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‫بسم الله‬

‫الرحمن الرحيم‬
Dr. Mohamed Elkhawanky
melkhawanky@yahoo.com
Diabetes = frequent
urination

Mellitus = honey
History of
Diabetes
 In the 2nd century Celsus immersed in his
encyclopedia a strange disease which
confused scientists every where.

 In 1670 Thomas Willis tasted the urine of the


patient and found it sweety & hence the
name DM.

 In Germany 1869 Paul Langerhans


discovered two types of cells in pancreas &
DM was caused by one of these cells which
where destroyed.
 In 1922 Fredrik Banting & Charles
Best extracted insulin from pancreas.

 In the 21st century different methods


are used for treatment; injections,
oral pills, inhaler devices and even
pancreas transplantation.
In Ancient Egypt Ebers
Papyrus was the
early description of
diabetes back to
1500 BC .
Diabetes Mellitus
DM comprises a group of common
disorders that share the phenotype
of hyperglycemia

DM is caused by:
 Genetic

 Environmental

 Life-style interactions
Etiologic classification of
DM
1. Type 1 diabetes mellitus.
2. Type 2 diabetes mellitus.
3. Gestational diabetes mellitus
(GDM).
4. Other specific types of diabetes.
:Type 1 diabetes mellitus
In type 1 diabetes B-cell destruction
occurs and usually leading to
absolute insulin deficiency.

Type 1 A: Immune-mediated

Type 1 B: Idiopathic
:Type 2 diabetes mellitus

It is characterized by
impaired insulin

action with relative insulin


deficiency.
:Epidemiology
 Prevalence of type 2 DM is about 2.8%
and is expected to rise more rapidly to
4.4% because of increase obesity and
decrease activity.

 In patients < 20 years old the prevalence


is
about 0.19%

 In patients >65 years old the prevalence


is about 20.1%
Diagnosis
1. Fasting plasma glucose (FPG) level: > 126 mg/dl
is a diabetic.

2. Two-hour post prandial plasma glucose level:


(PPG) > 200 mg/dl is a diabetic patient. If the
result between 140 – 200, the patient has
impaired glucose tolerance and 40% of these
cases have the risk of overt DM next 5 years.
3- Hemoglobin A1c (Hb A1c):
 Hemoglobin A1c (HbA1c) is a minor
component of hemoglobin to which
glucose is tightly bound.
 HbA1c also is referred to as
glycosylated or glucosylated
hemoglobin.
 In healthy, non-diabetic patients the
HbA1c level is about 3.0% to 6.5%
of total hemoglobin.
4- Glucose Tolerance Test (GTT):
 Theoral glucose tolerance test
(OGTT or GTT ) is a diagnostic
method for diabetes and reactive
hypoglycemia.

 Bloodis drawn at intervals for


measurement of glucose. The
intervals and number of samples
vary according to the purpose of
the test.
Gestational Diabetes
Mellitus
 fasting [greater than or equal to] 105 mg/dl
 1 hour [greater than or equal to] 190 mg/dl

 2 hour [greater than or equal to] 165 mg/dl

 3 hour [greater than or equal to] 145 mg/dl

GDM affects 4% of pregnancies


30 – 60 % have a risk of DM later
Insulin
 Insulin is produced in beta cells which
constitute 75% of the islets of
Langerhans of the pancreas.

 Insulin is synthesized in the form of a


single polypeptide chain, preproinsulin
which is transformed into proinsulin
which, itself, catalyzed by proteases to
give insulin and C peptide.
Proinsulin, Insulin, chains A and B linked by
two disulfide bonds, and C peptide
Insulin Secretion
 Insulin, as well as C peptide, are released
by exocytosis into the portal venous
system which leads it directly to the liver,
which takes up nearly 50%. The
remainder of insulin is distributed
throughout the body.
 The principal stimulant of insulin secretion
is glucose which is transported by (GLUT2)
glucose transporter.
Metabolic regulation of insulin secretion
Insulin action

