DIABETES MELITUS

Makbul M Aman
PUSAT DIABETES DAN LIPID
RSUP. Dr. WAHIDIN SUDIROHUSODO
SUB BAGIAN ENDOKRIN METABOLIK
BAGIAN ILMU PENYAKIT DALAM
FK-UNHAS
Definition
Diabetes mellitus is a group of metabolic
diseases characterized by hyperglycemia
resulting from defects in insulin secretion,
insulin action, or both (Expert Committee on the
Diagnosis and Classification of Diabetes mellitus 2002)

Long-term damage, dysfunction, and failure

of various organs especially the eyes, kidneys,
nerves, heart, and blood vessels
 The diabetes epidemic:
171 million in 2000 to 366 million people in 2030
2000 2030
People with People with
Ranking Country diabetes Country diabetes
(millions) (millions)
1 India 31.7 India 79.4
2 China 20.8 China 42.3
3 USA 17.7 USA 30.3
4 Indonesia 8.4 Indonesia 21.3
5 Japan 6.8 Pakistan 13.9
6 Pakistan 5.2 Brazil 11.3
7 Russian Fed. 4.6 Bangladesh 11.1
8 Brazil 4.6 Japan 8.9
9 Italy 4.3 Philippines 7.8
10 Bangladesh 3.2 Egypt 6.7

Wild S et al. Diabetes Care 2004;27:104753

3
Status of diabetes management
Symptoms :
Polyuria
Polydipsia
Weight loss
Sometimes polyphagia
Blurred vision
 50% of type 2 diabetes patients have
complications at the time of diagnosis
MICROVASCULAR MACROVASCULAR

Retinopathy, Cerebrovascular
glaucoma or disease
cataracts

Coronary
Nephropathy
heart
disease

Peripheral
Neuropathy vascular
disease

UKPDS Group. UKPDS 33. Lancet 1998; 352:837853.

 Current recommendations
Diabetes must be diagnosed earlier. And once
diagnosed, all types of diabetes must then be managed
much more aggressively
Canadian Diabetes Association

Therefore, the results of the UKPDS mandate

that treatment of type 2 diabetes include
aggressive efforts to lower blood glucose levels
as close to normal as possible
American Diabetes Association

Canadian Diabetes Association. Can J Diabetes 2003; 27 (Suppl 2): 1163;

American Diabetes Association. Diabetes Care 2003; 26: S2832.
ADA definition of hyperglycaemic states
Criteria for the diagnosis of diabetes
Symptoms of diabetes plus casual plasma glucose 200 mg/dl (11.1 mmol/l)
or

FPG
< 100 mg/dl (5.6 mmol/l) normal fasting glucose
100125 mg/dl (5.66.9 mmol/l) impaired fasting glucose
126 mg/dl (7.0 mmol/l) diabetes

or
OGTT 2-h post-load glucose
< 140 mg/dl (7.8 mmol/l) normal glucose tolerance
140199 mg/dl (7.811.1 mmol/l) impaired glucose tolerance
200 mg/dl (11.1 mmol/l) diabetes

ADA = American Diabetes Association

Adapted from American Diabetes Association. Diabetes Care 2004; 27:S5S10.

 IDF: Indications for OGTT
Most screening programmes use either fasting
or random glucose as the first step
OGTT should be performed on all people with
FPG of 5.65.9 mmol/l or
random plasma glucose of 5.611.0 mmol/l
NOTE
OGTT is not a test of control
HbA1c should not be used for the diagnosis of
Diabetes

