TATA LAKSANA TERKINI

DAN
PENANGANAN KOMPLIKASI DIABETES MELITUS

Pugud Samodro
Lab/SMF Ilmu Penyakit Dalam FK Unsoed/RSUD Prof
Margono Soekarjo Purwokerto
 PENATALAKSANAAN
Tujuan Umum: Meningkatkan Kualitas Hidup

• Jangka pendek: Menghilangkan keluhan dan

tanda DM, mempertahankan rasa nyaman,
dan mencapai target pengendalian
pengendalian gula darah
• Jangka panjang: mencegah dan menghambat
progresivitas penyulit
• Tujuan akhir: menurunkan morbiditas dan
mortalitas
Perkeni, 2011
 Classification of Diabetes

Type 1 Type 2 Other specific type of Gestational

diabetes due to other
causes
 Cells destruction Progressive insulin
leading to absolute secretory defect on Diabetes
insulin deficiency background of insulin • Genetic defect on diagnosed during
resistance pregnancy
 cell function
• Genetic defects in
insulin action
• Disease of the
exocrine pancreas
• Drug or chemical
induced diabetes
 Underlying causes of DM-T2
Insulin
-cell
resistance
Hyperinsulinaemia defect

Impaired
glucose
tolerance
Decreased insulin
Obesity secretion
Early
diabetes -cell failure

Late
Normal diabetes
4
Adapted from Saltiel AR. J Clin Invest 2000;106:163–164.
 PPAR α L162V
Genetik Obesitas
HNF4A, GCK,
Genetik

F HNF1A, IPF1,
TCF2,NEUROD1

Adipositokin Antibodi anti insulin

a Stres Kortisol

Sitokin inflamasi
X X
Antibodi anti reseptor
- Sindrom tipe A/B

k Adrenal X X
- Leprachaunisme
- Rabson-Mendenhal

Reseptor
t Merokok GH
insulin Pro12Ala Genetik

o Glukokortikoid X
X
X
IRS- 1 X X Aktivitas
r
hPL
hPGH X
AMPK
fisik rendah
MAPK PI3K

Kehamilan
X AKT/PKB

r PTEN
Genetik X GLUT44
e GLUT

s Kelebihan nutrisi mTOR Bradikinin

i
Resistensi insulin
k
DM tipe 2
o 5
 Loss of Early- phase Insulin Secretion
in Type 2 Diabetes

Pattern of insulin secretion is altered early in type 2 diabetes

Normal Type 2 diabetes

120
Plasma insulin (µU/ml)

120

Plasma insulin (µU/ml)

20g
20g glucose
glucose
100 100
80 80
60 60
40 40
20 20
0 0
–30 0 30 60 90 120
–30 0 30 60 90 120
Time (minutes)
Time (minutes)
Ward WK, et al. Diabetes Care 1984;7:491–502.
 Why does the -cell fail?
Oversecretion of insulin to
compensate for insulin
resistance1,2
Glucotoxicity2
Lipotoxicity3

Chronic Pancreas High circulating free

hyperglycemia fatty acids

-cell
dysfunction
Boden G & Shulman GI. Eur J Clin Invest 2002; 32:14–23.
1

2Kaiser N, et al. J Pediatr Endocrinol Metab 2003; 16:5–22.

3
Finegood DT & Topp B. Diabetes Obes Metab 2001; 3 (Suppl. 1):S20–S27.
Types of Insulin

-cell failure

Insulin
resistance
 Essential Elements in Comprehensive
Diabetes care of type 2 Diabetes

Management of
type 2 diabetes

Glycaemic control: Treat associated Screen for/or manage

• Diet/life style condition: complication of
•Dislipidemia
diabetes:
• Exercise • Retinopathy
• Medication • Hypertention • Cardiovascular
• Obesity
disease
• CHD • Nephropathy
• Nutrition • Neuropathy
•problems • Infection
• Other complication
 Aim of treatment:
to prevent the complications of diabetes

Non-vascular complications:
 Cancer
DIABETES  Infections
 Degenerative diseases
 Depression
 Cognitive disorders
MICROVASCULAR MACROVASCULAR …
COMPLICATIONS COMPLICATIONS*
Diabetes is more
• Coronary heart disease
• Ischaemic stroke than a vascular disease
• Congestive heart failure

Diabetic Diabetic Diabetic Limb

retinopathy nephropathy neuropathy amputation
* The most common cause of death
in patients with diabetes

Diabetes is a vascular disease

Adapted from Grobbee DE. Metabolism 2003; 52: 24–2
 Prinsip Dasar Terapi Diabetes Mellitus
1 2 3

PENYULUHAN AKTIFITAS FISIK

PENGATURAN MAKAN

4 5

OBAT SMBG
ANTIDIABETES/INSULIN
 Penyuluhan Kesehatan
Penderita Dokter Pihak lain
Kerjasama Terpadu
Rinci
Sistematis
Praktis
Menuntun Penderita
- memahami penyakitnya
- Menerima keadaan dirinya
- Menyongsong masa depan (Rasional)

