Adipose tissues

JMF Adam
Adipose Tissues
Storage of fat (TG)
Endocrine organ : produced
hormone (adipocytokine), leptin,
TNF-, IL-6, resistin pro-
inflammatory
adiponektin anti-inflammatory
Jaringan
lemak
TNF-,
IL-6,
Leptin,
Resistin
Adiponectin
Jaringan perifer
Ambilan glukosa
Asam
lemak bebas
(proses lipolisis)
Otot
Pankreas
Hati
Sekresi insulin terganggu,
apoptosis
Ambilan glukosa
Produksi glukosa
meningkat
Ambilan glukosa
Pro inflammatory
Adipocytokines
Leptin : dgn pe BB, bekerja pada
sistem saraf perifer dan pusat
TNF- : berperan pada resistensi insulin
perifer, mengganggu insulin signaling,
menekan ekspresi glucose transporter
(GLUT-4)
IL-6 : meningkatkan glukoneogenesis
Resistin : resistensi insulin
Anti-inflammatory
Adipocytokines
Adiponektin : hormon peptida
diproduksi oleh adiposit
mencegah terjadinya resistensi
insulin.
Adiponektin jika p BB
1. Lipid and dyslipidaemia
2. Lipoprotein Metabolism
3. Lipoprotein Metabolism in insulin resistance and
type 2 diabetes
4. Management of dyslipidaemia
LIPID
LIPOPROTEIN METABOLISM
AND
THE MANAGEMENT OF DYSLIPIDAEMIA
O
Pickup J, Williams G. Lipid Disorders in diabetes mellitus. Text Book of Diabetes. 1997:p. 55.1-31

HO
H
CH
3
CH
3
C

CH
3
CH
2
CH
2
CH
2 C

CH
3
CH
3
H
Kolesterol

H
3
C

(CH
2
)
7
C

H
C

(CH
2
)
7
C

O
O
CH

CH
2
CH
2
O C

(CH
2
)
1
4
CH
3
O
C

O
(CH
2
)
16
CH
3
Trigliserida

Fosfolipid
C H
2
.O.CO.R
R.COO.CH
C H
2
O P
OCH
2
.CH
2
.N
+

CH
3

CH
3

CH
3

O
O
LIPID PLASMA
Lipid plasma tidak larut
Untuk melarutkan perlu Apolipoprotein =
Apoprotein = Apo
9 Apo : Apo A1, Apo A2, Apo A3, Apo B48,
Apo B100, Apo C1, Apo C2, Apo C3, Apo
E
Kompleks lipid plasma + apoprotein
disebut lipoprotein

LIPOPROTEIN
+
K
TG
F
Apo
Apo
Apo Apo
K
TG
F
LIPOPROTEIN



Lipid Plasma
Jenis Lipoprotein :
- HDL : high density lipoprotein
- LDL : low density lipoprotein
- IDL : intermediate density lipoprotein
- VLDL : very low density lipoprotein
- Kilomikron
- Lipoprotein a kecil (Lp(a))

Setiap Lipoprotein t.d :
kolesterol (bebas/ester), trigliserida,
fosfolipid, dan apoprotein

LIPOPROTEIN
Apolipoprotein + Lipid = Lipoprotein
APAKAH LIPOPROTEIN ?
Feher MD, Richmond W. Lipids and Lipid Disorders Second ed. Bayer. 1996
JENIS LIPOPROTEIN
Lipoprotein class
Relative size, triglyceride
and cholesterol content
Major apoproteins
Chylomicrons B
48
, E, CII
VLDL B
100
, E, CII
IDL
B
100
, E
LDL B
100

