Type 1 insulin dependent diabetes mellitus or juvenile diabetes

1
(No Transcript)
2
Three types of diabetes

• Type 1 (insulin dependent diabetes mellitus or
  juvenile diabetes)
• Type 2 (non-insulin dependent diabetes mellitus
  or adult onset diabetes)
• Gestational diabetes

3
Causes of Type I diabetes
Gene-Environment
?
Gene
Environment
4
Type I Diabetes Mellitus

• Insulin-Dependent Diabetes, Juvenile Diabetes
• Autoimmune Disease
• Daily Shots of Insulin Must Be Taken
• Causes Are Unknown
• Affect Mostly Children and Young Adults

5
Autoimmune diseases

• Insulin-Producing Beta Cells within Pancreas
  Destroyed by Immune System
• Body Recognizes Itself as a Foreign Body
• Cells are Accordingly Eliminated

• Thyroid
• Adrenal gland
• Skin
• Neurotransmitters
• Intestine and stomach

6
Symptoms

• Severe
• blurred vision.
• drowsiness/difficulty waking up, lack interest
  in their normal activities.
• fast and shallow breathing
• strong, fruity breath odor.
• loss of appetite, abdominal pain, and vomiting

• Mild
• frequent urination
• extreme thirst
• dry mouth
• increased hunger
• fatigue
• weight loss

7
Ketoacidosis

• Mild Symptoms
• nausea
• vomiting
• abdominal pain
• rapid heartbeat
• abnormally deep breathing

• Severe Symptoms
• cerebral swelling
• aspiration pneumonia
• coma
• death

8
US Population

• Prevalence
• general pop 17 million (6.2 pop)
• lt 20yrs 151,000 people
• 1 in 400 to 500 children/adolescents
• Incidence (gt 20 yrs) 1 million/yr
• 6th leading cause of death (US)
• 100 in direct medical/indirect expenditures

9
Worldwide Population

• 150 million people affected
• 0.1/100,000 per year (China) to 36/100,000
  (Finland)
• gt350-fold variation in the incidence
• rising by 2-5 per annum

10
Who does Type I diabetes affect?

• Occurs in Males and Females equally
• More Common in Whites than in Nonwhites
• Usually Develops in Children and Young Adults
• Can Run in Families (20 of Cases)
• No One Gene Determines if Type 1 Diabetes Will
  Develop

11
Genetic Factors

• 18 Genes Isolated
• Of Varying Potency
• 2 Most Significant
• HLA Region (Within MHC Complex on Chromosome 6)
• Insulin Gene (Chromosome 11)
• Specific Mechanisms Unknown
• Part of More Complex Interaction

12
HLA Region

• Human Leukocyte Antigen
• Genes Make Proteins that Dot Surface of Immune
  System Cells
• Important in Helping Immune System Recognize Own
  Cells Vs. Infectious Agent
• If System Fails, Autoimmune Reaction

13
HLA Region

• DR Gene
• Alleles DR3 and DR4 Associated with Type 1
  (Present in 95 of Patients)
• 2 Alleles Cause Slight Difference
• Allele DR2 Protects Against Type 1
• DQ Gene
• DQB1 Genes Associated with Type 1
• DQB102.0302 Combination Most Closely Associated
  (22.2 of Type 1 Diabetics Had Allele)
• DQB10602.03 Protects Against Type 1

14
HLA Region-DR Gene

• Diabetics Inherited DR3 (but not DR4)
• Develop Diabetes at Older Age
• More Likely to Develop Thyroid Autoimmune Disease
• Diabetics Inherited DR4 (but not DR3)
• Develop Diabetes Earlier in Life
• Immune Reaction Against Insulin
• Diabetics Inherited both DR3 and DR4
• Diabetes at Youngest Age
• Most Susceptible in HLA Region

15
HLA Region-DQ Gene

• High Risk HLA-DQB102.0302 Allele More Common
  Among Children (23.4 vs. 8.5)
• Manifestation of Type 1 in Children Associated
  with Strong HLA-Defined Genetic Disease
  Susceptibility
• More Frequent Auto-Antibody Response to ß-Cell
  Antigens
• Higher Frequency of Preceding Infections
• Age of Clinical Onset Determined By Intensity of
  ß-Cell Destruction Process
• Protective HLA-DQB10602.03 Allele More Common
  Among Adults (10.2 vs. 1.6)

16
The Insulin Gene

• Region of DNA Coding for Protein Insulin
• Determines Amount of Insulin Made
• Composed of Variable Number of Tandem Repeats
  Section (VNTR)
• Different Lengths in Different People
• If 2 Short VNTR Regions Inherited 2 to 5 Times
  More Likely to Develop Type 1
• Longer Region Decreases Insulin Produced
• May Seem Contradictory

17
Chromosome 11p15 region
Pugliese and Miceli 2002
18
Management of Diabetes

• Keeping blood sugar low
• Frequent monitoring of glucose level
• Balanced diet
• Regular exercise
• Identifying and responding to problems
• Hyper/hypo-glycemia

