Download - Homeostasis glukosa
FISIOLOGI HOMEOSTASIS GLUKOSADAN
SEKRESI INSULIN
Alwi ShahabSubbagian Endokrinologi Metabolisme
Bagian Ilmu Penyakit DalamFK 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).
GlycerolGlycerol-3-P
Lactate Lactate Pyruvate
Pyruvate
Alanine Alanine Alanine
Intestine
MuscleLiver
Postabsorptive metabolism (overnight fast)
Adipose tissueGlucose
Glycolysis
Gluconeogenesis
GlycogenSynthesis
GlycogenSynthesis
GlycogenGlycogenolysis GlycogenGlycogenolysis Glycolysis
Fatty acidoxidation
Fatty acid
Fatty acid
Fatty acid
Protein
Lipolysis
Triglyceride
TCAcycle
TCAcycle
Glucose
TCAcycle
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 2400 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 malamMakan siangSarapan 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
DiabetesPhase 1 Type 2
DiabetesPhase 2
Type 2DiabetesPhase 3
- 12 - 10 - 6 - 2 0 2 6 10 14Years from diagnosis
Bet
a ce
ll f
un
ctio
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 sehatIn
sulin
se
cre
tion
(pm
ol/m
in)
800
6am
Time10am 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
GL
UC
OS
E T
OX
ICIT
Y
Primary defects in type 2 diabetes1-3
ß-celldysfunction
ß-celldysfunction
Loss of early phaseinsulin release
Loss of early phaseinsulin release
Postprandialglucose spikesPostprandial
glucose spikes
Insulin signalling defect
Insulin signalling defect
Insulin resistanceInsulin resistance
Increased basalglucose levels
Increased basalglucose levels
HyperglycaemiaHyperglycaemia
Adapted from Lebovitz, Ward and Yki-Järvinen
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
Glu
cose
(m
g/d
l)
Time (hours)Reaven G. Diabetes 1988;37:1020–1024
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;13:676–686.
300
200
100
0
Pla
sma
glu
cose
(m
g/d
l)
6 am 12 pm 6 pm 12 pm 6 am
Time of day
Mealtimeglucosespikes
Fastinghyperglycemia
Normal
Hyperglycemia
Acute toxicity Chronic toxicity
Diabetic complications
Improvement ofinsulin sensitivity
Spike Continuous
Tissue lesion
Hyperinsulinemia
Adapted from Ceriello A. Diabetic Medicine 1998;15:188–193
Patogenesis dan pencegahan komplikasi DM
Restoration ofearly-phase insulin
release
0 1 2 3 4hrs
0.2
0.4
0
0.6
8
12
16
20
4
Glu
co
se
(m
M)
Insu
lin (
nM
)
Adapted from Owens et al 1995
Early stage
Later stage
Early Insulin Secretion and Plasma Early Insulin Secretion and Plasma Glucose Levels After a MealGlucose Levels After a Meal
Type 2 diabetes
Normals
Bruce D, et al. Diabetes 1988;37:736–744.
b
loo
d g
luc
ose
(m
mo
l/l)
0 60 120 180
5
4
3
2
1
0
–1
ins
ulin
(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 DiabetesIV early-phase insulin
• Lowering HbA1c lowers risk of micro- and macrovascular disease
• Control of fasting and postprandial blood glucose optimizes overall glycemic control as assessed by HbA1c
• 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, HbA1C 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 6.1–6.9 7.0–7.7 7.8
11.1
7.8–11.0
<7.8
Fasting glucose (mmol/l) 2-ho
ur g
luco
se
(mm
ol/l)
Decode Study Group. Lancet 1999;354:617–21
Hazard Ratios for Death According to the Fasting and 2-hour Plasma Glucose
Peningkatan kadar HbA1c pada studi UKPDS
Simpulan :Simpulan :
1. Individu sehat, sekresi insulin berlangsung secara bifasik
2. Sekresi insulin fase awal (1st phase) akan menghambat produksi glukosa hati dalam keadaan puasa.
3. Sekresi insulin fase lanjut (2nd 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