AUW School of Medicine
Dr Awadelkarim A.Ibrahim
• 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
• Type 1 Diabetes Mellitus
• Type 2 Diabetes Mellitus
• Gestational Diabetes
• Other types:
LADA (Latent Auto immune diabetes of
MODY (maturity-onset diabetes of youth)
Secondary Diabetes Mellitus
Types of Diabetes
Type 1 diabetes
Type 1 diabetes is a multifactorial inflammatory
disease in genetically susceptible individuals
characterized by progressive autoimmune destruction
of pancreatic β-cells.
Genetic factors Environmental factors
TYPE 1 DIABETES IS AN AUTOIMMUNE DISEASE
-Genetic and familial clustering of diabetes and additional
-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
1-There is direct virus-induced lysis of β cells following
2-Molecular mimicry Partial sequence homology between the a
viral Ag & β cells protein that constitutes a target autoantigen in
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.
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.
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.
Allelic variation in the interleukin (IL)-2 receptor-
gene (IL2RA) region accounts for another genetic risk
factor implicated in T1D
Insulin Gene (INS)
Class I VNTR
Insulin Gene (INS)
Class III VNTR
The IDDM2 Locus
VNTR = Variable Number of Tandem Repeats
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
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
- 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
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
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.
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
“Stages” in Development of Type1Diabetes
Immunological Diagnosis of T1D
There are currently four standard autoantibodies whose presence is
used to predict the development of T1D:
-These are Autoantibodies against
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
•Type 2 Diabetes Mellitus (Insulin Resistance)
•Formerly known as “adult onset” or “ Non insulin
Type 2 diabetes (non-insulin-dependent diabetes
mellitus) Insulin concentrations are mostly increased but
peripheral tissues are resistant to insulin (insulin
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!
Onset of Disease Gradual onset Person may go many
years with undetected hyperglycemia
Gradual onset Person may go many years with undetected
Accounts for >90% of patients with diabetes
Usually occurs in people over 40 years old
80-90% of patients are overweight ,(lately in obese
About 30% of the Type 2 DM patients are undiagnosed
(they do not know that they have the disease) because
symptoms are mild.
Etiology and pathophysiology of type 2 diabetes
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
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
Progression Of Beta Cell Failure in Type
Progressive β-cell defect
in type 2 diabetes
Impaired glucose tolerance (IGT) ,Postprandial = after eating a meal while preprandial
is before a meal
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
Type 1 vs. Type 2
Type 1 Type 2
Age of onset Childhood, young adult
Usually > 40 + some
Pathogenesis Autoimmune process
Defect in insulin
resistance to insulin,
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
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
• 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
Presence of autoimmunity to islet protein is the feature
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)
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
Latent (months/years) Slow (years)
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.
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-
It is frequently mistaken for type 1 or type 2 diabetes
Gestational diabetes mellitus:
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