dr. Dita Ria Selvyana, Sp.

PD,
M.Sc

What is diabetes (DM)?

Glucose in your blood is from 2 mayor sources:

food and the liver

DM is a disease characterized by elevated blood

glucose level, it is result of defective insulin

secretion or action (resistance) or both.

Resulting chronic hyperglycemia is damage or

dysfunction of various organ (the eyes, kidneys,

nerves, heart, and blood vessels).

Clinical symptoms: 3P Excessive thirst

(polydipsia) increased urination (polyuria),

increased appetite (polyphagia) and weight loss.

IMPORTANT
Healthy pancreas have: 100 000

Langerhans island and every

Langerhans: 100 cells (insulin
production) 10.000.000
Insulin and insulin receptors like key and
the door

10

11

12

13

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)

Exessive ammount of urine

Sugary urine, Exessive
thirst
Described sugary urine
distinguished obese and
thinpatients
Sugary urine, gangrene &
impotence as
complications
Diabetic urine contains
sugar
Sugar in serum in
diabetes, diabetes may
follow pancreatic damage
Glucose stored as glycogen
on liver, exocrine
degeneration of pancreas
occurs after ligature of the
pancreatic duct
Pancreatic islets,
pancreatomy causes
15
diabetes

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

List of Top Ten Global Number of People

with Diabetes in 1995 and 2025 (in millions)
WHO 1998

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

Top Countries with Diabetes

Numbers of persons (millions)

Source: Diabetes Atlas 2000

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

Normal Glucose Metabolism

PANCREAS

LIVER
GLYCOGENOLYSIS

Insulin
Glucose
uptake +

HGP

G L UC O S E

GLUCOSE

GLUCONEO
GENESIS

NORMAL

G LYCOGEN

MUSCLE

- = Suppression
+ = Stimulation

Pathophysiology of Type 2 Diabetes

Impaired insulin action

Impaired insulin secretion

Hyperglycemia

Increased glucose production

Decreased glucose uptake

Pathogenesis of type 2 diabetes :

The (dys)-Harmonious quartet

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

DeFronzo ADF 2006

Impaired Insulin

Increased
lipolysis

secretion

Islet -cell

Hyperglycemia

Increase
glucagon
secretion

Decreased Glucose
uptake

Increased
HGP

Setaceous = smooth like fur

DeFronzo ADF 2006

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

Progression to Type2 Diabetes

Normal
Genes

Insulin Resistance

Acquired
Obesity
Sedentary Lifestyle
Aging

Hyperinsulinemia
Compensated Insulin Resistance
Normal Glucose Tolerance
Impaired Glucose Tolerance
- Cell Failure

Genes

Type 2 Diabetes
30

Physiology of insulin secretion

Ca++
S
U
R

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

ref version 2.1

Diab Care 1999;22:562

Diab Care 2000; 23(Suppl 1):54

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

Worsening B-cell functions

? Amyloid deposition
Malnutrition in utero

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

Type 2 diabetes mellitus

Weyer et al. J Clin Invest. 1999; 104: 787-94

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

Years From Diagnosis

38

Insulin secretion
50 %

Insulin sensitivity
T 2 DM

30 %

IGT

50 %

150 %

Impaired glucose
metabolism

70 %

100 %

Normal glucose metabolism

100 %

70 -100 %

The natural history of Type 2 Diabetes

39

3. Others type
Genetic defect of cell function

(MODY 1-4), mithochondrial DNA 3242 mutation

Genetic defect of insulin action
Diseases of exocrine pancreas
pancreatitis, trauma/surgery, neoplasia, cystic fibrosis
Endocrinopathies
Infections : rubella , CMV, Mumps, Coxsackie B
Drugs : steroid, norepinephrine and others
Immune-mediated DM : anti-insulin receptor antibodies
Others genetic syndrome associated DM
Down, Klinefelters, lawrence-Moon-Biedl, myotonic dystrophy, Turners

40

4. Gestasional DM
Pregnancy induces state of insulin

resistance with increases of the level of:

- Growth hormone
- progesterone
- placental lactogen
- cortisol
Untreated gestasional DM has been shown
perinatal mortality of 4,4 - 6,4% compared
0,5 1,5% in a similar ethnic
normoglycemic population.
41

Diagnosis (WHO
classification)

Venous plasma glucose

(mg/dL)

Normal

Fasting &
2h post-prandial

< 110
< 140

Diabetes mellitus Fasting &

2h post-prandial

> 126
> 200

Impaired
Glucose
Tolerance (IGT)

< 110
140-199

Fasting &
2h post-prandial

Impaired Fasting Fasting &

110 - 125
Glucose (IFG)
2h post-prandial < 140
NB:
In the absence of symptom, the diagnosis of DM must be confirmed
by a second
diagnosis test (i.e. fasting, random, or Oral Glucose Tolerance Test
(OGTT) on a separate day
42

Symptom of
Diabetes
Classical Symp
(+)
FBG
or
2h
pp

>126

<126
<200

Classical Symp (-)

FBG
or
2h pp

>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

Assesment of the newly

diagnosed patient

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

When you have diabetes,

youre:
Twenty times more likely to develop

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

Researchers continue to make great

progress what triggers complication

DM & how to manage or prevent them

Blood sugar close to normal reduce

risks of complication

Controlled blood sugar not to late to

start (As soon as begin managing blood

sugar level slow the progression of
complication & reduce chances of
developing complication
49

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

Long-term DM complications are those

that develop gradually and that may
become disabling or live-threatening.
They include nerve, kidney, eye, heart
and blood vessel disease

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

many tiny vessel. The blood vessels are

often among the first to be damaged by
blood sugar
Everyone with type 1 DM & 6/10 type 2 DM
developed retinopathy after 20 years
Most people only mild vision problems. For
others with severe including blindness
DM is leading cause blindness in adults
(each year 12000 24000 cases)
54

If bleeding is heavy or occurs in the

certain it can obscure your vision

New blood vessel (neo vascularisation)
also can form scar tissue can push & pull
on your retina and distour vision
Special treatment by an optalmologist
wth Laser or Vitrectomy
Important to cath the disease early so
that it can be treated

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

vessel filter waste from the blood

disposed to urine
DM can damage this delicate filtering
system, before developed any symptom
More 3/10 type 1 DM nephropathy
1/10 type 2 DM nephropathy
Type DM younger, longer have DM higher
risk of kidney damage

57

Sign & symptom

Swelling of ankles, feet and hands
Shortness of breath
High blood pressure
Confusion or difficulty concentrating
Poor appetite
Nausea and vomiting
Dry, itchy skin
Fatigue

58

How is treated?
(nephropathy)
Treatment depends on how advance the

disease is. Keeping BG level normal can

prevent your condition from getting
worse, possibly improve.
ACE inhibitors may help hypertension
& heart problem
ARB can improve kidney function and
decrease microalbuminuria
Low protein diet seems to reduce
workload of kidney (consult doctors &
dietician)
Severe damage with (ESRD) transplant,
Hemodialyse or CAPD (continous
ambulatory peritoneal dialyse)
59

Neuropathy
Have an intricate network of nerves runs

throughout the body, connecting brain to

muscles, skin and other organs.
Brain senses pain, control the muscles,
and perform automatic task such as
breathing and digestion
Neuropathy affect 6/10 type 2 DM

60

Sign & symptom

Many kind of nerve damage
Weakened muscles & an unsteady walk
Autonomic nerves can increase heart
rate & perspiration level
In men can interfere to ability erection
In sensory nerves damage unable
detect sensation such as pain, warmth,
coolness and texture

61

Sign & symptom

Commonly damage often in the legs
Tingling feeling, numbness, pain or

combination these sensation

Burning pain comes and goes
Discomfort as a crawling sensation
Begin in tips of toe or finger or both
and gradualy spread upward
Damage nerve in toe, if untreated can
lose of all sensation high risk for
injury without realizing
62