DIET
 Disesuaikan dengan Pola diit masyarakat
 Diberikan tiap jam KH 
Kalori berdasar BBR/IMT L
 MAKAN UTAMA :350 KALORI

SELINGAN 150 KALORI

1. Nasi 1 ons = 175 kalori
2. Ayam goreng ½ ons = 140 kalori
3. Tempe bakar ½ ons = 80 kalori
4. Plecing kangkung sambal mentah = 0 kalori
5. Apel 250 gram = ±150 kalori
(PERKENI 2011)
 Physical activity
30 minutes of moderate-intensity exercise (brisk walking)
5 days of the week.
Training zone 50-70% (220 – age).

a
Asian Food Information Centre. 2010. Calorie Expenditures Through Exercise and Other Activities. Available from
http://www.afic.org/Burner.htm. Accessed 21 June 2010.
 Obat Hipoglikemik Oral
MEKANISM KERJA - EFEK SAMPING - PENGARUH TERHADAP PENURUNAN A1c.

Jenis obat. Cara kerja Efek samping Penurunan A1c

utama utama
Sulfonilurea Meningkatkan BB naik, 1,5 – 2 %
sekresi insulin hipoglikemia

Glinid Meningkatkan BB naik, ?

sekresi insulin hipoglikemia.

Metformin Menekan HGP , Diare, dispepesia, 1,5 – 2 %

menambah asidosis laktat.
sensitivitas insulin
Penghambat alfa Menghambat Flatulen, tinja 0,5 – 1,0 %
glukosidase absorpsi glukosa lembek / diare.

Tiazolidindion Menambah Edema 1,3 %

sensitivitas insulin

DPP4 INH. Meningkatkan Rasa sebah, mual. 0.5 – 0.8 %

sekresi ins. Dan
menekan sekresi
glkg.
 Pharmacologic Targets of Current Drugs Used in the
Treatment of T2DM
GLP-1 analog (exenatide injectable)
Improves glucose-dependent insulin DPP-4 inhibitors
secretion, suppresses glucagon secretion, Prolong GLP-1 action, stimulate insulin
slows gastric emptying secretion, suppress glucagon release

Biguanide (metformin) Thiazolidinediones

Decreases hepatic glucose Increase glucose uptake in
production and increases skeletal muscle and
glucose uptake decrease lipolysis in
adipose tissue
Sulfonylureas
Increase insulin secretion
from pancreatic -cells
-glucosidase inhibitors
Delay intestinal carbohydrate
Meglitinides absorption
Increase insulin secretion
from pancreatic -cells
DDP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1; T2DM=type 2 diabetes mellitus
Adapted from Cheng AY, Fantus IG. CMAJ. 2005; 172: 213–226.
 Choice of agents in future use

Glipizide insulin
Gliclazide
Glimepiride
Glibenclamide Sulphonylureas Acarbose
Miglitol
Voglibose

a-glucosidase
TZDs Metformin inhibitors
Rosiglitazon
e
Pioglitazone
insulin Meglitinides
Repaglinide
Nateglinide
DPP-IV inhibitor / GLP-1
Syarat OHO berhasil baik adalah : Diet dan Latihan
Fisik harus dilaksanakan dengan benar (3J) dan
diberikan pada penderita DM yang :
1 Umur > 40 th .
2 Lama DM-nya kurang dari 5 th .
3 Belum pernah suntik insulin, atau bila pernah
suntik insulin : kebutuhan insulin kurang dari 20
unit per hari.
4 Belum pernah mengalami Keto Asidosis Diabetik.
J1 = Jumlah ; J2 = Jenis ; J3 = Jadwal
 Multiple Factors Contribute to T2DM

Decreased glucose Progressive -cell

uptake dysfunction

HYPERGLYCEMIA Lack of
Hepatic glucose
glucagon
production suppression

Impaired Increased Increased

lipolysis renal
incretin
glucose transport
signaling
1. Bode BW. Postgrad Med. 2009;121:82-93.
2. DeFronzo RA. Ann Intern Med. 1999;131:281-303.
3. DeFronzo RA. Diabetes. 2009;58:773-795.
 Multiple Factors Contribute to T2DM

Decreased glucose Progressive -cell

uptake dysfunction
GLINID, DPPIV,
Metformin
ACARBOSA
TZD
HYPERGLYCEMIA
Hepatic glucose Lack of
production glucagon
suppression
DPPIV
Metformin

Impaired Increased
incretin lipolysis Increased SGLT2
signaling renal
glucose transport
DPPIV
TZD
1. Bode BW. Postgrad Med. 2009;121:82-93.
2. DeFronzo RA. Ann Intern Med. 1999;131:281-303.
3. DeFronzo RA. Diabetes. 2009;58:773-795.
 OAD -Type 2 DM
Insulin
resistance

DIET- Physical activity

Fasting BG:
1. Metformin: Hepatic glucose production, Glucose uptake
2. Thiazolidinediones: Lipolysis, Glucose uptake
3. DPP IV inhibitor: Glucagon

