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