Asian-Pacific Type 2 Diabetes Policy Group. Type 2 diabetes: Practical targets and treatment 4th edn.
Hong Kong: Asian-Pacific Type 2 Diabetes Policy Group, 2005.
 PENJARINGAN DM TIPE
2
1. Idealnya untuk mendeteksi DM tipe 2 harus dilakukan
skrining populasi, kenyataan sulit oleh karena, biaya
mahal
2. Oleh karena itu penjaringan hanya dilakukan pada
mereka dengan resiko tinggi DM
 KELOMPOK RESIKO
TINGGI DM
Umur diatas 45 tahun
Kegemukan > 120% BB idaman atau IMT > 27 kg/m2),
Hipertensi >140/90 mmHg,
Riwayat keluarga DM,
Pernah melahirkan anak BB lahir bayi >4000 gram,
Riwayat DMG,
Dislipidemi, HDL <35 mg/dl atau trigliserid >250 mg/dl,
Pernah TGT atau GPPT
 III. Klasifikasi Etiologis DM
1. Diabetes Tipe-1 (destruksi D. Endokrinopati
sel beta) Acromegali, sindroma
Autoimun Cushing, Feokromositoma,
Idiopatik hipertiroidisme
2. Diabetes Tipe-2 ( resistensi E. Karena obat/zat kimia
insulin disertai defek sekresi Vacor, pentamidin, asam
insulin atau sebaliknya) nikotinat, Glukokortikoid,
hormontiroid, tiazid, Dilantin,
3. Diabetes Tipe lain interferon alfa
A. Defek genetik fungsi sel beta F. Infeksi : rubellakongenital, CMV
MODY 1,2,3. DNA G. Sebab imunologi yang jarang :
mitokondria
Antibodi anti insulin
B. Defek genetik kerja insulin
H. Sindroma genetik lain:
C. Penyakit eksokrin pankreas;
Sindroma Down, Klinefelter,
Pankreatitis, tumor pankreas,
pankreatektomi, pankreopati Turner dll.
fibrokalkulus 4. Diabetes Gestasional
 Type 2 diabetes: a growing problem
A serious, progressive disease
Characterised by two fundamental defects:
insulin resistance
-cell dysfunction

Accounts for 90% of diabetes cases worldwide

Associated with serious microvascular and
macrovascular complications
Represents a significant disease burden
Represents a considerable economic burden
Definition, Diagnosis and Classification of Diabetes Mellitus and its Complications. World Health Organization, 1999.
Diabetes Mellitus. Fact Sheet No 138. World Health Organization, 2002.
The Pathophysiology of Type 2 DM
Pancreas

LIVER
GLYCOGENOLYSIS

Insulin supply or action

G LYCOGEN

-
HGP +
+ GLUCOSE G L UC O S E

GLUCONEO FFA
GENESIS
LIPOLYSIS Lactic Acid
ADIPOSE TISSUE
 Management
A. Aim

Short term : Longer term :

Eliminate symptoms Prevent complications
Maintain general well being Reduce morbidity
and mortality

Strategy :
Normalizing glucose,
lipid, and insulin levels

Activities :
Management with holistic
approach and self care
principles
 Prinsip Dasar Terapi Diabetes Mellitus
1 2 3

PENGATURAN MAKAN LATIHAN PENYULUHAN

4 5
Pengaturan makan
Olahraga
Penyuluhan
Obat hipoglikemik
Cangkok Pankreas

OBAT HIPOGLIKEMIK CANGKOK PANKREAS

Konsensus Perkeni, 1998
 Lifestyle intervention
Represents the first step in treating type
2 diabetes
In the Belfast Diet Study, dietary management
was initially associated with reductions in FPG
and weight
However, after 6 years, a progressive rise in FPG
was observed, associated with declining
-cell function
Most patients required oral pharmacotherapy
within a few years of diagnosis
Levy J et al. Diabet Med 1998; 15: 2906.
Exercise

30 minutes: 3 - 4 times / week

Continuous
Rhytmical
Interval
Progressive
Endurance training
 Diet/Nutrition Therapy/Meal planning
Nutrient Composition of Diabetic Diet

PERKENI A D A and B D A
(Indonesian Soc.of Endoc.)
10-15% 10-15%
20-25% 30%

60-70%
55%

Carbohydrate Fat Protein Carbohydrate Fat Protein

OBAT HIPOGLIKEMIK
ORAL
Sites of Action of Antihyperglycemic Agents
Pancreas
2. Insulin
GLYCOGENOLYSIS secretagogue
3. Metformin
- TZD
1. Insulin