HDL AI,AII
Triglyceride
Cholesterol
Feher MD, Richmond W. Lipids and Lipid Disorders Second ed. Bayer. 1996
PARTIKEL KOLESTEROL HDL
Apo A-1
Apo A-2
Apo C
Apo E
Phospholipid
Trigliceride
Cholesterol Ester
Unesterified cholesterol
Diameter : 75-100
THE METABOLIC PATHWAY OF
LIPOPROTEINS
Endogenous pathway (LDL, TG)
Exogenous pathway (LDL,TG)
Reverse cholesterol transport (HDL)
Shepherd J. Eur Heart J Supplements 2001;3(suppl E):E2-E5
Exogenous
(metabolisme LDL,TG)
Lipoprotein Metabolism
Endogenous
(metabolisme LDL, TG)
Liver
Macrophage
RCTP (HDL)
RCTP = reverse cholesterol
transport pathway
Stool
remnants
kilomikron
Intestine
Food
Cholesterol
Cholesterol
(kolesterol , TG)
TG, kol
Apo B100
Enz. Lipoprotein lipase
Miskin kol. Apo A, C, E
Foam cells
TGFFA
Adipose
CE
CE
CETP
Chol
Chol
Chol
Kwiterovich PO, Jr. The metabolic pathways of high-density lipoprotein, low-density lipoprotein,
and triglycerides: A current review. Am J Cardiol 2000;86:5L-10L
Liver
Cholesterol
pool
Macrophage
SRB-1
HDL

Nascent HDL
Chol
Chol
Chol
IDL

LDL

VLDL

TG
TG
Reseptor LDL

Scavenger receptor-A / CD 36

Adenosine triphosphatebinding
cassette transporter-1 (ABC-1)
Endogenous pathway Reverse cholesterol transport Endogenous pathway and reverse
cholesterol transport
CE
THE METABOLIC PATHWAY OF
LIPOPROTEIN
IN
TYPE 2 DIABETES MELLITUS
AND
METABOLIC SYNDROME
IDL

Liver
Macrophage
VLDL

Cholesterol
Reverse cholesterol transport
HDL

Nascent HDL
LDL

Triglyceride

Cholesteryl ester

LDL Receptor

Scavenger receptor-A / CD 36

ABC-1 transporter
SRB-1 receptor
Insulin Resistance
Adipocytes
FFA
VLDL
large
VLDL
large
`
LDL
small
density
ApoA1
Kidney
DISLIPIDEMIA
Dislipidemi diabetes tipe 2 / resistensi insulin

Resistensi insulin mengakibatkan FFA meningkat
hati, menjadi sumber VLDL

VLDLLDL, pertukaran TG dan kolesterol LDL kecil
padat
ApoA1 dikeluarkan oleh ginjal, sehingga HDL
kolesterol rendah
Kesimpulan : TG tinggi,
HDL-kol rendah,
LDL-kol kecil padat tinggi

