BLOOD GLUCOSE

Intestine:
glucose absorption
Liver:
glucose production
glycogen
gluconeogenesis
Brain:
glucose uptake
Liver:
glucose uptake
Adipose tissue:
glucose uptake
Muscle:
glucose uptake
ENTRY = EXIT NORMAL BLOOD GLUCOSE
RBCs
Glycerol
Free fatty acid
Amino
acids
lactate
Blood glucose source
Fasting glucose
Hepatic glucose production
Hepatic sensitivity to insulin
Post-meal glucose
Pre-meal glucose levels
Prandial amounts and timing of insulin secretion
Suppression of hepatic glucose production
Insulin sensitivity in peripheral tissues
Factors determining
Fasting & Postprandial Blood Glucose level
100
80
60
40
20
0
8
6
4
2
0
Makan pagi makan siang makan malam
08.00 12.00 18.00 20.00
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(
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waktu (Jam)
Glukosa darah (mmol/l)
Insulin plasma (mU/l)
24 hours Blood Glucose and Insulin Profile
In Normal Individu
500
400
300
200
100
08.00 10.00 12.00 14.00 16.00 18.00 20.00 22.00 00.00 02.00 04.00 06.00 08.00
Non-diabetic
Moderate type 2 DM
Severe type 2 DM
G
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Waktu ( jam )
Reaven G. Diabetes 1988;37:10204
Blood Glucose Level in Non DM
And Type 2 DM
The Prevalence of Diabetes
Mellitus is increasing

Mostly Type 2 ( >90% )

Young Diabetes cases in
increasing
Epidemiology of DM in Indonesia
Prevalence in Indonesia : 1,5 - 2,3 %
(age > 15 years)
Increase in prevalence :
Jakarta (urban)
1982 : 1,7 %
1993 : 5,7 %
Makasar (urban)
1981 : 1,5 %
1998 : 2,9 %
Prevalence in urban area > rural area


INDONESIA :
2020 : 178 million > 20 years

Prevalence of diabetes : 4 %


7 million diabetes patients


Diagnostic criteria of diabetes
Symptoms of diabetes
plus a random blood sugar > 200 mg/dl
Fasting blood sugar > 126 mg/dl
OGTT :
2 hours after 75 gr glucose
Blood glucose > 200 mg/dl


Symptoms of diabetes mellitus :
Polyuria
Polydypsia
Polyphagia
Weight loss
General malaise


Chronic hyperglycemia
Dysfunction, damage, failure
of various organs
(eyes, kidneys, nerves.
Heart, blood vessels)
Classification of diabetes mellitus
I. Type 1 diabetes (B cell destruction, usually leading to absolute
insulin deficiency)
A. Immuno-mediated
B. Idiopathic
II. Type 2 diabetes (may range from predominantly insulin resistance
with relative insulin deficiency to a predominantly secretory defect
with insulin resistance)
III. Other spesific types
A. Genetic defects of B cell function
B. Genetic defects in insulin action
C. Diseases of the exocrine pancreas
D. Endocrinopathies
E. Drug-or chemical-induced
F. Infections
G. Uncommon forms of immune-mediated diabetes
H. Other genetic syndromes sometimes associated with
diabetes
IV. Gestational diabetes mellitus (GDM)





Type 1
-cell destruction
Absolute insulin deficiency
Insulin dependent
Hyperglycemia
Type 2
Insulin resistance
-cell insufficiency
Hyperglycemia
100
150
200
250
300
350
W
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l
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)

2000 2010 2025
The Worldwide Pandemic of
Type 2 Diabetes
International Diabetes Federation Diabetes Atlas 2000;
Amos et al. Diabet Med 1997;14 (Suppl 5):S1-S85.
150
221
300
0
50
100
150
200
250
0
50
100
150
200
250
0
50
100
150
200
250
0
50
100
150
200
250
0
50
100
150
200
250
0
50
100
150
200
250
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World Europe
North
America
Latin
America
Asia Africa
1995 2000 2010
Figure 1. Increasing prevalence of type 2 diabetes by region
General epidemiological points :

Type 2 diabetes prevalence rates show
marked differences according to lifestyle,
affluence and urbanisation


Remain low in traditional societies
Rising rapidly in association with
urbanisation & modernisation



Type 2 diabetes is becoming increasingly
common in young people




50-85% of identified cases had not been
previously diagnosed


Commonality of enviromental risk faktors for
Type 2 Diabetes:








Changing nutrition
Central obesity
Decreasing physical activity level
Urbanisation
General epidemiological points :
Top ten countries for estimated number of
adults with diabetes, 1995 and 2025
Country 1995 (millions) Country 2025 (millions)


Rank
1 India 19.4 India 57.2
2 China 16.0 China 37.6
3 U.S. 13.9 U.S. 21.9
4 Russian Fed. 8.9 Pakistan 14.5
5 Japan 6.3 Indonesia 12.4
6 Brazil 4.9 Russian Fed. 12.2
7 Indonesia 4.5 Mexico 11.7
8 Pakistan 4.3 Brazil 11.6
9 Mexico 3.8 Egypt 8.8
10 Ukraine 3.6 Japan 8.5
All other countries 49.7 103.6

Total 135.3 300.0
The prevalence of diabetes is
increasing

Type 2 diabetes (the most prevalent
type) is often asymptomatic in its
early stages and can remain
undiagnosed for many years
TYPE 2 DIABETES MELLITUS :
Insulin
Resistance
Type 2
Diabetes
-cell
Dysfunction
Janka HU. Fortschr Med 1992;110:63741.
Macrovascular
disease
Insulin sensitivity
Insulin secretion
Plasma glucose
Microvascular
disease
Impaired Glucose Tolerance Hyperglycemia
Pathophysiology of Type 2 Diabetes
Insulin sensitivity
Insulin sensitivity

/ Insulin sensitivity
Normal cell
Function

cell
Function


cell
Function
Normal glucose
tolerance

IGT
IFG

Type 2 DM
Risk factors for Type 2 Diabetes:
Age 45 years
Overweight (BMI 25 kg/ m
2
)
Family history of Diabetes
Habitual physical inactivity
Race / Ethnicity
Previously identified IFG or IGT
History of GDM or delivery of baby weighing > 9 lbs
Hypertension ( 140/90 mmHg in adults)
HDL cholesterol 35 mg/dL and/or a Triglyceride
level 250 mg/dL
Polycystic ovary syndrome
History of vascular disease
BMI
Body Weight (kg)
Height (m)
2

=
Body Mass Index :
> 25 : Overweight
> 30 : Obese


Obesity:
Central type = Android,
Visceral type
Peripheral type = Gynecoid,
Gluteofemoral type
STRATEGIES FOR THE TREATMENT OF
DIABETES MELLITUS :
Early detection screening of
diabetes in a clinical setting
Aggressive treatment
( DCCT, UKPPDS)
Criteria for the diagnosis of diabetes mellitus

Symptoms of diabetes plus casual
plasma glucose or concentration
200 mg/dL.
or
2. FPG 126 mg/dL.
or
3. 2-h postload glucose 200 mg/dL
during an OGTT.
Impaired Glucose Tolerance (IGT) :

2-h postload glucose 140 200
mg/dL.

Impaired Fasting Glucose (IFG) :

Fasting Plasma Glucose levels
100 mg/dL but < 126 mg/dL.
SCREENING TESTS :
1. Fasting plasma glucose (FPG)
2. 75 g oral glucose tolerance test (OGTT)
3. Casual plasma glucose
Insulin Resistance Syndrome
Insulin resistance
Hyperinsulinemia
(Visceral) obesity
Impaired glucose tolerance
Hypertension
Dyslipidemia
PAI
Atherosclerotic
cardiovascular
disease
Type 2 DM
Insulin resistance
& syndrome
Macrovascular
complications
Microvascular
complications
Hyperglycemia
(-cell defect)
IGT
IFG
Lipids
BP
Frank
diabetes
RR 2-3
RR 1,5
RR >>
Diagnosed
Type 2
Diabetics
~8 million
Undiagnosed
type 2
Diabetics
~8 million
9% have
neuropathy
Up to 50% have
underlying heart
disease
8% have
nephropathy
20% have
retinopathy
At Diagnosis of type 2 Diabetes :
Factors influencing insulin sensitivity :
Obesity
Physical activity
Age


Four pillar in the management of DM
1) Education
2) Dietary management
3) Physical exercise
4) Hypoglycemic agent
* Oral hypoglycemic agent
* Insulin