-
HGP +
GLUCOSE N
+

3. Metformin
GLUCONEO 4. Acarbose + TZD
GENESIS +

Intestine Adipose tissue

Oral Hypoglycemic Drugs Available in Indonesia
Initial dose Maximal dose Frequency of
mg/day mg/day administration /day
Sulphonylurea
Glibenclamide 2,5 15-20 1-2 X
Gliclazide 80 240 1-2 X
Glipizide : 5 20 2-3 X
Gliquidone 30 120 1X
Chlorpropamide 50 500 1X
Glimepiride 0,5 6 1X
Meglitinide
Repaglinide 1.5 mg 8 mg 3X
Nateglinide 120 mg 360 mg 3X
Metformin 500 3000 1-3 X
Alpha glucosidase inhibitor
Acarbose 50 300 3X
Derivat Thiozolidindiones
Pioglitazone
Roziglitazone
Fix Dose ( Campuran )
Glucovance 1,25/250 2,5/500 1-2 x
T2DM treatment strategies*

Expected HbA1c
(time allotted)

Lifestyle modification 1% (3 months)

1 to 2%
Monotherapy (13 months)

1 to 2% fall per
Combination oral therapy additional OHA
(13 months)

Insulin therapy Unlimited

*Individualise
Adapted from Bergenstal RM. In: De Fronzo RA, et al (eds). International Textbook of Diabetes Mellitus.
3rd ed. Chichester, New York: John Wiley & Sons; 2004:9951015.
 Proposed New Treatment Paradigm
for Type 2 Diabetes

Medical Nutrition Therapy, Exercise , Education and SMBG

HbA1c < 7 % HbA1c 7- 8 % HbA1c > 8 %

Consider oral Add Add

monotherapy insulin sensitizer insulin sensitizer
or secretagoque and secretagoque

Target not Met Target not Met Target not Met

Full Insulin therapy Start Insulin or

With Or without Oral agent(s) add Third oral agent
Practical management considerations

Diet and exercise Metformin Sulphonylurea

Patients not at goal

Addition of rosiglitazone

Improved estimates Effective and sustained Reduced insulin

of -cell function glycaemic control resistance

Potential to delay Reach and maintain Potential to improve

disease progression glycaemic goal CVD outcomes
 New treatment paradigms for
type 2 diabetes
Stepwise treatment

Diet/ Oral Oral Oral

Insulin
exercise monotherapy combination +/- insulin

Early aggressive
combination therapy
 Sulphonylureas
Have been a mainstay of type 2 diabetes treatment
for > 40 years
Bind to an SU receptor (SUR) on the -cell which
leads to depolarisation of -cell membrane and
stimulates insulin secretion
First generation : chlorpropamide
Second generation : glibenclamide, glipizide,
gliclazide
Third generation : glimepiride
Attention : Hypoglycemia (less in glipizide GITS and
glimepiride)
 Mode of Action of Sulphonylureas
Depola- Ca 2+ Voltage Dependent
ATP Sensitive risation Ca 2+Channel (VDCC)
K+ Channel
SU Islet cell

SUR Open
Closed
Ca 2+
ATP
ADP
Glucose Glucokinase
Proinsulin

Metabolism INSULIN

Am. acid C-PEPTIDE

SS 01
The Suppression Hepatic Glucose Production
Pancreas
LIVER
GLYCOGENOLYSIS

Insulin

-
HGP
GLUCOSE N

GLUCONEO
GENESIS

ADIPOSE TISSUE
The Stimulation of Glucose Uptake
Pancreas
LIVER
GLYCOGENOLYSIS

Insulin
G LYCOGEN
- +
HGP
GLUCOSE N G L UC O S E

Glucose
Uptake
GLUCONEO
GENESIS

ADIPOSE TISSUE
The Stimulation of Lipogenesis in Adipose Tissue
Pancreas
LIVER
GLYCOGENOLYSIS

Insulin
G LYCOGEN
- +
HGP
GLUCOSE N G L UC O S E

Glucose
FFA Uptake
GLUCONEO
GENESIS

+
Lipogenesis
ADIPOSE TISSUE
 Type 2 DM
Overweight Not Overweight
Severe metab. decompensation
Education Education
Meal planning Meal planning
Exercise Exercise
Evaluate 4-8 wks Evaluate 4-8 wks
controlled
controlled
Uncontrolled Uncontrolled
Stressing on