Management of dyslipidaemia

All three lipid profiles

kolesterol LDL, kolesterol HDL, dan trigliserid

play a role in the formation of
atherosclerosis

50
40
30
20
10
150 200 250 300 0
(3.87) (5.17) (6.46) (7.75)
0
Kadar serum kolesterol (mg/dl / mmol/L)
Hubungan antara kadar serum kolesterol dan risiko penyakit arteri koroner
Dari penelitian Multiple Risk Factor Intervention Trial (MRFIT)
Farnier M, Davignon J. Am J Cardiol. 1998;82:3J-10J
150
100
50
0
10
18
17
22
25
73
55
156
< 130 130 - 160 160 - 190
> 190
Insiden PAK / 1000 orang dalam 4 tahun menurut kadar trigliserid
dan LDL-kolesterol.
LDL-kolesterol
Assman G. Am J Cardiol 1992;70:10H-13H
Trigliserid < 200 mg/dl
Trigliserid > 200 mg/dl
Insidens PAK
(per 1.000 dalam 6
tahun)
80
120
< 35 35 - 55 > 55
HDL-kolesterol (mg/dl)
Hubungan HDL-kolesterol dengan insiden penyakit arteri koroner (PAK):
Dari Prospective Cardiovascular Munster (PROCAM) Study.
HDL-kolesterol secara meyakinkan berhubungan dengan risiko PAK ( p < 0.001).
100
60
40
20
0
PROCAM Study
CLASSIFICATION OF
LDL-cholesterol, Total-cholesterol,
HDL-cholesterol and Triglycerides
NCEP-ATP III
KLASIFIKASI TOTAL, LDL, HDL-KOLESTEROL,
DAN TRIGLISERID MENURUT NCEP ATP III
JAMA 2001;285:24862-497
LDL kolesterol
< 100 mg/dl
100 129 mg/dl
130 159 mg/dl
160 189 mg/dl
> 190 mg/dl
Total kolesterol
< 200 mg/dl
200 239 mg/dl
> 240 mg/dl
HDL kolesterol
< 40 mg/dl
> 60 mg/dl
Optimal
Mendekati optimal
Sedikit tinggi (Borderline)
Tinggi
Sangat tinggi
Diinginkan
Sedikit tinggi (Borderline)
Tinggi
Rendah
Tinggi
TRIGLISERIDA (NCEP-ATP III)
Optimal < 150 mg/dl
Sedikit tinggi(borderline) 150 - 199 mg/dl
Tinggi 200 - 499 mg/dl
Sangat tinggi > 500 mg/dl
Risk assessment: first step in
the management of
dyslipidaemia
Langkah pertama dalam terapi dislipidemia
adalah dengan menghitung berapa faktor
risiko yang dimiliki penderita tersebut (risk
assessment)
Faktor risiko dikelompokkan atas tiga kelompok
risiko rendah(low risk) , risiko sedang
(moderate risk), dan risiko tinggi (high risk)
T
h
e

8
t
h

M
A
D
A
M

RISK FACTORS FOR CORONARY ARTERY DISEASE (CAD)
AS DEFINED BY
THE NATIONAL CHOLESTEROL EDUCATION PROGRAM (NCEP 2001)
Age
(men > 45 years, women > 55
years)
Family history of premature
CHD* (CHD in male first-
degree relative < 55 years:
CHD in female first-degree
relative < 65 years)
Cigarette smoking
Hypertension (BP* > 140 / 90
mmHg or on antihypertensive
medication)
Low HDL C < 40 mg/dl

Irreversible Modifiable
Risk factors
* CHD = coronary heart disease; BP = blood preesure
JAMA 2001;285:24862497
HDL cholesterol > 60 mg/dl counts as a negative risk factor,
its presence removes 1 risk factor from the total count
T
h
e

8
t
h

M
A
D
A
M

Risk Category
LDL Goal
(mg/dl)
CHD, DM*, or equivalent

Multiple (2+) risk factors

0 1 risk factors
< 100

< 130

< 160
NCEP ATP III, THREE CATEGORIES OF RISK
THAT MODIFY LDL CHOLESTEROL GOALS
* Risk equivalents : Diabetes Mellitus, Stroke, PAD
JAMA 2001; 285: 2486-2497
EQUIVALENT CONDITIONS
JAMA 2001;285:24862-497
Other atherosclerotic disease , peripheral
arterial disease, aorta abdominalis aneurism,
stroke
Diabetes melitus ( type 2)
Multiple risk factors, which is in 10 years have
20% risk of CAD

diabetes melitus, stroke, peripheral
arterial disease
T
h
e

8
t
h

M
A
D
A
M

In high risk persons,
the recommended
LDL-C goals is <
100 mg/dl, but
when the risk is
very high, an
LDL-C of < 70
mg/dl is a
therapeutic
option
This therapeutic
option extends also
to patients at high
risk who have a
base line LDL-C <
100 mg/dl
NCEP REPORT 2004
Grundy SM Circulation. July, 2004;110:227-239
T
h
e

