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PD,
M.Sc
IMPORTANT
Healthy pancreas have: 100 000
10
11
12
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14
Historical milestones in DM
Date
Source
Observation
1550 BC
1-2nd cntry AD
5th century
Egypttian papyrus
Galen (Roman), Aretaeus (Greek)
Susruta, Charuka (Indian)
10th century
Avicenna (Arabia)
17th century
18th century
Willis (England)
Dobson, Cawley (England)
19th century
19th century
20th century
20th century
Bernard (French)
Langerhans, Minkowski,von
Mering (Germany)
Banting (Nov 14th ), Best,
Macleod, Collip (Canadian)
Hodgekin, Sanger (England)
Patient JL
15 December, 1922
Patient JL
15 February, 1923
16
EPIDEMIOLOGY
WHO Estimation: Indonesia have people
with DM (2030):
Rural : 7,2 % from adult (>20 years old)
Urban: 14,7 % from adult
17
India
China
Russian Federation
Japan
Brazil
Indonesia
Pakistan
Mexico
Ukraine
Egypt
1995
2025
19
16
9
6
5
5
4
4
4
?
57
38
12
9
11
12
15
12
?
9
18
19
60,3
70,6
12%
20,3
29,6
46%
170,0
263,7
55 %
21,4
39,4
84%
18,5
29,5
60%
5.6
8.2
20
Type of DM
1. Type 1 (IDDM: insulin dependent DM)
2. Type 2 (NIDDM: non insulin dependent
DM)
- obese
- non obese
3. Others (genetic cell function & insulin action,
disease of exocrine pancreas, drugs, endocrinopathies,
infections, immune, others.
4. Gestasional
21
1. Type 1 DM
5-25% of cases (pancreatic islet cell
deficiency)
Is a chronic-progressive autoimmune disease islet
cell and insulin antibodies
The incidence is higher in children
Associated with autoimmune features and includes a
broad range of clinical presentation of all age
Identification of autoantibodies in the general
population can predict type 1 DM
22
2. Type 2 DM
75-95% of cases (defective insulin action
or secretion)
Insulin resistance
Insulin secretory defect ( cell function)
23
LIVER
GLYCOGENOLYSIS
Insulin
Glucose
uptake +
HGP
G L UC O S E
GLUCOSE
GLUCONEO
GENESIS
NORMAL
G LYCOGEN
MUSCLE
- = Suppression
+ = Stimulation
QUINTESSENTIAL QUINTET
Decreased
Decreased
incretin
Incretin
effect
effect
Impaired Insulin
secretion
Quintus = five
Increased
lipolysis
Hyperglycemia
Increased
HGP
Decreased Glucose
uptake
DeFronzo ADF 2006
Setaceous
Decreased
Sextet Incretin
effect
Impaired Insulin
Increased
lipolysis
secretion
Islet -cell
Hyperglycemia
Increase
glucagon
secretion
Decreased Glucose
uptake
Increased
HGP
Septicidal Septet
Decreased
Incretin effect
Impaired Insulin
secretion
Increased
lipolysis
??
Islet -cell
Hyperglycemia
Increase
Glucagon
secretion
Neurotransmitter
Decreased Glucose
dysfunction
Increased
HGP
uptake
Septem = seven
Insulin Resistance
Acquired
Obesity
Sedentary Lifestyle
Aging
Hyperinsulinemia
Compensated Insulin Resistance
Normal Glucose Tolerance
Impaired Glucose Tolerance
- Cell Failure
Genes
Type 2 Diabetes
30
ATP-sensitive
K+ channel
Voltage-dependent
Ca2+ channel
Depolarization
ATP/ADP
Ca2+
Islet
transcription
factors
Mitochondria
Insulin
Pyruvate
Glucose-6-Phosphate
Glucokinase
Glucose
GLUT2
Glucose
Nucleus
Secretory
granules
Insulin Resistance
A core defect in most type 2 diabetes
patients
Definition:
Impaired response to the physiological
effects of insulin, including those on
glucose, lipid, protein metabolism and
vascular endothelial function
INSULIN RESISTANCE
Insulin signalling
Obesity and diet
Endocrine diseases
Pregnancy
Drug
Malnutrition in utero and early
childhood
Mutation
Insulin receptor
Post receptor defect
INSULIN RESISTANCE
DEFECT OF INSULIN
ACTION
1. Muscle
2. Adipose
3. Liver
