Download Dr Shahjada Selim

Etiopathology of Diabetes
Dr Shahjada Selim
Assistant Professor
Department of Endocrinology
Bangabandhu Sheikh Mujib Medical University, Dhaka
Email: [email protected]
© DR. SHAHJADA SELIM
Pathogenesis of Type 1 diabetes.
Autoimmune Type 1 Diabetes




Beta cells destroyed via autoimmune mechanism.
Genetically predisposed people:triggering factor
= production of islet cell Ab.
Islet cell Ab destroy Beta cells.
Insulin production decreases.
© DR. SHAHJADA SELIM
Pathogenesis of Type 1 diabetes.
Autoimmune Type 1 Diabetes


Viruses + other environmental agents have
been shown to be triggering factors.
Viruses can damage beta cells by:
1.Direct invasion.
2.Triggering an auto
immune response.
© DR. SHAHJADA SELIM
Pathogenesis of Type 1 diabetes.
Autoimmune Type 1 Diabetes
 Implicated viruses:
mumps, intrauterine rubella, coxsackie B
virus, echo virus, gytomegalo virus and
herpes virus.
 Chemical substances that reduce diabetes:
alloxan, streptozotosin and dietary
nitroamides.
© DR. SHAHJADA SELIM
Pathogenesis of Type 1 diabetes.
Idiopathic Type 1 Diabetes
 No known aetiology.
 Permanent insulinopaenia.
 This form is strongly inherited.
 Not HLA associated.
© DR. SHAHJADA SELIM
Type 1


is characterized by
pancreatic islet beta cell destruction and
absolute deficiency.
The onset of the
disease is generally in
youth, but it can
occur at any age.
Patients have
dependence on daily
insulin administration
for survival.
© DR. SHAHJADA SELIM
Pathogenesis of type 1 DM
© DR. SHAHJADA SELIM
© DR. SHAHJADA SELIM
Clinical features of Type 1
diabetes.




Presents acutely. Symptoms due to
hyperglycaemia (thirst, polyuria, tiredness,weight loss).
Ketone production - abdominal pain, nausea and
vomiting.
Other symptoms: blurred vision, repeated
infections.
No chronic complications at diagnosis, may
only be apparent 5-10 years post diagnosis.
© DR. SHAHJADA SELIM
Incidence of Type 1 diabetes.




Incidence peaks at 11-13 years.
Seasonal variation: lowest rates in spring
and summer.
Geographical variation: Japan has a very
low incidence.
10% of Type 1 diabetics are over 65 years
of age.
Glucose (mg/dL)
Natural history of type 2 diabetes
350
300
Prediabetes
(Obesity, IFG, IGT)
250
200
Fasting glucose
150
100
50
Relative Changes
Postmeal Glucose
Diabetes
diagnosis
-15
-10
-5
0
5
250
10
15
20
25
30
Years
β-cell failure
200
Insulin resistance
150
100
Insulin level
50
0
-15
-10
-5
0
Onset
diabetes
5
10
15
20
25
30
Years
Macrovascular changes
Microvascular changes
Kendall DM, et al. Am J Med 2009;122:S37-S50.
Kendall DM, et al. Am J Manag Care 2001;7(suppl):S327-S343.
11
© DR. SHAHJADA SELIM
r
© DR. SHAHJADA SELIM
© DR. SHAHJADA SELIM
© DR. SHAHJADA SELIM
© DR. SHAHJADA SELIM
Pathophysiology of type 2 diabetes
Skeletal
Muscle
GI tract
Pancreas
Adipocyte
Muscle
α cells
 cells
Altered fat
metabolism
CNS
Hyperglucagonaemia
↑ hepatic sensitivity
to glucagon
INSULIN
RESISTANCE
INADEQUATE
INSULIN
SECRETION
↑ HEPATIC
GLUCOSE
PRODUCTION
↑ BLOOD GLUCOSE
CNS, central nervous system; GI, gastrointestinal; T2DM, type 2 diabetes mellitus
Cernea S & Raz I. Diabetes Care 2011;34(suppl 2):S264–S271
Enhanced glucose
reabsorption
Incretin
deficiency
Kidney
8/4/2017
GLP1 & DM
17
© DR. SHAHJADA SELIM
© DR. SHAHJADA SELIM
Pathophysiology of type 2 diabetes
Skeletal
Muscle
GI tract
Pancreas
Adipocyte
Muscle
α cells
 cells
Altered fat
metabolism
CNS
Hyperglucagonaemia
↑ hepatic sensitivity
to glucagon
INSULIN
RESISTANCE
INADEQUATE
INSULIN SECRETION
Incretin
deficiency
↑ HEPATIC GLUCOSE
PRODUCTION
Kidney
↑ BLOOD GLUCOSE
CNS, central nervous system; GI, gastrointestinal; T2DM, type 2 diabetes mellitus
Cernea S & Raz I. Diabetes Care 2011;34(suppl 2):S264–S271
Enhanced glucose
reabsorption
© DR. SHAHJADA SELIM
© DR. SHAHJADA SELIM
© DR. SHAHJADA SELIM
© DR. SHAHJADA SELIM
Pathogenetic and clinical difference of type 1
and type 2 DM
N
Signs
Type 1
Type 2
1
Beginning of
disease
Acute
Gradual
2
Duration
Labile
Stable
3
Ketosis,
ketoacidosis
Often develops
Rarely develops
4
Body weight
Decreased or
normal
Obesity in 80-90 %
of patients
5
Age
Young (under 35) Old, middle
© DR. SHAHJADA SELIM
Pathogenetic and clinical difference
of type I and type II DM
N
Signs
Type 1
Type 2
6
Treatment
Insulin, diet
7
Degrees of severity
Middle, hard
Diet, drugs,
insulin
Mild, middle,
hard
8
Connection with
HLA-system
Present
9
Level of insulin and
C-peptide
Absent
Decreased Frequently
or normal level
absent
© DR. SHAHJADA SELIM
Pathogenetic and clinical difference
of type I and type II DM
N
Signs
Type 1
10.
Antibodies
to β-cells
Present in 80-90
Absent
% of patients on
first week, month
Microangiopathies Macroangiopathies
11.
Type 2
Late
complication
s
12. Mortality
Less than 10%
More than 20%
13.
80-90%
Spreading
10-20%
© DR. SHAHJADA SELIM
Pathophysiology of DM
Insulin lack
Defective polymorphonuclear function →
infection
↑
Hyperglycemia → glucosurea → polyurea
→ dehydration
↓
Hyperosmolality
Proteolysis → weight loss → muscle
wasting → polyphagia
Lipolysis → free fatty acid release →
ketosis → acidosis
© DR. SHAHJADA SELIM
Stages of DM development