C O N T I N U E
Meal planning
C O N T I N U E

Exercise SU or Acarbose

controlled Uncontrolled controlled

Uncontrolled

Metformin or Acarbose
SU + A / M
controlled
Uncontrolled controlled
Uncontrolled
M / A + SU
controlled
Uncontrolled SU + A + M
controlled M +A + SU controlled
Uncontrolled Insulin Uncontrolled

Depends on the response: Diet or OHA

ADA Treatment Goals for Glycemic Control

Glycemia Normal Goal Further Action

Required*
Average Preprandial <110 80 to 120 <80
Fasting Glucose (mg/dL) >140

Average Postprandial <140 <160 >180

Glucose (mg/dL)

HbA1C (%) <6 <7 >8

Further Action Required = Get off your rear and DO something

Adapted from the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus
Diabetes Care 1999;22:S32-S41
 Current ADA treatment targets
HbA1c < 7%
Blood pressure < 130/80 mmHg
LDL-cholesterol < 100 mg/dl (2.6 mmol/l)
HDL-cholesterol
Men > 40 mg/dl (1.1 mmol/l)
Women > 50 mg/dl (1.3 mmol/l)
Triglycerides < 150 mg/dl (1.7 mmol/l)

American Diabetes Association. Diabetes Care 2004; 27 (Suppl 1): S1535.

Ten steps to help more patients with type 2
diabetes achieve glycemic goal
1. Aim for good glycaemic control, defined as HbA1c < 6.5%*
2. Monitor HbA1c every 3 months in addition to regular glucose
self-monitoring
3. Aggressively manage hyperglycaemia, dyslipidaemia and hypertension with
the same intensity to obtain the best patient outcome
4. Refer all newly diagnosed patients to a unit specialising in diabetes care
where possible
5. Address the underlying pathophysiology, including the treatment of insulin
resistance
6. Treat patients intensively so as to achieve target HbA1c < 6.5%* within 6 months
of diagnosis
7. After 3 months, if patients are not at target HbA1c < 6.5%,* consider combination
therapy
8. Initiate combination therapy or insulin immediately for all patients with HbA1c
9% at diagnosis
9. Use combinations of oral anti-diabetic agents with complementary mechanisms
of action
10. Implement a multi- and interdisciplinary team approach to diabetes management
to encourage patient education and self-care and share responsibility for patients
achieving glucose goals

*Or fasting/preprandial plasma glucose < 110 mg/dl (6.0 mmol/l) where assessment of HbA1c is not possible
Del Prato S et al. Int J Clin Pract 2005; 59: 134555.
 Treatment Priority
of Type 2 DM

Control of Insulin resistance:

Glucose control as Hyperinsulinemia, Obesity,
near to normal as Glucose intolerance,
Dyslipidemia, Hypertension,
reasonably possible Procoagulant state

Microvascular Macrovascular
disease disease
 Control of Insulin Resistance

Hyperglycemia

Intervention/Control
Dyslipidemia

Insulin Hypertension Cardiovascular

resistance disease

Obesity

Pro-coagulant State

PAI-1,Factor VII, Fibrinogen

Insulin resistance associated with
multiple factors involved in CVD
Hyperglycaemia

Dyslipidamia Hypertension

Hypofibrinolysis Microalbuminuria

INSULIN
RESISTANCE

Inflammation Endothelial
dysfunction

Atherosclerosis, cardiovascular disease

Festa A et al. Circulation 2000; 102: 427; Reaven GM et al. Annu Rev Med 1993; 44: 12131.
 1a. Insulin

Insulin actions include :

Ability of insulin to lower circulating glucose
concentrations
Suppress glucose production : liver
Stimulate glucose utilization : muscle plus fat

Additional metabolic, vascular & mitogenic actions

 JENIS INSULIN
Jenis insulin menurut cara kerja
Mulai Kerja Kerja Maksimal Lama Kerja
Lama Kerja Nama Insulin
(Jam) (Jam) (Jam)