Sign & symptom

Foot care very important

If lost feeling in the feet and not to

check them each day, may not realize

have a cut or open wound until serious
infection
The main cause of amputations in DM
60.000 amputation each year in DM

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

Heart and blood vessel

DM dramatically increased your risk of
developing one of many cardiovascular
problems, including:
Chest pain (angina)
Heart attack
Stroke
Narrowing of the arteries (legs and brain poor
blood circulation) peripheral vascular disease
High blood pressure
DM can damage mayor arteries (supply heart &
brain) easier for fatty deposits (plaques)
increase pressure in arteries & reduce blood
circulation
64

Sign & symptom

Symptoms heart disease vary. Early stage
produce no symptom. Later may include:
Shortnss of breath
Pain of the chest, jaw or arm
Fatigue or weakness
Swelling (edema)
Rapid or irreguler heart beat (palpitation)
People with DM are particular risk for silent
(asymptomatic) heart attacks without
typical symtomps (painless)

65

How it is treated?
Many forms of heart disease are treated

with medicationto prevent symptom

from worsening
If accumulation of plaques in the arteries
may procedure angioplasty to open
arteries sometimes bypass arteries
surgery
To prevent including healthy diet, more
exercise, stopping smoking, losing
weight (if over weight)
66

Risk of infection
High BG impaired function the immune

cells to fight off germ &

bacteriainfection
Location: mouth, gums, lungs, skin, feet,
bladder and genital
High BG damage nerve otherwise
alert infection
damage nerves to control bladder
sensation fail alert bladder is full
overstreched lose muscle tone ability
yo empty completely bacteria may
grow infection
67

Sign and symptom

Many vary depending location of

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

injured area and remove infected tissue

Reduce risk of gum disease by brushing
and flossing the teeth regularly
Reduce risk of bladder infection by going
the bathroom regularly and making sure
to empty the bladder

69

IMPOTENCE in DM
Refers: inability an erection of the penis

or

inability an erection long enough

for sexual intercourse
Physical: excess blood sugar can damage
the nerves & blood vessel no longer
communication nerves to small blood
vessel & large blood vessel narrowed or
blocked not enough blood to erection
(common in DM)
Psychological: anxiety, stress or
depression impaired Brain and Hormones
respond
Medication: drugs for hypertension,
anxiety & depression
70

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

Fasting blood glucose (mg/dL)

80 - 109

110 125

> 120

2Hour post prandial (mg/dL)

110 144

145 179

> 180

HbA1c (%)

< 6,5

6,5 8

>8

Total Cholesterol (mg/dL)

< 200

200 239

> 240

LDL Cholesterol (mg/dL)

< 100

100 129

> 130

HDL Cholesterol (mg/dL)

45

Triglyseride (mg/dL)

< 150

150 199

> 200

BMI (kg/m2)

18,5 - 22,9

23 25

> 25

Blood Pressure (mmHg)

< 130/80

130-140/80- > 140/90

90

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)
77

LIFE STYLE CHANGES MODIFICATION

78

MANAGEMENT of DM
1. EDUCATION

2. EXERCISE

3.NUTRITION & DIET

4. PHARMACOLOGY

79

NUTRITION and DIET

Important of Food
1.Various/contents
2. Schedule
3.Total weight or calories
Standard diet:
< 30% form all fats (< 10% form saturated
fats)
50-60% form carbohydrate (complex high fibre)
15-20% form protein
Sugar limited 25 g/day
Sodium <6 g/day, if hypertensive <3 g/day
80

NUTRITION and DIET

Ideal body weight:

Men (<160 cm) Height in cm 100 = Kgs

( >160 cm) 90% (Height in cm 100)= Kgs
Women (<150 cm) Height in cm 100 = Kgs
(>150 cm) 90% (Height in cm 100)=
Kgs
Normoweight: 90-110% (Ideal BW) or BMI 18,5 25
30 calories/KgBW/day
Underweight: <90% (Ideal BW) or BMI < 18,5
40 calories/Kg BW/day
Overweight: 110 - 120% (Ideal BW) or BMI 25-30
20 calories/Kg BW/day
Obese: >120 % (ideal BW) or BMI >30
81