Environmental factors
Overeating
Inactivity
Smoking
Diabetogenic drugs
Environmental factors
Genetic factors
Unknown
Genetic factors
Unknown
Insulin resistance
Pregnancy
Endocrine diseases
Diabetogenic drugs
Malnutrition in utero
B- cell defects
Glucose toxicity
Hyperglycaemia
Impaired glucose
tolerance
NIDDM
Normal -cell
hyperinsulinemia
NGT
Normoglycemia
1.8 years
IGT
1-5%
per year
Impaired glucose
tolerance
-cell exhausted
3.3 years
Normo-, or hypoinsulinemia
T2DM
37
100
75
Beta Cell
Function
(%)
IGT
Postpandrial
Hiperglycemi
T-2 DM phase I
Beta Cell function
50 %
50
Stages of Type
2 Diabetes
T2 DM
phase I
25
T2 DM
phase II
T2 DM
phase III
0
-12 -10
14
Lebovitz, 2000
-6
-2
10
Insulin secretion
50 %
Insulin sensitivity
T 2 DM
30 %
IGT
50 %
150 %
Impaired glucose
metabolism
70 %
100 %
100 %
70 -100 %
39
3. Others type
Genetic defect of cell function
40
4. Gestasional DM
Pregnancy induces state of insulin
Diagnosis (WHO
classification)
Normal
Fasting &
2h post-prandial
< 110
< 140
> 126
> 200
Impaired
Glucose
Tolerance (IGT)
< 110
140-199
Fasting &
2h post-prandial
Symptom of
Diabetes
Classical Symp
(+)
FBG
or
2h
pp
>126
<126
<200
>200
Repeat FBG or 2h
pp
FBG
or
2h pp
>126
<126
>200
<200
>126
<110
>200
110-199
OGTT
2h pp
>200
DIABETES
110 - <126
MELLITUS
140 - 199
IGT
IFG
<140
NORMAL
43
Risk
Factors
of
DM
Family history
DM
Relative with DM
Risk of
DM
Type 1
Mother
Father
Sister or brother
Twin sister or brother
2%
9%
10%
50%
Type 2
Mother
Father
Both parents
Sister or brother
Twin sister or brother
Over weight/obese/inactivity
Age
Hypertension
Dyslipidemia
19%
14%
25%
75%
99%
44
Hystory:
Duration of symptom: thirst, polyuria,
weight loss
Possible secondary causes of diabetes
Family history
Pressence of complication of diabetes
Risk factor for developing complications:
smoking, hypertension, hyperlipidemia
45
Examination:
BMI (body mass index weight (kg)/height 2(m)
Clues for secondary causes
Cardiovascular system (BP + pulse)
Sign of autonomic and peripheral neuropathy
Eyes for retinopathy
Investigation:
Blood test for: GDP, GD2JPP, HbA1C, urea ,
creatinin & electrolytes, full lipid profil
Urine tests for macro and (if negative) micro
albuminuria
An ECG in all type 2 DM
46
47
KIDNEY disease
Four times more likely to have a STROKE
Four times more likely become BLIND
Two to four times more likely to have a
HEART attack
48
risks of complication
COMPLICATIONS of DM
ACUTE
1.Diabetic ketoacidosis (DKA)
2.Hyperglycemic hyperosmolar state (HHS)
3.Hypoglycemia
CHRONIC
1.Microangiopathy (retinopathy,
nephropathy,
neuropathy,
Cardiomyopathy, Diabetic foot, etc)
2.Macroangiopathy (Heart attack/IMA,
Stroke, PAD)
50
Chronic complications
Development of other diseases
51
CHRONIC COMPLICATIONS
MICROVASCULAR
RETINOPATHY
NEPHROPATHY
CARDIOMYOPATHY
NEUROPATHY
AUTONOMIC
CARDIAC
GASTRIC
UROGENITAL
52
CHRONIC COMPLICATION
MACROVASCULAR
CHD
RISK
24x
DEATH 60 %
CEREBROVASCULAR
STROKE
: 4x
PERIPHERAL VD
40 50 % NON-TRAUMATIC AMPUTATIO
53
Retinopathy
Retina is back part of eye, is nourished by
55
How is it Treated?
(retinopathy)
Reguler eye examinations to identity
problem early
Laser procedure to seal weak blood vessel
In most cases only one eye is treated at a
time may several treatments pain
Bleedin in the middle eye need surgical
procedure to remove the blood an replace
with clear fluid
Detached (ablatio) retina by scar tissue
requires surgery to position the retina in
place
56
Nephropathy
Inside kidney are million tiny blood
57
58
How is treated?