Actrapid 0,5 2,5 - 5 4-8

Kerja Singkat
Humulin R 0,5 2,5 - 5 4-8
1-2 4-6 8 - 24
Monotard
Kerja Sedang Insulatard 1-2 4 - 16 8 - 24
Humulin N 1-2 4-8 8 - 22

Kerja Lama Ultratard 2-4 8 - 24 28

Indications of Insulin Treatment
Indication for the use of insulin in
Type 2 DM
In severe metabolic decompensation
Ketoacidosis
Hyperosmolar non ketotic coma
Lactic acidosis
Severe stress :
Systemic infection
Major surgery
Weight loss within a short period of time
Pregnancy if diet does not succeed to control
glycemia
OHA failure or contra-indication of OHA
Combination Therapy in T2DM:
Insulin Plus Oral Hypoglycemic Agents
Insulin Plus Sulphonylurea - BIDS
Some insulin is endogenous, with natural
secretory pattern
Biguanide Plus Insulin
Reduces hepatic insulin resistance
May achieve better control with less insulin
Can reduce weight gain
Alpha Glucosidase Inhibitor Plus Insulin
Reduces posotprandial glucose level
Thiazolidinedione Plus Insulin
Reduces peripheral insulin resistance
Reduces insulin requirement
Must balance TZD and insulin carefully to minimize
weight gain
Benefits of Insulin and Oral Agents Combination

Improves glycemic control

Treats multiple physiologic abnormalities
Less insulin is needed to achieve good glycemic
control
Reduces potensial for weight gain
Patients:
more practical and less frightening
improved psychological acceptance, patients
continue the oral drugs
less / minimal education is needed
treatment can be started in an
outpatients-setting
better compliance, and cost may be less
 Complications :

Acute : Chronic :

Microangiopathy Macroangiopathy

Ketoacidosis Retinopathy CAD

Nonketotic Nephropathy PVD
Hyperosmolar syndrome Neuropathy Stroke
 KOMPLIKASI AKUT
1. Metabolik
Ketoasidosis diabetik
Koma hiperglikemik hiperosmoler non-ketotik
Hipoglikemi
Asidosis laktat
2. Infeksi berat
 KETOASIDOSIS DIABETIK (1)
DIAGNOSIS
1. Klinis
- Dehidrasi, kesadaran menurun sampai koma,
hipotensi-syok, pernafasan Kussmaul, panas
2. Laboratorium
- Hiperglikemi, GDS > 300 mg/dl
- Asidosis, pH arteri <7.35 atau bikarbonas serum <15 meq/l
- Ketonemi, keton total serum >3 mM
3. Pada DM tipe 2 faktor pencetus biasanya infeksi
Catatan: Setiap penderita DM dengan kesadaran menurun
dan panas harus di curigai ketoasidosis
 KETOASIDOSIS DIABETIK (2)
PENATALAKSANAAN
1. Cairan
- Infus NaCl 0.9% sebanyak 500 ml selama 15 menit pertama,
diteruskan sesuai kebutuhan
- Bila GDS < 250 mg/dl, NaCl 0.9% diganti Dextrose 5%
2. Insulin
- Pada awal diberikan 10 U insulin kerja singkat i.v secara
bolus (Actrapid, Humulin R) diteruskan dengan insulin
drips 6 U/jam
3. Potassium
- Pada pemberian insulin biasanya kalium plasma menurun
oleh karena itu perlu diberikan tambahan potassium
4. Antibiotik bila ada infeksi
 KETOASIDOSIS DIABETIK
(3)
Komplikasi
1. Infeksi
2. Gagal ginjal akut
 KOMA HIPERGLIKEMIK
HIPEROSMOLER NON-KETOTIK (KHHNK) (1)

DIAGNOSIS
1. Klinis
- Dehidrasi, koma, hipotensi-syok.
- Beda dengan ketoasidosis, oleh karena tanpa asidosis
tidak ada Kussmaul
- Orang tua > 60 tahun

2. Laboratorium
- Hiperglikemi, GDS > 400 mg/dl
- Osmolalitas plasma >= 315 mmol/kg
 KOMA HIPERGLIKEMIK
HIPEROSMOLER NON-KETOTIK (KHHNK) (2)