8
t
h

M
A
D
A
M

Multiple major risk factors (especially
diabetes)
1
Severe and poorly controlled risk factors
2
Multiple risk factors of the metabolic
syndrome
3
Acute coronary syndromes (PROVE IT)
4
Established CVD, plus:
THE VERY HIGH RISK PATIENTS
Mortality from coronary heart disease in
subjects with type 2 diabetes and in non-
diabetic subjects with and without prior
myocardial infarction
Haffner SM, et al.
N Engl J Med 1998; 339: 229234
3,5%
18,8%
20,2%
45,0%
0
5
10
15
20
25
30
35
40
45
50
No DM, No MI
No DM, MI DM, No MI
DM, MI
7
-
y
e
a
r

i
n
c
i
d
e
n
c
e

o
f

M
I

Type 2 diabetes mellitus (DM) and coronary artery disease (CAD). The 7 year
incidence of fatal or nonfatal myocardial infraction (MI) is essentially the same in
patients who have diabetes without a history of CAD and in patients with CAD who
are not diabetic. P < 0,001 for the difference between patients with and without MI in
both group.
Non diabetic Diabetic
Haffner SM, et al. N Engl J Med 1998;339:229-34
PREVENTION OF CORONARY HEART
DISEASE IN TYPE 2 DIABETES MELLITUS
Heart Protection Study with Simvastatin
40 mg

RESULTS
Lowering LDL-cholesterol from
< 116 mg/dl to < 77 mg/dl
The lower the better ?
PREVENTION OF CORONARY HEART
DISEASE IN TYPE 2 DIABETES MELLITUS
Heart Protection Study with Simvastatin
Conclusions
The present study provides direct evidence that
cholesterol-lowering therapy is beneficial for people
with diabetes even if they do not already have
manifest coronary disease or high cholesterol
concentrations
Statin therapy should now be considered routinely
for all diabetic patients at sufficiently high risk of
major vascular events, irrespective of their initial
cholesterol concentrations
Perubahan gaya hidup
Obat lipid
PENATALAKSANAAN

No over-eating!!
Exercise
Stop smoking, stop alkohol
Perubahan gaya hidup
Obat lipid
PENATALAKSANAAN
OBAT PENURUN LIPID
* bezafibrat, cipofibrat dan fenofibrat menurunkan LDL-kolesterol
lebih banyak daripada gemfibrozil
Persentasi penurunan LDL-kolesterol dan
trigliserid, serta kenaikan HDL-kolesterol
Obat LDL-K HDL-K TG
Statin

Resin

Fibrate*

Nicotinic acid

Ezetimibe
18 - 55%

15 - 30%

5 - 25%*

5 - 25%

10 - 15%
5 - 15%

3 - 5%

10 - 20%*

15 - 35%

-
7 - 30%

- /

20 - 50%*

20 - 50%

-
Overview of Cholesterol Metabolism:
Absorption and Synthesis
Statin
SASARAN LDL - KOLESTEROL
PENGOBATAN PERUBAHAN GAYA HIDUP
(DIET, OLAHRAGA), DAN PENGOBATAN STATIN
JAMA 2001;285:2487-2497
Kelas risiko
Sasaran LDL
(mg/dl)
Kadar LDL dimana
dimulai diet -
olahraga (mg/dl)
Kadar LDLdimana
dimulai obat (mg/dl)
PJK atau yang
disamakan
> 2 faktor risiko
0 - 1 faktor risiko
< 100
< 130
< 160
> 100
> 130
> 160
> 130
(100-129 dapat
dipertimbangkan
obat)
> 160
> 190
PJK ekuivalen : DM, strok, peny pembuluh darah perifer
THE VERY HIGH RISK PATIENTS
Established CVD plus:
1. Multiple major risk factors (especially diabetes)
2. Severe and poorly controlled risk factors (especially
continued cigarette smoking)
3. Multiple risk factors of the metabolic syndrome
(especially high triglycerides > 200 mg/dl plus non-
HDL-C > 130 mg/dl with low HDL-C < 40 mg/dl
4. On the basis of PROVE IT, patients with acute coronary
syndromes
Grundy SM et al. Circulation. July, 2004; 110: 227-239
LDL GOAL : < 70 mg/dl
Pria umur 50 tahun, ke dokter untuk pemeriksaan
kesehatan. Ia tidak merokok, melakukan olah
raga teratur. Kedua orang tua masih hidup.
Pada pemeriksaan ditemukan sbb: TB 150 cm, BB
76 kg, TD 185/95 mmHg. Pemeriksaan fisik lain
baik. Pem jantung : dlm bts normal
Ia membawa hasil laboratorium sbb: pemeriksaan
rutin baik, GDP 114 mg/dl, total -kol 198 mg/dl,
LDL- kol 138 mgdl, HDL 35 mg/dl, TG 186 mg/dl.
Diagnosa? Berapa sasaran LDL-kol?
CONTOH KASUS (1)
Pria , 50 tahun
Hipertensi
GDPT/ IFG
HDL < 40 mg/dl
TG > 150 mg/dl



