PATHOPHISIOLOGY OF
DIABETES MELLITUS
R. Mohammadi
Biochemist (Ph.D.)
Faculty member of Medical Faculty
BLOOD GLUCOSE
REGULATION
METABOLIC FUELS
Glucose
F tt Acids
Fatty
A id
Ketone Bodies
Aminoacids
ECONOMIC OF FUELS
Cellular Capacity
C ll Needs
Cell
N d
Fuel Availability
Hormonal Condition
ROLE OF TISSUES
Liver
F tt Tissue
Fatty
Ti
Muscle
ROLE OF HORMONES
Insulin
Glucagon
E i
Epinephrine
hi
Cortisol
Thyroid Hormone
Growth Hormone
GLUCOSE TRANSPORTERS
GLUT1
GLUT1
GLUT2
GLUT
2
GLUT3
GLUT3
GLUT4
GLUT
4
GLUT5
GLUT
5
GLUT7
GLUT
7
All tissues
Liver, β-cell,
I t ti
Intestine,
kid
kidney
All Tissues
Fatty Tissue, Muscle
Intestine kidney
Intestine,
Endoplasmic Reticulum
BLOOD GLUCOSE
REGULATION
G
O
FEEDING STATE
NONFEEDING STATE
FEEDING STATE
‫‪ABSORPTION OF‬‬
‫‪MONOSACCHARIDES‬‬
‫‪O OS CC‬‬
‫‪S‬‬
‫ب درر دوو م رـرحله ور‬
‫مكانيسممها‬
‫ين ي‬
‫كليه ازز همين‬
‫تليالل ي‬
‫سلولهايي اپپيـي ي‬
‫ون‪ .‬ول‬
‫ش خون‬
‫گردش‬
‫ل ر‬
‫تليالل ببهداخل‬
‫ول اپپيـي ي‬
‫تليالل و )‪ (۲‬انتقالل ازز سلول‬
‫پي ي‬
‫ول اپـي‬
‫ل سلول‬
‫جري روروده ببهداخل‬
‫پذيرد‪ (۱) :‬انتقالل ازز مجراي‬
‫صورت مييپ ير‬
‫ين ججذب‬
‫منوساكاريدها ازز روروده‪ .‬اين‬
‫ب و ري‬
‫ل ‪ ۲۵ -۳‬ججذب‬
‫شكل‬
‫بـراي بازجذب گلوكز و گاال كـتوز استفاده ميكنند‪.‬‬
HEXOKINASE & GLUCOKINASE
Glc + ATP
Glc 6-p + ADP
PATHWAYS OF
G COS METABOLISM
GLUCOSE
O S
Triacylglcerol
Glycogen
Glc 6-p
Glcolysis
Pentose
Phosphate
Uronic
Acid
INSULIN
Prepro
Pre
proinsulin
insulin
(100 aa)
Signal Peptide
Proinsulin
Pro
insulin
(86 aa)
Peptide C
I
Insulin
li
(A Chain with 21 aa & B Chain 30 aa)
‫مكانيسم ٓازا ازي‬
‫فعاليت‬
‫ت‬
‫واسطه ف ال‬
‫گلوكز هبه ا طه‬
‫انكرااس ميششود‪ .‬گل كز‬
‫هاي پانك‬
‫سلوللهاي‬
‫طريق ‪ GLUT2‬اوارد ل‬
‫ايش مي ايابد‪ ،‬از ط ق‬
‫گردش خخون افزا ش‬
‫گلوكز در گ ش‬
‫وقتي گل كز‬
‫گلوكز‪ (۱) .‬قت‬
‫توسط گل كز‬
‫انسولين ت ط‬
‫ادسازي ان ل‬
‫احل كان‬
‫شكل ‪ ۳۹-۸‬مرا ل‬
‫ٓ‬
‫ٓ‬
‫گلوكوكيناز وارد مسير گليكوليز شده كه نتيجه ان افزايش غلظت ‪ ATP‬ميباشد )‪ ATP .(۲‬كانال پتاسيمي وابسته بـه ‪ ATP‬را ميبندد كه نتيجه ان دپوالريزاسيون غشاء و بازشدن كانال كلسيمي‬
‫وابسته به ولتاژ ميباشد )‪ .(۳‬با افزايش غلظت كلسيم داخلسلولي )‪ ،(۴‬اگزوسيتوز گرانولهاي ترشحي حاوي انسولين تحريك ميشود )‪.(۵‬‬
NONFEEDING
STATE
GLUCAGON
