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FISIOLOGI HOMEOSTASIS GLUKOSA

DAN
SEKRESI INSULIN

Alwi Shahab
Subbagian Endokrinologi Metabolisme
Bagian Ilmu Penyakit Dalam
FK Unsri/ RSMH Palembang

Puasa --> glukosa darah -->
hasil glukoneogenesis didalam hati.

Sesudah makan (prandial) -->
hasil absorbsi makanan dari usus halus.

Peningkatan glukosa darah akan merangsang
pankreas mensekresi insulin.

HOMEOSTASIS GLUKOSA DARAH :

Insulin menurunkan kadar glukosa darah
melalui 2 cara :
Pertama :
Menekan glukoneogenesis dan meningkatkan
sintesis glikogen hati.
Produksi glukosa di hati dirangsang oleh
glukagon dan katekolamin.
Glukosa sendiri menekan proses glukoneo-
genesis oleh hati.

Kedua :
Meningkatkan transpor dan metabolisme
glukosa dijaringan perifer --> otot dan jaringan
lemak.
Glukosa darah puasa (fasting = post absorbtive ) dan
glukosa darah sesudah makan (prandial) berbeda
secara metabolik dan hormonal.

GDP --> resultan aktivitas glukoneogenesis -->
dipengaruhi kadar insulin puasa (basal) dan glukagon
serta katekolamin.

Peningkatan kadar GDP --> akibat kurangnya insulin
puasa atau peningkatan glukagon/ katekolamin atau
keduanya.

In the postabsorptive state, glucose, in the absence of exogenous supply, is provided from
endogenous sources (glycogenolysis and gluconeogenesis).
Glycerol Glycerol-3-P
Lactate Lactate Pyruvate
Pyruvate
Alanine Alanine Alanine
Intestine
Muscle
Liver
Postabsorptive metabolism (overnight fast)
Adipose tissue
Glucose
Glycolysis
Gluconeogenesis
Glycogen
Synthesis
Glycogen
Synthesis
Glycogen
Glycogenolysis
Glycogen
Glycogenolysis
Glycolysis
Fatty acid
oxidation
Fatty acid
Fatty acid
Fatty acid
Protein
Lipolysis
Triglyceride
TCA
cycle
TCA
cycle
Glucose
TCA
cycle
Low,insulin-independent uptake
-
-
+
+
+
-
AcetylCoA
AcetylCoA
+
+
-
-
AcetylCoA
Pyruvate
-
Glukosa prandial --> resultan aktivitas absorbsi
glukosa dari usus halus atau metabolisme (ambilan
dan penggunaan) glukosa di jaringan perifer (lemak
dan otot) yang tergantung insulin.

Peningkatan glukosa prandial --> akibat dari :
- Asupan kalori (makanan) berlebihan
- Dan atau kekurangan insulin prandial
absolut atau relatif (resistensi insulin).

Insulin
Puasa
Glukosa
Puasa
Glukagon
Insulin Prandial
(glucose uptake/utilization)
Glukosa
Prandial
Makanan
Glukosa darah puasa
Glukosa darah prandial
Postprandial metabolism. In the postprandial state insulin directs metabolism towards
storage and synthesis (anabolism). DHAP, dihydroxyacetone phosphate.
Postprandial metabolism
Sekresi insulin pada individu normal

1. Sekresi insulin basal (post absorptive)
- Dipertahankan terus menerus
- Jumlah yang relatif tetap (~ 1 uU/ jam)
- Terjadi diantara 2 makan, malam hari atau selama puasa.
- Untuk metabolisme glukosa oleh sel-sel otak.
- Korelasi yang tinggi dengan kadar glukosa darah basal.

2. Sekresi insulin prandial
- Terjadi waktu makan (fed state)
- Meningkat tajam (5 10 x basal rate) dlm waktu singkat
(1/2 1 jam sesudah makan).
- Normal kembali ke keadaan basal dalam waktu 2 4 jam.
- Berkaitan erat dgn kemampuan ambilan glukosa oleh jaringan.