LDL < 130 mg/dl


TTGO : 332 mg/dl


LDL < 100 mg/dl


Wanita umur 56 tahun, ke dokter untuk pemeriksaan
kesehatan. Ia tidak merokok, melakukan olah raga
teratur. Kedua orang tua masih hidup. Riw DM
tdak berobat teratur, Riwayat PJK + berobat
teratur
Pada pemeriksaan ditemukan sbb: TB 150 cm, BB 65
kg, TD 150/90 mmHg. Pemeriksaan fisik lain baik
Ia membawa hasil laboratorium sbb: pemeriksaan
reduksi positif, GDP 256 mg/dl, A1C 9,0%, total -
kol 180 mg/dl, LDL- kol 110 mg/dl, HDL 50 mg/dl,
TG 156 mg/dl.
Diagnosa ? Berapa sasaran LDL-kol?
CONTOH KASUS (2)
Wanita 56 thn
Riw DM
Riwayat PJK
Obesitas
Hipertensi
HDL 50 mg/dl
TG 156 mg/dl

LDL < 70 mg/dl
Lipoprotein Metabolism
in Insulin Resistance
Insulin
IR
Adipocytes
FFA
Liver
(CETP)
(CETP)
LDL
small
density
(lipoprotein or
Hepatic lipase i)
ApoA1
Kidney
TG
HDL
TG
Kwiterovich PO, Jr. The metabolic pathways of high-density lipoprotein, low-density lipoprotein,
and triglycerides: A current review. Am J Cardiol 2000;86:5L-10L
LDL
VLDL
large
CE
FFA : Free Fatty Acid
CE : Cholesteryl Ester
CETP : Cholesteryl Ester Transfer
Protein
CE
ADULT TREATMENT PANEL REPORTS
ATP III update 2004
Since the publication of ATP III, 5 major clinical trials
with statin therapy and clinical endpoints have been
published
Heart Protection Study (HPS)
Prospective Study of Pravastain in the Elderly at Risk
(PROSPER)
Antihypertensive and Lipid-Lowering Treatment to Prevent
Heart Attack Trial Lipid-Lowering Trial (ALLHAT LLT)
Anglo-Scandinavian Cardiac Outcomes Trial Lipid-Lowering
Arm (ASCOT-LLA)
Pravastatin or Atorvastatin Evaluation and Infection Throm-
bolysis in Myocardial Infraction 22 (PROVE IT-TIMI 22)
Primary Prevention of Cardiovascular Disease With Atorvas-
tatin in Type 2 Diabetes in the Collaborative Atorvastatin
Diabetes Study (CADRS)
Jaringan perifer
Otot
Pankreas
Hati
Jaringan
lemak
Substrat
glukoneogenik
Produksi glukosa
meningkat
Sekresi insulin terganggu,
apoptosis
Ambilan glukosa
Asam
lemak bebas
TNF-,
IL-6,
Leptin,
Resistin
Adiponectin
Mekanisme molekuler hubungan antara jaringan lemak dan resistensi insulin pada obesitas dan diabetes melitus.
Henry RR, Mudaliar S. Obesity, mechanisms and clinical management. Eckel RH (ed.). Lippincott Williams &
Wilkins, Philadelphia 2003; 229-272
Ambilan glukosa
Major Risk Factors (Exclusive of LDL-
cholesterol) That Modify LDL Goals
Cigarette smoking
Hypertension (blood pressure > 140/90 mmHg,
or on antihypertension)
Low HDL cholesterol (< 40 mg/dl)*
Family history of premature (CHD in male first-degree relative <
55 years; CHD in female first-
degree relative < 65 years
Age male > 45 years, female > 55 years
JAMA 2001;285:24862-497
HDL cholesterol > 60 mg/dl counts as a negative risk factor,
its presence removes 1 risk factor from the total count
Three categories of risk that modify
LDL cholesterol goals
JAMA 2001;285:24862-497
Risk group LDL-C goals (mg/dl)
Subjects with CHD or equivalent
(high risk)
Faktor risiko multipel ( > 2)
(moderate risk)
0 - 1 Risk Factor
(low risik)
< 100