(Diabetes) Nurse
Medical Doctor
Persadia - IDF
Family
Diet
Daily calory demand
25 30 kcal / kg body weight
Composition of food
Carbohydrate 60 70%
Protein 10 15%
Fat 20 25%
Meal schedule
Diet
Specific goals :
Maintenance of blood glucose level
as near normal as possible
Achievement of optimum serum lipid
Provision of adequate calories for
maintaining/attaining optimal weight
Prevention and treatment of acute and
chronic complications
Improvement of overall health
Physical exercise :
Continuous
Rhythmical
Interval
Progressive
Endurance training


MOA Agents
Insulin
secretion
Sulphonylureas
Other insulin
secretagogues
Glucose
production
Biguanides
Thiazolidinediones
Slow carbohydrate
digestion
-
-glucosidase
inhibitors
Peripheral insulin
sensitivity
Thiazolidinediones
(biguanides)
Site and Mode of action of oral
Antidiabetic Medications
Site of action
DeFronzo. Ann Intern Med 1999;131:281-303
Normoglycemia
Increased insulin
secretion
Decrease in hepatic
glucose production
Increase in glucose uptake
Biguanides
Thiazolidinediones
Sulfonylureas
Non-sulfonylurea secretagogues
Thiazolidinediones
Biguanides
Alpha-glucosidase
inhibitors
Decreased digestion of
complex sugars
Sites/Mechanisms of Action of
Antihyperglycemic Agents
Diabenese
Daonil
Minidiab
Glucotrol-XL**
Diamicron
Diamicron-MR**
Glurenorm
Amaryl
NovoNorm

Starlix
Actos

Glucobay

Glucophage*
Klorpropamid
Glibenklamid
Glipizid

Gliklazid

Glikuidon
Glimepirid
Repaglinid

Nateglinid
Pioglitazon

Acarbose

Metformin

100 - 250
2,5 - 5
5 10

80

30
1; 2; 3; 4
0,5; 1; 2

120
15, 30

50 100

500 - 850

100 500
2,5 15
5 20

80 240

30 120
0,5 6
1,5 6

360
15 30

100 300

250 3000


24 36
12 24
10 16

10 20

-
24
-

-
24



6 - 8


1
1 2
1 2
1
1 2
1
1 2
1
3

3
1

3

1 - 3


Sebelum
makan
Tidak
bergantung
jadwal
makan
Bersama
suapan
pertama
Bersama/
sesudah
makan
Sulfonilurea







Glinid


Tiazolidindion

Penghambat
Glukosidase
Biguanid

Generik Produk orsinal
Mg/tab Dosis
harian
Lama
kerja
Frek /
hari
Pemberian
OBAT HIPOGLIKEMIK ORAL
Insulin

Short acting
Intermediate acting
Long acting
Ultra short acting

Treatment :
stepwise approach Blood
Glucose Control
1
2
3
4
5
+
+
+
CONTROL OF INSULIN RESISTANCE :
HYPERINSULINEMIA, OBESITY,
GLUCOSE INTOLERANCE,
DYSLIPIDEMIA, HYPERTENSION,
PROCOAGULANT STATE
TREATMENT PRIORITIES
IN TYPE 2 DM
GLUCOSE CONTROL AS NEAR
TO NORMAL AS
REASONABLY POSSIBLE
MICROVASCULAR
DISEASE
MACROVASCULAR
DISEASE
TREATMENT PRIORITY IN TYPE 2 DIABETES
BLOOD GLUCOSE CONTROL
INSULIN RESISTANCE CORRECTION
CORRECTION OF OTHER RISK FACTORS OF
ATHEROSCLEROTIC CARDIOVASCULAR DISEASE



ASSESSMENT OF GLYCEMIC CONTROL :
FPG and 2h-pp PG
S M B G
A 1c
A1c :
For assessing treatment efficacy
A1c :
At least 2 times a year in :
Patients who are meeting
treatment goals
Patients who have stable
glycemic control
4 times a year in :
Patients whose therapy has
changes

Patients who are not
meeting glycemic goals
Targets for Glycemic Control
ADA
1

IDF (Europe)
2

HbA1c% FPG mmol/L
< 7 < 6.7 (120)*
< 6.5 < 6.0 (110)*
*mg/dl
1
Diabetes Care 1999;22(Suppl 1):S1-S114.
2
Diabetic Medicine 1999;16:716-30
Criteria for Diabetes Control
Good Fair Poor
Fasting blood glucose (mg/dl) 80-109 110-125 126
2hpp blood glucose (mg/dl 80-144 145-179 180
A1C (%) <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
Triglyceride (mg/dl) <150 150-199 200
Body mass index (kg/m2) 18.5-22.9 23-25 >25
Blood pressure (mmHg) <130/80 130-140/80-90 >140/90
Perkeni, 2002
Hyperglycemic crisis