Synthesis as Proglucagon
29 Amino Acids
Act on Liver & Fatty Tissue
Increased Glycogenolysis
Glycogenolysis,
Gluconeogenesis, Lipolysis, β-Oxidation
EPINEPHRINE
Synthesis from Tyrosine
A t on Li
Act
Liver & Muscle
M
l
Increased Glycogenolysis &
Gluconeogenesis
CORTISOL
Synthesis from Cholesterol
I
Increased
d Gluconeogenesis
Gl
i
Increased Proteolysis
Increasesd or Decreased Lipolysis
THYROID HORMONE
Sythesis from Tyrosine
I
Increased
d Glycogenolysis
Gl
l i
Increased Glucose Absorption
GROWTH HORMONE
191 Amino Acids
I
Increased
d Gluconeogenesis
Gl
i
Inhibition of Glc Uptake
Increased Lipolysis
DIABETES MELLITUS
(DM)
DEFINITION Of DM
Clinical DM Is A Syndrome of
Disordered Metabolism with
Inappropriate Hyperglycemia Due to an
Absolute or Relative Deficiency of
Insulin
It May Be Due to Deficiency of Insulin
Secretion Defect in Insulin Action or
Secretion,
Both
Clinical Presentation of DM
DM Is Clinically Presented by Three
Polys which Are Due to Glycosuria
Polyuria
Polydipsia
Polyphagia
yp g
COMPLICATIONS OF DM
Acute
Chronic
ACUTE COMPLICATIONS OF DM
Are Due to Reduced Insulin Activity and
Increased Counter Regulatory Hormenes,
Hormenes,
specially glucagon
Severity of Complications Are Dependent on
Glucagon / Insulin Ration
Acute Complications Are
1) Hyperglycemia
2) Diabetic Ketoacidosis (DKA)
yp
Coma
3) Hyperosmolar
4) Hypoglycemia
HYPERGLYCEMIA
Postprandial Hyperglycemia
Fasting Hyperglycemia
Glucosuria which results in Three Polys which
are first presentations of overt DM:
1) Polyuria (and Nocturia
Nocturia))
2) Polydipsia
3) Polyphagia (and weight loss)
loss)
DIABETIC KETOACIDOSIS (DKA)
Is duo to increased lipolysis due to absence of
insulin activity, so it is more common in type 1
DM and is uncommon in type 2 DM
May results in Coma due to hyperosmolality and
acidosis
Electrolyte imbalance may occurs:
1) Hyponatremia occurs due to sodium excretion in urine and
i
increased
d plasma
l
water
t because
b
off increased
i
d osmolality
l lit
2) In spite of potassium excretion, plasma potassium level remains
normal because of a shift of K+ out of cells. But during insulin
therapy,, K+ move back into cells and hypokalamia results.