Insulin increases glucose transport


through PI-3 kinase pathway which
promotes the translocation of
intracellular vesicles containing
glucose transporter (GLUT4) to the
plasma membrane and hence
increases glucose uptake
by the cell.
Insulin action
Pathogenesis of type -1
DM
Type-1 DM develops as a result
of synergistic effects of
genetic, environmental &
immunological factors leading
to progressive destruction of B
cells by autoimmune process.
Immunological markers
of type -1 DM
Islet cell auto-antibodies (ICA) are directed against
:many islet B cell molecules as
 GAD-65
 Insulin

 IA-2/ICA-512

 Islet ganglioside

ICAs present in > 75% of type -1A DM ,

5 – 10 % of type -2 DM &
<5% with GDM
Structure of a gene
Prevention of type -1
DM
Trials of prevention have
targeted the immune system
through:
 Immunosuppressant
 Selective T-cell subset deletion

 Induction of immunologic tolerance to


islet proteins
Novel therapy of DM
type-1
Human Islet
Transplantation
In islet transplantation, islets
containing beta cells are taken from a
donor pancreas. When they have
been purified, these islets are infused
into the portal vein of a diabetic
recipient's liver. There they produce
the insulin that helps control the
body's blood sugar.
Human Islet Transplantation
Diabetes
Mellitus Type-
2
Type-2 Diabetes Mellitus
Type-2 DM is a polygenic (MODY1-5) and
multifactorial (such as nutrition, physical
activity and obesity) disorder.

It is characterized by:
 Peripheral insulin resistance

 Impaired insulin secretion

 Excessive hepatic glucose


production
Pathophysiology of Type-
2 DM
 Insulin resistance:
 Decrease the ability of insulin to act effectively
on peripheral target tissue (muscle & liver).
 In obesity; adipocytes secrete substances that
modulate insulin action and makes insulin
resistance as leptin. TNF-α, free fatty acids and
adiponectin which decrease insulin receptor
level, tyrosine kinase activity & translocation of
GLUT4 to plasma membrane.
Insulin action
 Impaired insulin secretion
Early, there is initially insulin increase, then
mild defect progresses till inadequate insulin
secretion occurs.
Due to:
Genetic defects: leads to amyloid deposits in
B cells.
Glucose toxicity: chronic hyperglycemia may
impair the function of B cells, also do FFAs.
 Excessivehepatic glucose
production
The decrease in the ability of insulin
action on peripheral target tissue
leads to increase hepatic glucose
output to overcome cells
hypoglycemia through stimulation of
gluconeogenesis and glycogenolysis.
Risk factors of DM
 Family history of diabetes
 Obesity
 Habitual physical inactivity
 Previously identified IFG or IGT
 History of GDM or delivery of baby >
4 kg
 Hypertension
 Decreased HDL and increased LDL
Prevention of type-2 DM
Diabetes Prevention program (DPP)
 Proper diet &exercise for 30 min/d 5
times/w delay or prevent type-2 DM
by 58%.
 Metformin delays DM-2
 Pravastatin decreases the incidence
of DM-2
 Decrease body weight.
Acute complications of
DM
 Diabetic ketoacidosis
 In insulin deficiency with glucagon
excess there is increase in
gluconeogenesis leads to ketone
body formation and acidic PH
 Increase FFA may be severe
enough to cause pancreatitis.
 Hyperglycemic hyperosmolar
state
There is increase in blood
glucose which induce osmotic
diuresis with absent of ketosis.
Chronic complications of
DM
Mechanisms of chronic
complications
 Increase glucose alters the function of endothelial
nitric oxide.
 Increase glucose intracellular is converted to
sorbitol which alters redox potential leading to
cellular dysfunction.
 Increase glucose activates PCK which increases
collagen and contractile proteins (fibronectin)in
endothelial cells and neurones.
 Increase glucose forms advanced glycosylation
end products (AGEs) which accelerates
atherosclerosis.
 Increase vascular endothelial GF
(VEGF) leading to diabetic
proliferative retinopathy.
 Increased platelet derived GF and
Insulin like GF.

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