(nephropathy)
Treatment depends on how advance the
Neuropathy
Have an intricate network of nerves runs
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61
How is it treated?
(neuropathy)
Good BG control will reduce your
symptoms
To relieve pain: pain reliever or
antidepressantor antiseizure
medication
Capsaicin cream (hot pepper extract)
63
65
How it is treated?
Many forms of heart disease are treated
Risk of infection
High BG impaired function the immune
infection
Low grade fever
Gum : red and bleeding
Bladder: frequent urination, urgency and
burning sensation
Vagina: itching &/or discharge in vagina
Foot: redness & pus are warning an
infection
68
How it is treated?
Antibiotic to kill bacteria
A foot injury: procedure to clean the
69
IMPOTENCE in DM
Refers: inability an erection of the penis
or
MEDICATION of
I. Sildenafil (Viagra, Androz, Edegra,Silagra)
IMPOTENCE
isnt effective for everyone
1 hour before activity effective 4 hours
II. Alprostadil (synthetic of prostaglandin E-1)
not a pill self intraurethral (a grain rice)
or self injection therapy (5-20 minutes before
and 1 hour erection)
III. Vacuum device
IV. Penile implant
a. semirigid, benabled rod (permanent
erection)
b. inflantable (with pump in scrotum produce
an erection only when you want)
71
V. Counseling (if psychologycal factors)
Preventing complication
Tight BG control normal or near-
normal
Diabetes Control and Complication Trial
(DCCT): Tight BG control reduce 50%
risk of many complication
United Kingdom Prospective Diabetes
Study (UKPDS):
Keep BG normal: 1/4 fewer
complications (eyes, kidneys and nerves)
and reduce risk of heart disease
Kumamoto study:
study the intensive insulin
therapy have delay in the start and
progression of eye, kidney and nerve
complication
72
MANAGEMENT of DM
1. EDUCATION
2.
3.
4.
EXERCISE
NUTRITION & DIET
PHARMACOLOGY
73
Education
Very important, included:
Pathophysiology of DM
Targets of DM management
Management of nutrition and diet
Phamacologik intervention
Exercise and physical activity
Self monitoring blood glucose (SMBG)
Prevent and manage of acute and chronic
complication
Psychosocial aspect
Management of Stress
Health care system
74
Criteria of DM
management
Good
Moderate
Poor
80 - 109
110 125
> 120
110 144
145 179
> 180
HbA1c (%)
< 6,5
6,5 8
>8
< 200
200 239
> 240
< 100
100 129
> 130
45
Triglyseride (mg/dL)
< 150
150 199
> 200
BMI (kg/m2)
18,5 - 22,9
23 25
> 25
< 130/80
75
MANAGEMENT of DM
1. EDUCATION
2.EXERCISE
3. NUTRITION & DIET
4. PHARMACOLOGY
76
Excersice
Minimal 30 minutes (fat burning), 150
minutes/weeks
CRIPE:
Continous
Rhythmic
Interval (Sai)
Progresive
Endurance maximum PULSE=80% (220age in year)
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MANAGEMENT of DM
1. EDUCATION
2. EXERCISE
79
MANAGEMENT of DM
1. EDUCATION
2. EXERCISE
4.PHARMACOLOGY
82
PHARMACOLOGY
1. INCREASED INSULIN
SECRETION
2. INCREASED INSULIN SENSITIVITY
3. ALPHA GLUCOSILASE INHIBITORS
4. INSULIN
83
INCREASED INSULIN
SECRETION
Sulfonilureas:
First line treatment in non obese patients
with type 2 DM
Stimulating a receptor on the surface cells
closing K+ channel and opening Ca++ channel insulin
release
Reduction HbA1c 1-2% in long term
Side effects hypoglycemia and weight gain, skin reaction,
alteration liver function, minor gastrointestinal symptom
and cholestatic jaundice and marrow supression
84
INCREASED INSULIN
SECRETION
Sulfonylure
a
Length
of
action
Begins
of
action
Daily