I. Prediabetes (risk factors or predispose
factors).
II. Impaired glucose tolerance (latent DM).
III. Clinical manifestation of DM.
© DR. SHAHJADA SELIM
Prediabetes (risk factors or predispose
factors)
-
-
-
obesity
positive family history of
DM
persons which were born
with weight more than
4,0 kg
women who had-children
with weight more than
4kg, abortions and dead
child in anamnesis;
© DR. SHAHJADA SELIM
Prediabetes (risk factors or predispose
factors)
-
-
-
persons with:
atherosclerosis,
hypertension
auto-immune diseases
Furunculosis
rubella, mumps, Coxsackie
virus, infectious hepatitis,
cytomegalovirus, infection
mononucleosis;
endocrine disorders
© DR. SHAHJADA SELIM
© DR. SHAHJADA SELIM
Type 2 diabetes.




Patients frequently undiagnosed for many
years.
May present with hyperglycaemia
symptoms.
Coma is rare in type 2 diabetes.
May progress to an absolute state of insulin
deficiency.
© DR. SHAHJADA SELIM
Pathogenesis of Type 2 diabetes.


1.
2.
3.
4.
Cause: a combination of impaired insulin
secretion and insensitivity of target tissues to
insulin.
Impaired insulin secretion due to beta cell
malfunction can be associated with:
Incorrect secretion pattern.
Ratio of proinsulin to insulin.
Amyloid deposits.
Slow destruction of beta cells
© DR. SHAHJADA SELIM
Mechanisms for insulin
resistance.
1.
Receptor numbers are decreased. (Often
seen in obese and aged patients.)
2.
3.
Receptor structure is abnormal.
Insulin resistance at post receptor events.
© DR. SHAHJADA SELIM
Clinical features of Type 2 diabetes.

Diagnosis due to presence of complications.(At
least 30% patients have complications at diagnosis).

Symptoms are mild, gradual onset. Classic
diabetic symptoms may be present.

Type 2 diabetics are usually:
fat (“apple obesity”) and no ketones are present.
© DR. SHAHJADA SELIM
© DR. SHAHJADA SELIM
800
Insulin Secretion (pmol/min)
© DR. SHAHJADA SELIM
Insulin Secretion in Non-Diabetics
and Type 2 Diabetics
Normal
Type 2 DM
700
600
500
400
300
200
100
06:00
O'MEARA et al. Am. J. Medicine, 1990;89
10:00
14:00
18:00
22:00
Clock Time (Hours)
02:00
06:00