Profil insulin dan glukosa plasma 24 jam pada individu normal.
POLA SEKRESI INSULIN
SETELAH BEBAN GLUKOSA ORAL
10 20 30 60 120 240
0
minutes
Sekresi insulin pada DM tipe 1 :
- Tergantung dari sisa massa sel beta pankreas
Individu
normal
DM tipe 1
dg sisa
sekresi insulin
DM tipe 1 tanpa sisa sekresi insulin
Makan malam Makan siang Sarapan pagi
Sekresi insulin pada DM tipe 2 :
Bervariasi dari hiperinsulinemia akibat resistensi insulin
sampai kekurangan insulin absolut akibat gangguan fungsi
sel beta pankreas
I
G
T
Postprandial
Hyperglycemia
Type 2
Diabetes
Phase 1 Type 2
Diabetes
Phase 2
Type 2
Diabetes
Phase 3
- 12 - 10 - 6 - 2 0 2 6
10 14
Years from diagnosis
B
e
t
a

c
e
l
l

f
u
n
c
t
i
o
n

(
%
)

Stages of Type 2 Diabetes in
Relationship to -cell Function
25
0
50
75
100
UKPDS Group.Diabetes 1995;44:1249-1258
Profil sekresi insulin pada pasien
DM tipe 2 dan individu sehat
I
n
s
u
l
i
n

s
e
c
r
e
t
i
o
n

(
p
m
o
l
/
m
i
n
)

800
6am
Time
10am 2pm 6pm 10pm 2am 6am
700
600
500
400
300
200
100
Healthy people
Type 2 diabetic patients
Defek primer pada DM tipe 2
1 Lebovitz HE. Diab Rev 1999; 7: 139-153. 2 Ward W, et al. Diab Care 1984; 7: 491-502. 3 Yki-Jarvinen H. Endocrine Revs 1992; 13: 415-431.

Terjadinya DM tipe 2
adalah akibat kombinasi
disfungsi sel pankreas
dan resistensi insulin
G
L
U
C
O
S
E

T
O
X
I
C
I
T
Y

Primary defects in type 2 diabetes
1-3

-cell
dysfunction
Loss of early phase
insulin release
Postprandial
glucose spikes
Insulin signalling
defect
Insulin resistance
Increased basal
glucose levels
Hyperglycaemia
Adapted from Lebovitz, Ward and Yki-Jrvinen
Glukosa puasa vs glukosa post-
meal/ prandial : determinan
Glukosa puasa
Produksi glukosa hati
Sensitivitas hati terhadap insulin
Glukosa Post-meal/ prandial
Kadar glukosa sebelum makan / pre-meal
Jumlah dan waktu sekresi insulin
Supresi terhadap produksi glukosa hati
Sensitivitas insulin didalam jaringan perifer
Hilangnya sekresi insulin fase awal mnenyebabkan
gelombang2 peningkatan (spikes) glukosa setelah makan
500
400
300
200
100
0800 1000 1200 1400 1600 1800 2000 2200 0000 0200 0400 0600 0800
Non-diabetic
Early type 2 diabetes
Severe type 2 diabetes
G
l
u
c
o
s
e

(
m
g
/
d
l
)

Time (hours)
Reaven G. Diabetes 1988;37:10201024
Mealtime
HbA1c refleksi peningkatan kadar glukosa
puasa dan post prandial
Relative contributions of FPG and mealtime glucose spikes to 24-hour
glycemic control
Riddle MC. Diabetes Care 1990;13:676686.
300
200
100
0
P
l
a
s
m
a

g
l
u
c
o
s
e

(
m
g
/
d
l
)

6 am 12 pm 6 pm 12 pm 6 am
Time of day
Mealtime
glucose
spikes
Fasting
hyperglycemia
Normal
Hyperglycemia
Acute toxicity Chronic toxicity
Diabetic complications
Improvement of
insulin sensitivity
Spike Continuous
Tissue lesion
Hyperinsulinemia
Adapted from Ceriello A. Diabetic Medicine 1998;15:188193
Patogenesis dan pencegahan
komplikasi DM
Restoration of
early-phase insulin
release
0 1 2 3 4hrs
0.2
0.4
0
0.6
8
12
16
20
4
G
l
u
c
o
s
e

(
m
M
)

I
n
s
u
l
i
n

(
n
M
)

