Types and the immune effector mechanisms of diabetes.

1. Diabetes Mellitus
AUW School of Medicine
Dr Awadelkarim A.Ibrahim

2. • Diabetes mellitus (DM)
The term diabetes mellitus describes a metabolic
disorder of multiple aetiology characterized by
chronic hyperglycaemia with disturbances of
carbohydrate, fat and protein metabolism
resulting from defects in insulin secretion, insulin
action, or both.
The effects of diabetes mellitus include long–term
damage, dysfunction and failure of various
organs.

3. • Type 1 Diabetes Mellitus
• Type 2 Diabetes Mellitus
• Gestational Diabetes
• Other types:
LADA (Latent Auto immune diabetes of
Adulthood )
MODY (maturity-onset diabetes of youth)
Secondary Diabetes Mellitus
Types of Diabetes

4. Type 1 diabetes
Type 1 diabetes is a multifactorial inflammatory
disease in genetically susceptible individuals
characterized by progressive autoimmune destruction
of pancreatic β-cells.

5. 5
Regulation of Plasma Glucose Level

6. Genetic factors Environmental factors
Population 9%
Monogenic
Polygenic
Aging
Lifestyle
Infections
Diabetes
Type I
<10%
Type II
>90%
Eatiology

7. TYPE 1 DIABETES IS AN AUTOIMMUNE DISEASE
-Genetic and familial clustering of diabetes and additional
autoimmune disorders
-Presence of high-affinity autoantibodies and T cells reactive
to islet cell autoantigens
-Strong HLA association (DR3/DR4)
-Ability to transfer the disease in animal models through
adoptive transfer of islet cell-reactive T-cell clones
-Recurrence of disease in pancreas transplanted between
identical twins

8. 8

9. 1-There is direct virus-induced lysis of β cells following
infection
2-Molecular mimicry Partial sequence homology between the a
viral Ag & β cells protein that constitutes a target autoantigen in
T1D pathology.
The ir directed towards the viral Ag lead , by cross reactivity , to
the production of cytotoxic T lymphocytes ( Tc) and/or Abs that
are able to attack the pancreatic tissue & ,thus, participating in
the pathogenesis of T1D
3- Bystander activation or innocent -bystander killing.

10. 1-Strong HLA association : DR3/DR4
&Strong HLA protection :DR2 DR6 DR7
CTLA-4 gene mutation
The cytotoxic T-lymphocyte antigen (CTLA-4)
gene encoded on chromosome 2q33 was
recognized as T1D susceptibility gene.
Inherited changes in the CTLA-4 gene
expression can increase T cell self-reactivity and
therefore play an important role in autoimmune
diseases such as T1D.

11. PTPN22 (Protein tyrosine phosphatase, non-receptor
type 22 )
PTPN22, a gene found
on chromosome 1p13 that encodes lymphoid protein
tyrosine phosphatase, was found to be associated with
susceptibility to T1D.
A SNP in the PTPN22 gene potentially contributes
to susceptibility to T1D because of increased negative
regulation of T cell activation.
IL2RA
Allelic variation in the interleukin (IL)-2 receptor-
gene (IL2RA) region accounts for another genetic risk
factor implicated in T1D

12. Insulin Gene (INS)
Class I VNTR
26-63 repeats
21 alleles
Predisposing
IDDM2
Insulin Gene (INS)
Class III VNTR
140-200 repeats
15 alleles
IDDM2
Protective
The IDDM2 Locus
VNTR = Variable Number of Tandem Repeats

13. The variable number of tandem repeat (VNTR ; also named the
insulin gene minisatellite ) is promoter upstream of the insulin
gene translation initiation site where the transcription factor Pur1
bind .

14. Pathogenesis: Diabetes mellitus type 1 is an autoimmune disease.
The autoimmune process begins many years before clinical
detection and presentation.
It is directly against beta cell of the islets of Langerhans. The
destruction must be very heavy, more then 90 percent of beta cells
must be destroyed for clinical symptoms to develop. The speed of
the beta cell destruction is variable.
Causes :viruses and other environmental factors in genetically
susceptible individuals.

16. - CD4 T lymphocytes reactive with islet antigens maydestroyb-cells
through MQ activation, production of inflammatorycytokines, etc
- Cytolytic CD8 T lymphocytes may lyse islet cells and locally
produce cytokines (TNF and IL-1) that damage islet cells
- The role of B lymphocytes debated: data from the NOD model
suggest that B lymphocytes are required as antigen presenting cells
early during induction of disease. Possiblyalso later to present antigen
and maintain autoreactivity.
- At later times, autoantibodies further damage β-cells
Immune effector mechanisms of T1D

18. Viral antigens released from β cells is processed by macrophages
and presented to T - helper lymphocytes (CD4+) associated with
HLA class II antigens.
Activated T lymphocytes then secrete interleukin (IL) - 2 and other
cytokines that activate other immune cells.
B lymphocytes produce immunoglobulins against the viral antigens,
while activated natural killer (NK) cells and cytotoxic (CD8+)
lymphocytes cause destruction of β cells that carry the viral
antigens.
Macrophages, activated by interferon - γ (IFN - γ ), also participate
in the destruction of the target cells.
NKCF, natural killer cell factor; TNF, tumour necrosis factor.