therapy
HYPEOSMOLAR COMA
Is More Common in type 2 DM
Results from Sever hyperosmolality due to sever
hyperglycemia
yp g y
( >800
>800 mg/
mg/dL
g dL)) and severe
dehyratation
HYPOGLYCEMIA
Is complication of insulin treatment in both type 1
DM and type 2 DM, but may also occur with oral
oral hypoglycemic drugs, such as sulfonyureas
Acute response is mediated by counter
regulatory hormones
Common symptoms are night sweats,
nightmares, morning headaches
CHRONIC COMPLICATIONS OF DM
Microvascular
Macrovascular
M
l
Others
CHRONIC COMPLICATIONS OF DM
Microvascular
Eye Disease
R ti
Retinopathy,
th Macular
M
l Edema
Ed
Neuropathy
Sensory & Motor, Autonomic
Nephropathy
CHRONIC COMPLICATIONS OF DM
Macrovascular
Coronary Artery Diseases
P i h l Vascular
Peripheral
V
l diseases
di
Cerebrovascular Diseases
CHRONIC COMPLICATIONS OF DM
Others
Gastrointestinal
p
Diarrhea,, Gastroparesia
Genitourinary
Uropathy, Sexual Dysfunction
Dermatology
Infections
Eyes
Glucoma, Cataract
CLASSIFICATION OF
DIABETES MELLITUS
American Diabetes Association (ADA)
Classify DM into Four Calss
Calss::
Type 1
Type 2
Other Specific
p
Types
yp
GDM
DM Type
ype 1
5% - 10%
10% Frequency
Previoysly Named
Juvenile-onset DM
JuvenileInsulin--dependent DM
Insulin
Abruptt Onset
Ab
O
t
Normal Body Weight
Family History Is
Less Common
Autoimmune
Often Ketones Present
Total Insulin
Deficiency
DM Type 2
90% - 95
90%
95%
% Frequency
Previoysly
y y Named
Adult-onset DM
AdultNoninsulin--dependent DM
Noninsulin
GraduaI Onset
Obesity
Family History Is
Common
No Autoimmune
No Ketones
Partial Insulin
D fi i
Deficiency
/ Resistance
R i t
DIABETES MELLITUS TYPE 1
Is an autoimmune disease caused by selective
destruction of pancreatic beta cells
Genetic susceptibility
p
y is related,, at leaset in p
part,,
to the inheritance of specific immune response
genes associated with HLA
HLA--DR/DQ on
chromosome 6, as well as other genes and
genetic markers
I hypothesized
Is
h
h i d that
h a precipitating
i i i events
occurs, such as viral infection,
infection, toxin exposure,
exposure, or
other environmental influence,
influence, which trigers the
autoimmune destruction of beta cells.
DIABETES MELLITUS TYPE 1
Have 2 subtypes
1) Ia including 95
95%
% 0f patients who have
autoantibodies
2) Ib including 5% of patients who have not
autoantibodies
Autoantibodies includes
Islet cell antibodies (ICA)
glutamic acid decarboxylase (GAD)
tyrosine phosphatasephosphatase-2 protein (IA2
(IA2)
Insulin Autoantibodies (IAA)
DIABETES MELLITUS TYPE 1
Is More common in Children Whom have rapid
onset
Also, may be seen in adults who often have slow
progression which may results in Wrong
Diagnosis as type 2 , so they are called Latent
Autoimmune Diabetes of Adulthood (LADA)
OBESITY ,
METABOLIC SYNDROME
& TYPE 2 DIABETES
OBESITY IS LIFE THREATENING
Obesity Increases the Chance of Developing
Type
T pe II Diabetes
Atherosclerosis
Cancers of Colon, Breast, Prostate &
Endometrium
BODY MASS INDEX (BMI)
Obesity
y Is Defined in Terms of BMI
Weight in Kg
BMI =
(Height in m)2
BMI
BMI
BMI
BMI
BMI
< 18.
18.5
= 18.
18.5 – 24
24..9
= 25 – 29
29..9
= 30 – 40
> 40
Underweight
Normal
Overweight
Obese
Morbidly Obese
FATTY TISSUE IS AN
ENDOCRINE
OC
ORGAN
O G
Adipocytes Secrets Different Adipokins
Adipokins::
Leptin
Adiponectin
Resistin
Cytokines such as TNFH
TNFH
TNF
H INCDUCES DYSLIPIDEMIA
TNFH
Hormone-sensitve
Lipase
Lipoprtein Lipase
Clearance of VLDL
from Circulation
Hepatic Synthesis
of TAGs
Release of FFAs
Into Circulation
Hepatic Uptake
off FFAs
Blood VLDL
Hepatic Synthesis
of VLDL
TNFH
TNF
H INDUCES DYSLIPIDEMIA
TNFH
Expression & Activity
of LCAT
Expression of
ABC Transporters
Blood HDL
Expression of
APo A-I
A I & Apo
Apo-A-IV
A IV
FFAs INDUCE HYPERGLYCEMIA
FFAs
Competitive
Inhibition of
GLUT2 & GLUT4
Activation of PKC
Phosphorylation of
IRS-1
IRS
1 & IRS-2
IRS 2
GLUT4 Translocation
In Muscle
Blood
Glucose
Interfering with
Down-Regulation of
Gluconeogenesis
In Liver
PANCREATIC COMPENSATION
Hyperinsulinemia
yp
Increased
Cell Proliferation
Stimulation of Sympatthetic
Nervous System
Normal or Near Normal
Blood Glucose
Increased Risk of
Different Types
Of Cancers
Na & Water Retention
Vasoconstriction
Hypertension
DECOMPENSATION PROCESS
Increased FFAs and/or Cytokines
Gradual Loss of the Ability
of the Pancreas to Overproduce Insulin
Increased Blood Glucose
Type 2 Diabetes Begins
MTABOLIC SYNDROME
The insulin resistance associated with obesityy
increases the risk of developing type 2 diabetes,
diabetes,
heart disease,
disease, hypertension
hypertension,, and several types
of cancers
cancers..