19
Nutrition Vitamin D Deficiency

• animal studies in NOD mice
• EURODIAB Study

20
Nutrition Cow Milk Proteins

• 5 major whey proteins (including casein, BLA,
  BSA)
• Major theories

• molecular mimicry age of introduction of
  supplementary milk feeding
• broken tolerance to dietary antigens due to
  regulatory defects in gut immune system

21
Nutrition Cow Milk Proteins

• Pros
• elevated antibody titres to cows milk proteins
  in patients with IDDM
• elevated cellular immune response to cows milk
  proteins in patients
• sequence homologies between cows milk protein
  and auto-antigens in IDDM
• elevated antibody titres to bovine insulin in
  non-breast-fed infants

• Cons
• not confirmed in all studies
• variable outcomes, other proteins are more
  diabetogenic
• major overlap between patients and controls
• methodological problems, HLA-matched controls
  required
• substantial overlap association with later type 1
  diabetes mellitus remains to be proven

22
Viruses

• Mechanisms of enteroviruses
• Infects beta cells directly and destroys
• Induce autoimmune response

• in vitro damage to induce interferon-a HLA class
  I molecules in b cells
• molecular mimicry (entervirus 2C protein and
  GAD65)
• proven in animal studies only

• RT-PCR to measure cell-mediated immunity to
  enterovirus

23
Viruses Evidence

• association observed when the case and control
  subjects were matched for confounding factors
  like age, sex, and HLA-type
• beta-cell damage in patients with severe
  enterovirus infections
• epidemiological association observed in several
  studies in different countries using various
  methods (virus antibodies, viral RNA, cellular
  immunity)
• association observed in prospective studies in
  addition to case-control studies
• association specific for enteroviruses and not
  observed in other virus infections
• clustering of enterovirus infections to the time
  period immediately preceding the appearance of
  autoantibodies (prospective studies)

24
Gut Immune System

• Two possible responses
• - tolerance
• - immunity

25
Gut Immune System Evidence

• diet modifies autoimmune diabetes in BB rates and
  NOD mice
• expression of gut-associated homing receptor ?7
  integrin in islet-infiltrating T cells
• autoimmune diabetes has been transferred to
  recipients by mesenterial lymphocytes from young
  NOD mice
• feeding autoantigen induced development of
  autoreactive cytotoxic lymphocytes and
  acceleration of autoimmune diabetes

26
Toxins N-nitroso Compounds

• Sources vegetables and meat products
• Swedish case-control study
• US ecological studies
• role of antioxidants (Vitamins C E)

27
www.wehi.edu.au/research/ autoimm/rapid.html
28
Antibody Screening

• When Immune System Attacks ß-Cells, Antibodies
  are produced
• ICA (islet cell antibodies)
• IAA (insulin autoantibodies)
• GADA (glutamate decarboxylase antibodies)
• IA-2A (IA-2 or thyrosine phosphatase antibodies )

29
Antibody Screening-Siblings

• Frequency of antibodies significantly higher
  among HLA-identical siblings
• Siblings with antibodies have a higher risk for
  progression to Type 1
• 54.5 with Antibody Presence vs. 9.0 Without
• Increased Number of Antibodies Present Leads to
  Higher Risk for Progression to Type 1

30
Cumulative risk
1 Marker
2 Marker
Type I diabetes-free ()
3 Marker
4 Marker
Follow-up (years)
Bingley et al., 1999
31
Genetic Screening of HLA DQB1 alleles vs.
antibodies
Kimpiläki et al. 2000
32
Benefits of antibody screening

• Combination of Genetic Markers and Antibodies
  Increased the Predictive Values
• Antibodies Alone Recommended as 1st Line of
  Screening, ONLY IF
• Child Has Parent or Sibling with Type 1
• Child Intends to Enter Diabetes Prevention Study
• Can reduce the size of screening populations
  needed for recruitment in future intervention
  trials

33
Difficulties in genetic testing

• Not all gene mutations responsible for Type 1
  identified
• Influence environmental factors
• Inheritance Patterns Are Complicated
• 90 of diabetics do not have a close relative who
  also has diabetes
• Different Genes Influence Risk
• Not Inherited in Clearly Dominant or Recessive
  Manner

34
Genetic screening only if

• Exclude subjects with protective HLA alleles from
  intervention trials
• Parent or sibling has Type 1 diabetes
• Early detection may help prevent development of
  complications from diabetes

35
Major advances

• Genetically engineered human insulin
• Self-monitoring of blood glucose levels
• Hemoglobin A1c testing
• External and implantable insulin pumps
• Laser treatment for diabetic eye disease
• Successful kidney transplantations
• Improving diabetic pregnancy outcomes

36
Current research

• Vaccines
• Injected or oral insulin to high-risk individuals
• Better methods of transplanting pancreatic tissue
• Artificial islet cells to secrete insulin