dose
(mg)
Route of
excretion
Glibenclamid
e
16 24h
2 4h
1,25 15
R = 50%, B =
50%
Gliclazide
10 24h
2 4h
40 320
R = 70%, B =
30%
Glipizide
6 24h
2 4h
2,5 40
R = 80%, B
=20%
Chlorpramide 24 72h
2 4h
100 500
Renal
Tolbutamide
6 10h
2 4h
100
1000
Renal
Glimepiride
24h
2 4h
1-6
R = 40%, B
=60%
gliquidon
18 - 24h
2 - 4h
30 - 120
R = 5%, B =
95%
85
PHARMACOLOGY
1. INCREASED INSULIN SECRETION
2. INCREASED INSULIN
SENSITIVITY
3. ALPHA GLUCOSILASE INHIBITORS
4. INSULIN
86
INCREASED INSULIN
Biguanides
SENSITIVITY
First line treatment for obese patient with type 2
DM
Used combination with insulin treatment
The UKPDS showed significantly better metformin
compared with the other therapies in reduced
complication and mortality in the overweight DM
Although 1-2 Kg weight loss is seen, but not
signifucant in over a 10 years period, and not
make hypoglycemia
Decreasing hepatin gluconeogenesis, increasing
muscle glucose uptake and insulin sensitivity
Long period 0,8 2,0% HbA1c reduction
87
INCREASED IN SULIN
Side effects:
SENSITIVITY
The major side effects of metformin is
INCREASE INSULIN
SENSITIVITY
Thiazolidinedione
PPAR agonist (reducing HbA1c 1%)
Act on adipose tissue, liver and muscle as insulin
PHARMACOLOGY
1. INCREASED INSULIN SECRETION
3. ALPHA GLUCOSILASE
INHIBITORS
4. INSULIN
90
ALPHA GUCOSIDASE
Acarbose
INHIBITORS
Act by inhibiting disaccharidases in the small
bowel
Delay enzymatic digestion of complex
carbohydrate delay absortion gradual flux
in of glucose concetration in portal vessels
Reducing postprandial hyperglycemia (HbA1c:
0,5%)
Side effects:
Significant carbohydrate malabsorption
flatulence, abdominal bloating and diarrhoea
Reduced the starting dose of 50 mg/day and
maintenance 50-100 mg each meal
91
PHARMACOLOGY
1. INCREASED INSULIN SECRETION
4.INSULIN
92
20g
glucose
80
60
40
20
0
30 0
30 60 90 120
Time (minutes)
Type 2 diabetes
Plasma insulin (U/ml)
Normal
120
20g glucose
100
80
60
40
20
0
30 0 30 60 90 120
Time (minutes)
93
Begining
15-30 mnt
Peaks Duration
2-4hr 6-8hr
Premixed
Humulin 30/70
Mixtard 30/70
15-30mnt
1-8hr
14-15 hr
2-4hr
1-8hr
14-15 hr
Short action
Actrapid
Humulin R
95
75
Breakfast
Lunch
Dinner
50
25
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
96
Bolus regimens
Plasma Insulin
Breakfast
Lunch
Actrapid
4:00
8:00
12:00
Dinner
Actrapid
16:00
Actrapid
20:00
24:00
4:00
8:00
Time
97
Basal/Bolus regimens
Plasma Insulin
Breakfast
Lunch
Actrapid
Dinner
Actrapid
1940s,
1st long-acting insulin
NPH, Neutral pH
Basal-bolus possible
Ideal,
but too many injections
Actrapid
Insulatard
Insulatard
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
98
Premix regimens
Plasma Insulin
Breakfast
Lunch
Dinner
Mixtard
Mixtard
(30% reg + 70% intermediate)
4:00
8:00
1964,
Fixed dose combination
Mixtard
Premix becomes choice
12:00
16:00
20:00
24:00
4:00
8:00
Time
99
25
NovoMix 30
Mixtard HM 30
***
20
15
10
5
NovoMix
30 matches therapy to
physiology
0
8:00 11:00 14:00 17:00 20:00 23:00 2:00 5:00 8:00
Time of day
Jacobsen L et al. Eur J Clin Pharm 2000;56:399403
101
Breakfast
Lunch
Dinner
Human insulin (Human Mixtard )
Slow to appear ~ Unwanted high sugar levels
50
25
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
102
begining
peaks duration
Rapid action
Lyspro (Humalog)
Aspart (Novo Rapid)
Gluisine (Apidra)
5-15 mnt
2 hr
4-6hr
5-15mnt
2-4hr
12-14 hr
Premixed
Humalog 25/75
Novomix 30/70
Long action
Lantus
Levemir
No peaks 24 hr
103
104
Sistem NovoLet
105
106