< 130

< 160
Baseline LDL-C
(mg/dl)
Statin
(n =10,269)
Placebo
(n =10,267)
< 100
100 129
> 130
All patients
282 (16.4%)
668 (18.9%)
1,083 (21.6%)
2,033 (19.8%)
358 (21.0%)
871 (24.7%)
1,356 (26.9%)
2,585 (25.2%)
Event Rate Ratio
Statin Better
0.4 0.6 0.8 1.0 1.2 1.4
Statin
Worse
0.76 (0.72 0.81)
p<0.0001
Major vascular events by baseline low-density lipoprotein cholesterol (LDL-C) level
in the Heart Protection Study (HPS). Numbers in parentheses represent event rates
for the subset of 3,421 patients with entry LDL-C levels < 100 mg/dl (2.6 mmol/l).
See Figure 1 for an explanation of event rate ratio figures. CI = confidence interval.
Ballantyne CM. Am J Cardiol 2003;92 (suppl):3K-9K
HEART PROTECTION STUDY WITH
SIMVASTATIN (HPS)
From the PROVE IT study
Divided into two groups:
LDL cholesterol > 70 mg/dl
< 70 mg/dl
hsCRP > 2 mg/L
< 2 mg/L

Is there a difference in recurrent myocardial
infarction and death from coronary causes
between these groups?
Subjects and methods
RATIONAL FOR OPTIMAL VERY LOW
LDL-CHOLESTEROL GOAL (< 70mg/dl)
Lesson from HPS
Lesson from PROVE IT study

A question raised from these studies:
is LDL-C < 100 mg/dl sufficient low in high-
risk patients who already have low LDL-C
at base line?
C-REACTIVE PROTEIN LEVELS AND
OUTCOMES AFTER STATIN THERAPY

Ridker PM, Cannon CP, Morrow D, Rifai N, Lynda M, Rose MS, Carolyn
H, McCabe BS, Preffer MA, Braunwald E.
N Engl J Med 2005; 352: 20 28


PROVE - IT
Circulation. July, 2004;110:227-239
WHAT ARE NEW?
THE VERY HIGH RISK PATIENTS
Established CVD plus:
1. Multiple major risk factors (especially diabetes)
2. Severe and poorly controlled risk factors (especially
continued cigarette smoking)
3. Multiple risk factors of the metabolic syndrome
(especially high triglycerides > 200 mg/dl plus non-
HDL-C > 130 mg/dl with low HDL-C < 40 mg/dl
4. On the basis of PROVE IT, patients with acute
coronary syndromes
Grundy SM et al. Circulation. July, 2004; 110: 227-239
PENATALAKSANAAN
Perubahan gaya hidup (therapeutic
lifestyle changes )
Perencanaan makan (diet)
Olahraga
Berhenti merokok
Batasi alkohol

Obat penurun lipid