated?

  • Drugs and Chemicals
  • Virus
  • Nutritional components
  • Gut microbes

• Q.  Is there a relationship between birth weight and risk of type 1 diabetes?

  • Low birth weight is protective of type 1 diabetes

• Q. Which drugs and chemicals are implicated in causing type 1?

  • Alloxan
  • Streptozotocin
  • Pentamidine

• Q. Which viruses are implicated in causing type 1?

  • Mumps
  • Coxsackie
  • Rotavirus- new candidate
  • Rubella

• Q.. Is there molecular mimicry involved?

  • It is possible because antigens of Coxsackievirus is similar to GAD65

• Q. Is childhood immunization responsible for type 1 diabetes?

  • No
  • There is no evidence at present that immunization has an impact on type 1 diabetes

• Q. Which are diet and nutritional factors implicated?

  • cow’s milk exposure in early life has been implicated
  • Early introduction of cereals
  • Nitrates in drinking water
  • Protective
  • Omega 3 fatty acid
  • Vitamin D

• Q. Which component of cow’s milk is responsible?

  • Beta casein in cow’s milk

• Q. Which was the study done to see the effect of Cow’s milk on the pathogenesis of type 1?

  • Childhood diabetes in Finland study first found a relation between Cow’s milk and risk of type 2
  • TRIGR is an ongoing project to study if breast milk can protect from type 1 diabetes

• Q. Is vitamin D protective?

  • This is an area of debate
  • Some studies do show a protective role of vitamin D supplementation

• Q. What is the role of cereals in type 1?

  • Early introduction of cereals before three months of age-associated with increased risk of type 1 diabetes

• Q. Any role of fatty acids?

  • Omega 3 fatty acid may be protective

• Q. What is the Leaky gut concept?

  • Increased gut permeability  increase entry of foreign substances, → increase immunogenicity

• Q. Summarize the various environmental factors implicated in the etiology of type 1 diabetes?

• 1. Perinatal factors- low birth weight may be protective
• 2. Nutritional factors
  • Harmful- Cow’s milk, early introduction of cereals (before three months), nitrate in water
  • Protective- vitamin D, omega three fatty acids
• 3. Virus
  • Coxaciae virus, mumps, rubella, rota virus
• 4. Drugs and chemicals- alloxan, pentamidine, Streptozotocin
• 5. Role of gut microbes and leaky gut concept

• Determinants of insulin deficiency

• Q. How do we predict the development of type 1 diabetes before it manifests?

  • 1. Reduce acute insulin response to glucose (AIRg)
  • 2. Presence of insulin autoantibodies
  • 3. Development of impaired glucose tolerance

• Q. What is the role of IGF1 in type 1 diabetes?

  • Local IGF1 in the islet can help in the recovery of beta cells
  • This is being studied

• **NATURAL HISTORY OF TYPE 1 **

• Q. Summarize with diagram the time course for the development of type 1 diabetes?

  • This is Eisenbarth’s model
  • 

• Q. What are the two main stages of type 1 diabetes?

  • Insulinitis  initial stage
  • Full-blown type 1 diabetes
  • Insulinitis → type 1 does not occur always and may wax and wane

• Q. What are alternative models to Eisenbarth’s linear model?

  • Some people say it is not always linear. There are four types of progression
    • Primary progressive model
    • Benign / slowly progressive model
    • Relapsing-remitting model
    • Secondary chronic progressive model

• Q. Who first described LADA?

  • Paul Zimmet