MANAGEMENT of DM
1. EDUCATION
2. EXERCISE

3. NUTRITION & DIET

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

garointestinal with nausea, vomiting and

diarrhoea prominent (taken with meals or
started at low dose minimized side
effects
Not given to high risk patients with:
Severe cardiac failure
Renal failure
Hepatic cirrhosis
Respiratory failure
Alcoholism
88

INCREASE INSULIN
SENSITIVITY
Thiazolidinedione
PPAR agonist (reducing HbA1c 1%)
Act on adipose tissue, liver and muscle as insulin

sensitizers, potentiating the action of insulin

Improved glycaemic control and beneficial effects on
lipid profile, Blood Pressure and microalbuminuria
Be careful with hepatic failure fatalities (troglitazone)
Rosiglitazone (4-8mg/day) & Pioglitazone (15-30mg/day)
Combination with sulfonylureas or metformin, or both.
Side effects: fluid retention & hepatotoxicity
89

PHARMACOLOGY
1. INCREASED INSULIN SECRETION

2. INCREASED INSULIN SENSITIVITY

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

2. INCREASED INSULIN SENSITIVITY

3. ALPHA GLUCOSILASE INHIBITORS

4.INSULIN

92

Pattern of insulin secretion is altered early in type

2 diabetes
120
100

20g
glucose

80
60
40
20
0

30 0

30 60 90 120

Time (minutes)

Type 2 diabetes
Plasma insulin (U/ml)

Plasma insulin (U/ml)

Normal
120

20g glucose

100
80
60
40
20
0

30 0 30 60 90 120
Time (minutes)

Ward WK, et al. Diabetes Care

1984;7:491502.

93

Indication of Insulin therapy:

Type 1 DM
Type 2 DM Uncontrolled with diet,

exercise and OHA (included allergy

and contra-indication).
Gestasional DM
Severe hepatic and kidney failure.
Acute Infection(cellulitis, gangren),
severe tuberculosis, critical illness
(stroke/AMI)
DAK & HHS (HONK)
Mayor surgical and fracture of bones
Underweight, DM related
malnutrition
Corticosteroid teraphy
94

Type of Human Insulin

Type

Begining
15-30 mnt

Peaks Duration
2-4hr 6-8hr

Premixed
Humulin 30/70
Mixtard 30/70

15-30mnt

1-8hr

14-15 hr

Intermediate actian /NPH

Humulin N
Insulatard

2-4hr

1-8hr

14-15 hr

Short action
Actrapid
Humulin R

95

Evolution of insulin regimens begins

with understanding Physiological Insulin Secretion Profile

Plasma Insulin U/ml)

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

1920s, 1st insulin

Short-acting, acid pH
Only bolus regimen
No basal insulin

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

(30% reg + 70% intermediate)

20:00

24:00

4:00

8:00

Time
99

Here you see a bolus of insulin delivered in the Subcutaneous

space..
100

Doubleblind, cross-over, single dose study in healthy volunteers, N=24

Serum insulin (mU/l)

25

NovoMix 30
Mixtard HM 30

***

20

***p < 0.0001

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

Premix analogue (NovoMix) matches therapy to

physiology
Normal physiological
75

Plasma Insulin U/ml)

Breakfast

Lunch

Dinner
Human insulin (Human Mixtard )
Slow to appear ~ Unwanted high sugar levels

50

Slow to disappear ~ Unwanted low sugar levels (Hypo)

Premix Analogue (NovoMix)

Matches normal

25

4:00

8:00

12:00

16:00

20:00

24:00

4:00

8:00

Time
102

Type of Analogue insulin

Type

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

Insulin Regimen Evolution

104

Sistem NovoLet

105

Sites of INSULIN injection

(move every 2 weeks)

106