Increased risk of some of these diseases may
occur long before the patient becomes diabetic,
so the condition between the onset of insulin
resistance and development of type 2 diabetes
is referred as metabolic syndrome
METABOLIC SYNDROME
WHO Defines Metabolic Syndrome as Two or
More of the Following Conditions:
Abdominal
Abd
i l obesity
b it
Dyslipidemia (Increased VLDL and Decreased HDL)
Hypertenstion
Insulin Resistant (Modest increase in FBS)
METABOLIC SYNDROME
Defining criteria according to the Third Report of
NCEP Expert panel on Detection, Evaluation, and
Treatment of High Blood Cholesterol in Adults
i l d the
include
th presence off Three
Th
or More
M
off the
th
following conditions:
Impaired
p
Fasting
g Glucose
Blood Pressure ≥ 135 / 85 mmHg
Waist circumference > 102 cm in men and >
>88
88 cm in
women
Serum TG ≥ 150 mg/dL
mg/dL
HDL--C < 40 mg/
HDL
mg/dL
dL in men and < 50 mg/
mg/dL
dL in women
RISK FACTORS OF TYPE 2 DM
Family
y History
y Of Diabetes
Obesity
Inactivity
Hi h Blood
High
Bl d Pressure
P
Low HDL or High TG
History of GDM or Child Birth > 4 kg
History of Impaired GTT
Race : Americans, Africans
Polycystic Ovary Syndrome or
Acanthosis Nigricans
History of Vascular Diseases
OTHER SPECIFIC TYPES
1) Genetic Defects of Beta Cell Function
M t it -onsett diabetes
MaturityMaturity
di b t off the
th young (MODY)
2) Genetic Defects in Insulin Action
Leperchaunism syndrome
3) Pacntreatic Diseases
Pancreatitis, Cystic Fibrosis, Hemochromatosis, Neoplasms
4) Endocrinopathies
Hyperthyroidism, Cushing, Pheochromocytoma,
Pheochromocytoma, Glucagonoma,
Glucagonoma,
Aldostronoma
5) Drugs
Glucocorticoides,, Nicotinic Acid, Thyroid Hormones, Phenytoein,
Glucocorticoides
Phenytoein,
Thiazides, α-Interferon, Beta
Beta--Blockers
4) Infections
Congenital Rubella, Coxsakie
Coxsakie,, CMV
5) Genetic Defect of B Cell Function
6) Other Genetic Syndromes
Down, Klinfelter,
Klinfelter, Turner, Chorea, Porphyria
GESTATIONAL DIABETES
S (G
MELLITUS
(GDM))
Is defined as glucose intolerance
that develops
p or is first recognized
g
during pregnancy
Develops during approximately 7%
of all pregnancies
There is both insulin insensitivity
and failure to increase insulin
secretion
Low-Risk Women
LowLess than 25 years
Normal weight before pregnancy
Race
Race
Absence of DM in first related
Absence of abnormal glucose
intolerance
Absence of complicated pregnancy
High-Risk Women
HighMore than 37 years
Pregnancy weight > 80 kg
Race
Race
Family
y history
y of DM
Polycystic ovary syndrome
Previous macrosomia
Previous unexplained stillbirth