Hypoglycemia

Infections
HYPERGLYCEMIC CRISES IN DIABETES :
Diabetic ketoacidosis
Hyperosmolar hyperglycemic state
Table 1. DIAGNOSTIC CRITERIA FOR DKA AND HHS :
D K A
Plasma glucose (mg/dl)
Arterial pH
Serum bicarbonate (mEq/L)
Urine ketones*
Serum ketones*
Effective serum osmolality
(mOsm/kg)
Anion gap
Alteration in sensoria or
mental obtundation
Mild Moderate
Severe HHS
> 250
7.25 7.30
15 18
Positive
Positive
Variable

> 10
Alert
> 250
7.00 7.24
10 to < 15
Positive
Positive
Variable

> 12
Alert/
drowsy
> 250
< 7.00
< 10
Positive
Positive
Variable

> 12
Alert/coma
> 600
< 7.30
< 15
Small
Small
> 320

Variable
Stupor/
coma
* Nitroprusside reation method : calculation: 2 [measured Na (mEq/L)] +
glucose (mg/dl)/18; calculation : (Na
+
) (Cl
-
+ HCO
3

-
) (mEq/l). See text
for details
PRECIPITATING FACTORS :
Infection
Cerebrovascular accident
Alcohol abuse
Pancreatitis
Myocardial infarction
Trauma
Microangiopathy

Macroangiopathy

Neuropathy
Microangiopathy :
Hyperglycemia


Dyslipidemia
Hypertensi

Classification of diabetic vascular disease
Small blood vessels
(capillary & precapillary arterioles)

Thickening of the capillary basement
membrane





Microvascular disease (Microangiopathy)

A
Diabetic Retinopathy

Diabetic Nephropathy

Peripheral Vascular Disease

Neuropathy
25 50% of diabetic patients

Kidney disease
Dialysis
Kidney transplantation

Macroangiopathy :
Coronary heart disease
Cerebrovascular disease
Peripheral vascular disease


Classification of diabetic vascular disease
An accelerated form of atherosclerosis


Macrovascular disease (Macroangiopathy)
B
Coronary heart disease, MCI
Stroke
Peripheral vascular disease,
THE RISK FOR CARDIOVASCULAR DISEASE
IN PATIENTS WITH DIABETES IS
25 TIMES THAT IN NON DIABETIC PERSON
Epidemiology of macroangiopathy
in DM :
Mortality from CHD :
Type 2 DM : 1,5 - 3 fold increase
Mortality rate from stroke :
Type 2 DM : 2 times higher
Prevalence of PVD :
22 %
Greater prevalence of multivessel
disease



CARDIOVASCULAR DISEASE
IN TYPE 2 DIABETES
MORBIDITY
MORTALITY


THE RISK FOR CARDIOVASCULAR DISEASE
IN PATIENTS WITH DIABETES IS
25 TIMES THAT IN NON DIABETIC PERSON
80% death in diabetics is related
to cardiovascular disease
Risk factors :
Dyslipidemia
Hypertension
etc.
But hyperglycemia
remains an important
cardiovascular risk factor !
Lifestyle Modifications:
a. stop smoking
b. regular physical exercise
c. dietary intervention
d. weight reduction in obese cases
e. stress coping
Peripheral Neuropathy

Autonomic Neuropathy
means
EVERY 1%
reduction in A1C
REDUCED
RISK*
Deaths from diabetes
Heart attacks
Microvascular complications
Peripheral vascular disorders
UKPDS 35. BMJ 2000; 321: 405-12.
UKPDS :
BETTER CONTROL MEANS FEWER COMPLICATIONS
*p<0.0001
1%
Management of Diabetes
Complications
Cardivascular disease : management of risk
factors and Screening for CAD
A. Blood pressure control
B. Lipid management
C. Anti-platelet agents in diabetes
D.Smoking cessation
Gestational Diabetes Mellitus
Any degree of glucose intolerance
with onset or first recognition
during pregnancy