19. There are four stages in the development of Type 1 DM:
1-Preclinical period with positive β-cell antibodies
2-Hyperglycemia when 80-90% of the β- cells are destroyed
3-Transient remission (honeymoon phase).
4-Establishment of the disease

20. “Stages” in Development of Type1Diabetes
Age (years)
Genetic
Predisposition
Betacellmass
(?Precipitating Event)
Overt
immunologic
abnormalities
Normal insulin
release
Progressive
loss insulin
release
Glucose
normal
Overt
diabetes
C-peptide
present
No
C-peptide

21. Immunological Diagnosis of T1D
There are currently four standard autoantibodies whose presence is
used to predict the development of T1D:
-These are Autoantibodies against
1-Insulin,
2-Glutamic acid decarboxylase (GAD65),
3-A tyrosine phosphatase-like protein (ICA512 also termed IA-2)
4-Zinc T8 transporter (ZnT8) .
-Islet-associated protein–2 (IA-2) and IA-2β (also known as phogrin)
are unique neuroendocrine-specific protein tyrosine phosphatases
(PTPs).

22. •Type 2 Diabetes Mellitus (Insulin Resistance)
•Formerly known as “adult onset” or “ Non insulin
dependent Diabetes”.
Type 2 diabetes (non-insulin-dependent diabetes
mellitus) Insulin concentrations are mostly increased but
peripheral tissues are resistant to insulin (insulin
resistance).
.
It results from insulin resistance with a defect in
compensatory insulin secretion. (Beta cells are not able
increase secretion of insulin to overcome this resistance. )
Insulin may be low, normal or high!

23. Onset of Disease Gradual onset Person may go many
years with undetected hyperglycemia
Gradual onset Person may go many years with undetected
hyperglycemia .
Accounts for >90% of patients with diabetes
Usually occurs in people over 40 years old
80-90% of patients are overweight ,(lately in obese
adolescents.)
About 30% of the Type 2 DM patients are undiagnosed
(they do not know that they have the disease) because
symptoms are mild.

24. Etiology and pathophysiology of type 2 diabetes

25. Activation of the NLRP3 Inflammasome
The inflammasome is a large multiprotein complex which plays a
key role in innate immunity by participating in the production of the
pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-18.
These related cytokines cause a wide variety of biological effects
associated with infection, inflammation and autoimmune processes.
They are both produced as inactive precursors, pro-IL-1β and pro-
IL-18, and share a common maturation mechanism that requires
caspase-1
IL-1β induced within the islet impairs β cell insulin secretion and
induces Fas death receptor–dependent, apoptotic β cell. Glucose-
induced IL-1β is a key mediator of islet dysfunction and
destruction.

26. Progression Of Beta Cell Failure in Type
2 Diabetes
Progressive β-cell defect
in type 2 diabetes
Impaired glucose tolerance (IGT) ,Postprandial = after eating a meal while preprandial
is before a meal

27. Acanthosis
Nigricans
Skin Tags
Acanthosis nigricans
Currently thought to be an effect of
insulin-like growth factor 1 (IGF-1).
At one point was thought to be a result of
skin folds rubbing together

28. Type 1 vs. Type 2
Type 1 Type 2
Age of onset Childhood, young adult
Usually > 40 + some
obese children
Pathogenesis Autoimmune process
Defect in insulin
secretion, tissue
resistance to insulin,
increased HGO
Autoantibodies Positive Negative
Body cells Responsive to insulin Resistant to insulin
Endogenous insulin Little or none Low Normal or high
Pancreatic function Beta cells not functional Beta cell normal
Severity of symptoms Severe; liable to DKA
Mild; few or none, not
liable to DKA

29. Characteristics Type I DM Type II DM
% of diabetic pop 5– 10% 90 %
Obesity Uncommon Common
Family history Generally not strong Strong
Acute complication Ketoacidosis Hyperosmolar coma
Treatment Insulin, Diet
Exercise
Diet ,Exercise
Oral antidiabetics,Insulin
Diabetic ketoacidosis

30. • Latent Auto immune diabetes of Adulthood
(LADA) or type 1.5 diabetes
A slowly progressive form of type 1 diabetes mellitus.
Patients are often diagnosed as type II diabetes, but have
Positive pancreatic islet antibodies, especially to
glutamic acid decarboxylase (GAD).
Pts. do not immediately require insulin for treatment, are
often not overweight, and have little or no resistance to
insulin

31. Presence of autoimmunity to islet protein is the feature
of IDDM.
However there are some pts over 30 yrs of age present
with diabetic symptoms and require insulin therapy
within one to two yrs, many of these pts. have
autoantibodies to islet protein. They are called as LADA
About 10-15% have ICA (Islet cell antibody) and / or
Glutamic acid decarboxylase antibody (GADA)

32. Diabetes Types
Key characteristics of type 1, LADA (latent autoimmune diabetes
in adults), and type 2.
Type 1 LADA Type 2
Typical age of onset Youth or
adult
Adult Adult
Progression to
insulin dependence
Rapid
(days/weeks)
Latent (months/years) Slow (years)
Presence of
autoantibodies*
Yes Yes No
Insulin dependence At diagnosis Within 6 years Over time, if at all
Insulin resistance No Some Yes
*Proteins that indicate the body has launched an autoimmune attack on the insulin-
producing beta cells in the pancreas.

33. MODY (maturity onset diabetes of the young) –is a
monogenic and autosomal dominant form of diabetes
mellitus (single-gene disorder) with onset of the disease
often before 25 years of age ( early onset ) strong family
history, present as type 2 diabetes .
It is due to dysfunction of pancreatic ß cells characterised
by non-ketotic diabetes and absence of pancreatic auto-
antibodies.
It is frequently mistaken for type 1 or type 2 diabetes
mellitus

34. Gestational diabetes mellitus:
◆ Definition:
Carbohydrates intolerance of variable severity Develops
during pregnancy .Detected at 24 to 28 weeks of gestation
As type II is characterized by insulin resistance, usually is mild,
but show risk of later development of diabetes 2 type
Associated with high risk for cesarean delivery, perinatal
death, and neonatal complication