Adapted from Owens et al 1995
Early stage
Later stage
Early Insulin Secretion and Plasma
Glucose Levels After a Meal
Type 2 diabetes
Normals
Bruce D, et al. Diabetes 1988;37:736744.
D

b
l
o
o
d

g
l
u
c
o
s
e

(
m
m
o
l
/
l
)

0 60 120 180
5
4
3
2
1
0
1
D

i
n
s
u
l
i
n

(
m
U
/
l
)

0 60 120 180
80
60
40
20
0
Time (minutes) Time (minutes)
Shaded = non-diabetic
Early Type 2 diabetes
Replacing Early Insulin Secretion with Exogenous
Insulin Improves Postprandial Glucose Excursions
in Type 2 Diabetes
IV early-phase insulin
Lowering HbA
1c
lowers risk of
micro- and macrovascular disease
Control of fasting and postprandial
blood glucose optimizes overall
glycemic control as assessed by
HbA
1c

Clinically significant reduction in
HbA1c can be achieved by lowering
postprandial plasma glucose
May be a risk for cardiovascular
morbidity and mortality
(Epidemiology studies)

Importance of Mealtime and
Post-Prandial Glucose
Elevated
postprandial
plasma glucose
is present in
most Type 2
diabetics and
is often the
earliest clinical
manifestation
DECODE study, 1999 CHD mortality is more related to 2-hour post-meal glucose than
to FPG. FPG does not identify subjects at risk for CHD
Honolulu Heart Program, 1987 CHD incidence and mortality increase stepwise with increasing
glucose intolerance
Diabetes Intervention Study, 1998 Post-meal, but not fasting, glucose is associated with CHD
Funagata Diabetes Study, 1999 IGT, but not IFG, is a risk factor for CVD
The Rancho Bernardo Study, 1998 2-hour post-challenge hyperglycemia alone more than doubles
the risk of fatal CVD and heart disease in older adults
. . . the use of fasting glucose alone for diabetes screening or
diagnosis may fail to identify most older adults at high risk for
CVD and should be re-evaluated.
Paris Prospective Study, 1999 Death rates for CHD increase with increasing 2-hour
post-meal glucose levels
Whitehall Study, 1999 Men in the upper 2.5% of the 2-hour post-meal glucose
distribution had significantly higher CHD mortality
HOORN Study, 1999 High plasma glucose levels, especially 2-hour post-load
glucose concentrations and to a lesser extent, HbA
1C
values,
indicate a risk for CVD mortality
Pacific and Indian Ocean Population
Study, 1999
Isolated 2-hour post-glucose challenge increases total mortality
and cardiovascular mortality, and carries a greater risk than
isolated fasting hyperglycemia



Relationship Between Mealtime Glucose
Levels and Risk of Cardiovascular Disease
0.00
0.50
1.00
1.50
2.00
2.50
<6.1 6.16.9 7.07.7 7.8
11.1
7.811.0
<7.8
Fasting glucose (mmol/l) 2
-
h
o
u
r

g
l
u
c
o
s
e
(
m
m
o
l
/
l
)
Decode Study Group. Lancet 1999;354:61721
Hazard Ratios for Death According to the
Fasting and 2-hour Plasma Glucose
Peningkatan kadar HbA1c pada studi UKPDS
Simpulan :

1. Individu sehat, sekresi insulin berlangsung secara
bifasik

2. Sekresi insulin fase awal (1
st
phase) akan menghambat
produksi glukosa hati dalam keadaan puasa.

3. Sekresi insulin fase lanjut (2
nd
phase) berfungsi
meningkatkan ambilan glukosa oleh jaringan perifer.

4. Hiperglikemi post prandial pada DM tipe 2 terjadi akibat
hilangnya sekresi insulin fase awal dan resistensi
insulin serta hiperinsulinemi

5. Hiperglikemi yang persisten menyebabkan gangguan
respons sekresi insulin dari sel-sel beta pankreas,
sehingga memerlukan terapi insulin untuk mengem-
balikan respons sekresi insulin fase awal dan
memperbaiki kontrol glukosa darah.

6. Terapi insulin juga memperbaiki regulasi reseptor
insulin dijaringan perifer dan memperbaiki kontrol
glukosa darah serta menurunkan resistensi insulin.

Jaringan target utama dari insulin : hati, otot dan jaringan lemak.
Efek metabolik dari Insulin

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