Rhodes CJ & White MF. Eur J Clin Invest 2002; 32 (Suppl. 3):3–13.
 OAD-Type 2 DM

b-cell
 dysfunction

2 hours pp BG
1. DPP IV inhibitor: Incretin, Insulin sensitivity in
peripheral tissues, decrease in glucagon suppression
2. Acarbosa: Glucose load from meal
3. Glinide: Glucose load from meal

Rhodes CJ & White MF. Eur J Clin Invest 2002; 32 (Suppl. 3):3–13.
 Pharmacokinetics of the different Types of Insulin
Profil
Type of Insulin Insulin Name Onset Peak
Fast-acting Analogue Insulin Insulin Aspart (NovoRapid) 0.2 – 0.5 0.5 - 2

Insulin Lispro (HumaLog) 0.2 – 0.5 0.5 - 2

Insulin Glulisine (Apidra) 0.2 – 0.5 0.5 - 2

Fast-acting Human Insulin ActRapid 0.5 – 1 0.5 - 1

Humulin R 0.5 – 1 0.5 - 1

Intermediate Human Insulin Insulatard 1.5 – 4 4 - 10

Humulin N 1.5 – 4 4 - 10

Long-acting Analogue Insulin Insulin Detemir (Levemir) 1-3

Insulin Glargine (Lantus) 1-3

Pre-mix Analogue Insulin Insulin Aspart (NovoMix) 0.2 – 0.5 1-4

Insulin NPL (HumaLogMix) 0.2 – 0.5 1-4

Pre-mix Human Insulin Mixtard 0.5 – 1 3 - 12

Humulin Mix 0.5 – 1 3 - 12

Slide 28
Adapted from Mooradian et al. Ann Intern Med 2006; 145: 125-34
 Indikasi Injeksi Insulin
(Konsensus
(Konsensus PERKENI
PERKENI 2002)
2002)

1 Penurunan Berat Badan yang cepat

2 Hiperglikemia berat yang disertai ketosis
3 Ketoasidosis Diabetik
4 Hiperglikemia Hyperosmolar Non Ketotik
5 Hiperglikemia dengan Asidosis Laktat
6 Gagal dengan kombinasi OHO dosis hampir maksimal
7 Stres berat (injeksi sistemik, operasi besar, IMA, stroke)
8 Kehamilan dengan DM/diabetes mellitus gestasional
yang tidak terkendali dengan perencanaan makan
9 Gangguan fungsi Ginjal atau Hati yang berat
10 Kontraindikasi dan atau alergi terhadap OHO
ASK-DNC
Kelemahan Human Insulin (Actrapid/Mixtard)

Period of unwanted
hyperglycemia
Normal insulin secretion
at mealtime
Change in serum insulin

Human insulin

Period of unwanted
hypoglycemia

Human Insulin HARUS

Baseline
disuntikkan 30 menit
level
sebelum makan

Time (h)
SC injection
 Kelemahan Human Insulin Insulatard (NPH)
Memiliki puncak  risiko nokturnal hipo sangat tinggi

Absorbsi insulin bervariasi, bahkan

di pasien yang sama kendali gula darah
tidak terprediksi

tidak bekerja 24 jam

ANALOG INSULIN NOVO NORDISK
ANALOG INSULIN

NOVORAPID - RAPID ACTING

NOVOMIX - PREMIX

LEVEMIR -LONG ACTING ANALOG

Levemir (Insulin
Structural DesignDetemir)
Human Insulin
NovoRapid
(Insulin
C1
4
Aspart)
Asp
ch fatt
a ya
(My in cid
ris Phe Gly Arg
tic Phe
ac Glu
id) Tyr
Thr Gly
Pro
Pro Cys
Lys
Thr Val
B29 A21 Asn Cys
Tyr Leu
Gly Lys
A1 Asn Tyr
Ile Glu Leu
Val Leu Ala
Glu
Gln Glu
Gln
Tyr Val
Cys Leu Leu
Cys Thr Ser Ile Cys Ser
His
Ser
Gly
Cys
Leu
B1 Phe Val Asn Gln His
Profil Insulin Analog sangat mirip dengan Insulin E
---- Insulin endogen

Levemir

---- NovoRapid

NovoMix

Makan Makan Makan Sebelum tidur

Pagi Siang Malam
Analog vs Human Insulin

Profil farmakokinetik analog yang lebih mirip insulin alami, sehingga menghasilkan :
Efektivitas, Keamanan dan Flexibility lebih baik dibanding human Insulin

 Efektivitas :
Superior mengendalikan GD 2 jam pp
Superior mengendalikan GD puasa
Superior mengendalikan HbA1c
 Keamanan  Risiko Hipoglikemi lebih minimal
 Fleksibilitas  Waktu penyuntikan lebih fleksibel (tidak menunggu 30
menit)
ALHAMDULILLAH
terima kasih
 Mechanisms of metformin

Skeletal
Liver Muscle Gut Pancreas Fat

Decreased Improves Decreases May improve Improves

hepatic peripheral appetite and insulin peripheral
glucose glucose colorie secretion glucose
production uptake intake, may (secondary uptake, may
(gluconeogen (secondary decreases effect of decrease
esis) effect of (intestinal decreasing lipolysis
decreasing glucose glucose
glucose absorption) toxicity)
toxicity)