PENATALAKSANAAN
1. Cairan
Sama dengan ketaosidosis, hanya biasanya penderita
dalam keadaan syok sehingga perlu pemberian NaCl 0.9%
cepat. Untuk seterusnya diberikan cairan NaCl 0.45%
2. Insulin sama dengan ketoasidosis
3. Potassium
4. Antibiotik kalau perlu
 HIPOGLIKEMI (1)
Pada DM reaksi hipoglikemi terjadi bila GDS
< 50 mg/dl
Penyebab : Insulin berlebihan, OHO berlebihan,
gagal ginjal kronik mendapat OHO

Gambaran klinis
Keringat dingin, takhikardi, rasa lapar, pusing,
penglihatan kabur, kesadaran menurun sampai
koma
 HIPOGLIKEMI (2)
PENATALAKSANAN
1. Segera hentikan insulin atau OHO
2. Bila masih sadar segera berikan teh gula
3. Dalam keadaan koma berikan Dextrose 40% sebanyak
50 ml i.v langsung
4. Dilanjutkan dengan infus Dextrose 10% selama 48 jam
 KOMPLIKASI KRONIK
Komplikasi vaskuler
Makrovaskular
Penyakit jantung koroner, strok, pembuluh darah perifer
Mikrovaskular
Retinopati,nefropati
Komplikasi neuropati
Neuropati sensorimotorik,Neuropati otonomik
Gastroparesis, diare diabetik, buli-buli neurogenik, Impotensi,
gangguan refleks kardiovaskular
Campuran vaskuler-neuropati
Ulkus kaki
Komplikasi pada kulit
 RETINOPATI
DIABETIK (1)
Dikenal empat bentuk yaitu :
1. Tipe background
2. Tipe pre-proliferatif
3. Tipe proliferatif
4. Makulopati

Tipe background adalah paling ringan, sedang

tipe proliferatif penyebab kebutaan
RETINOPATI DIABETIK (2)
RETINOPATI
DIABETIK (3)
 RETINOPATI
DIABETIK (4)
Pengobatan
1. Kendali glukosa darah sebaik mungkin
(HbA1c < 7%)
2. Pengobatan terhadap hipertensi, dislipidemia
bila ada
3. Hentikan merokok
4. Aspirin
 NEFROPATI DIABETIK
(1)
1. Merupakan penyebab utama gagal ginjal
terminal di negara maju

2. Diperkirakan 40% DM tipe 1 menjadi nefropati

diabetik setelah menderita DM 20 tahun dan
5-10% pada DM tipe 2 dengan riwayat DM 20
tahun
 NEFROPATI DIABETIK (2)
Pengertian proteinuri
Normo-albuminuri (Albustix negatif)
Ekskresi albumin per menit < 20 ug atau jumlah albumin
< 30 mg/24 jam
Mikro-albuminuri (Albustix negatif)
Ekskresi albumin per menit 20-200 ug atau jumlah
albumin 30-300 mg/air seni 24 jam
Makro-albuminuri = proteinuri klinik (Albustix positif)
Ekskresi albumin per menit > 200 atau jumlah albumin >
300 mg/air seni 24 jam
 NEFROPATI DIABETIK (3)
Diagnosis
1. Adanya proteinuri menunjukkan nefropati diabetik
2. Nefropati diabetik klinik bila tes Albustix posistif
sedikitnya 3 kali dengan interval beberapa mili
3. Nefropati diabetik dini bila ditemukan mirkroalbuminuri
2 sampai 3 kali pemeriksaan dalam 6 bulan
 NEFROPATI DIABETIK (4)
Pengobatan
1. Kendali glukosa darah sebaik mungkin
(HbA1c < 7%)
2. Pengobatan terhadap hipertensi, dislipidemia
bila ada
3. Obat anti hipertensi sebaiknya ACE inhibitor
4. Hentikan merokok
Catatan : TD sistolik < 135 mmHg, diastolik
=< 80 mmHg
 NEFROPATI DIABETIK
(5)
Pengobatan gagal ginjal terminal :
1. Hemodialisa

2. Transplantasi ginjal
 We are not getting
older

We are getting better