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Patofisiologi Diabetes

Husaini Umar

Divisi Endokrin dan Metabolik, Bagian Penyakit Dalam


Fakultas Kedokteran Universitas Hasanuddin
RSUP Dr. Wahidin Sudirohusodo/ RSP. UNHAS
Makassar
Apakah Diabetes itu ?
Faktor Faktor
keturunan Lingkungan/
Cara hidup Gaya hidup
berisiko:
Makan
berlebihan
Insulin kurang jumlahnya Kurang sport
Insulin kurang baik kerjanya Stres

DIABETES = penyakit dengan


kadar gula (glukosa) darah meningkat

Insulin = hormon pengatur kadar glukosa darah yang dikeluarkan oleh pankreas
adalah suatu kelompok penyakit metabolik yang disifati
oleh adanya hiperglikemi yang disebabkan oleh kelainan
sekresi insulin, gangguan kerja insulin atau keduanya

b-cell Type 2 Insulin


Dysfunction Diabetes Resistance
Perjalanan penyakit DM Tipe 2 ditandai dengan
penurunan fungsi sel ß pankreas

100 Saat didiagnosis


?
Fungsi sel -b (% dari normal HOMA)

80

60

Fungsi pankreas
40
= 50% dari normal

20

0
―10 ―8 ―6 ―4 ―2 0 2 4 6
Waktu (tahun)

HOMA=homeostasis model assessment.


UKPDS Group. Diabetes 1995;44:1249―58.
Adapted from Holman RR. Diabetes Res Clin Pract 1998;40(suppl 1):S21―5.
Tipe diabetes
DM tipe 1 DM tipe 2

DM gestasional

DM tipe lain
5
DIABETES IS A HUGE AND GROWING PROBLEM
(IDF ATLAS 2014)
Indonesia is One of The Largest Diabetes Population
in The World

Top 10 Countries/Territories of number


Of people with diabetes (20-79 years), 2014

China 96,2

India 66,8

USA 25,7

Brazil 11,6

9,1
Indonesia
5
Mexico 9

7 Egypt 7,5

German 7,2

Turkey 7,2

Japan 7,2

Prevalence: 5,55% (adult pop.) Prevalence: 5,55% (adult pop.)

Sources :
1. IDF Diabetes Atlas, 6th ed
2. IDF Diabetes Atlas 6th ed UPDATE
Indonesia: Penyakit Kronik dari peserta
ASKES di 2010
Total Kasus Terdiagnosa
No. Diagnosis
(Ribu)
1 Gagal Ginjal 11,875
2 Hipertensi 629,315
3 Diabetes Mellitus 420,743
4 Kanker 132,810
5 Penyakit jantung 247,203
6 Stroke 117,356
7 Asma 105,689
8 Osteoporosis 15,084
9 Penyakit kronik lainnya 220,151
ASKES= Indonesian national health insurance plan
Pola penyebab kematian semua umur
No Jenis Penyakit Proporsi (%) No Jenis Penyakit Proporsi (%)

1 Strok 15,4 11 Penyakit jantung 4,6

2 TB 7,5 12 Pnemonia 3,8

3 Hipertensi 6,8 13 Diare 3,5

4 Cedera 6,5 14 Ulkus lambung dan usus 12 jari 1,7

5 Perinatal 6,0 15 Tifoid 1,6

6 Diabetes Mellitus 5,7 16 Malaria 1,3

7 Tumor ganas 5,7 17 Meningitis Ensefalitis 0,8

8 Penyakit hati 5,1 18 Malformasi kongenital 0,6

9 Penyakit jantung iskemik 5,1 19 Dengue 0,5

10 Penyakit sal nafas bawah 5,1 20 Tetanus 0,5

Riskesdas Depkes RI, 2007


In the CODE study of a European cohort of over
7000 patients with T2DM, ONLY 31% of patients
had adequate glycemic control

100

80
Patients with adequate glycemic

60

40
control (%)

20

0
Belgium France Germany Italy Netherlands Spain Sweden UK All

aHbA1c
10
≤6.5%.
HbA1c=haemoglobin A1c; T2DM=type 2 diabetes mellitus.
Liebl A, et al. Diabetologia. 2002; 45: S23–S28.
Poorly managed diabetes leads to serious
complications and early death

Diabetes caused 5.1 million deaths in 2013.


Every six seconds a person dies from diabetes

(IDF ATLAS 2013)

Diabetes caused 4.9 million deaths in 2014.


Every six seconds a person dies from diabetes
(IDF ATLAS 2014)

11
GLUCOSE HOMEOSTASIS:
three mechanisms

• 1) Glucose production in the liver.

• 2) Glucose uptake and utilization by peripheral


tissues, chiefly skeletal muscle.

• 3) Actions of insulin and counter-regulatory


hormones, including glucagon, on glucose
uptake and metabolism
Regulation of Insulin secretion
(glucose, Intestinal hormones, Amino acid certain)

• Intracellular transport of
glucose is mediated by
GLUT-2 (insulin-independent
glucose transporter in b
cells).
• Glucose undergoes oxidative
metabolism in the b cell to yield
ATP.
• ATP inhibits an inward K+ channel
receptor.

• Inhibition of this receptor leads to


membrane depolarization, influx of
Ca2+ ions, and release of stored
insulin from b cells.
Metabolic actions of insulin in striated muscle,
adipose tissue, and liver.
Insulin action on a target cell

MAP kinase=mitogen-activated protein kinase pathway for insulin &insulin-like


growth factor (mitogenic=proliferation).
PI-3K= phosphatidylinositol-3-kinase (Metabolic activity)
Insulin

GLUT 4 Translocation
Insulin Receptor

Glycogen synthesis,
Protein synthesis
Anti-lipolysis
MAP-K IRS 1,2 PI3K  Akt  eNOS  NO

Proliferation ET 1 Anti-apoptosis Vasioilatation Anti-inflamation Anti-oxidative stress


VSMC,
PAI-1
Vasoconstriction

(Atherogenic) (Antiatherogenic)
PATHOGENESIS OF TYPE 2 DIABETES
Much less in known–multifactorial complex disease.

1) Environmental factors, such as a sedentary life style


and dietary habits.
2) Genetic factors are also involved:
a) Concordance rate of 35% -60% in monozygotic twins.
b) Risk for type 2 diabetes in an offspring is more than double if
both parents are affected
c) No HLA association or autoimmune reaction.
Pathogenesis of type 2 Diabetes
Two major pathogenetic factors:

1. Insulin resistance.
obesity plays an important role by decreasing
insulin receptors.

2. B cell dysfunction.
inability of pancreas to produce insulin to
compensate for insulin resistance.
Patophysiology of Insulin Resistance
( Further studies are needed in order to evaluate this hypothesis )

Post-receptor the most important sites


Insulin
Insulin receptor ( α & β )
activation of p100
Activation of kinase and phosphorylation in IRS serine phosphoryl
protein mutation.
PI3K / p85, p100 no amplification
IRS (-1 and -2), of signal

En
protein mutation
PDK
PKB / Akt.
PKC
MAPK Glycogenesis
pathway Gluconeogenesis

Synthesis of GLUT
Translocation of GLUT
Draznin B, DIABETES, Vol. 55, 2006 19
ADA.
1997 Consensus Development on Insulin Resistance.
Insulin Resistance
Insulin

GLUT 4 Translocation
Insulin Receptor

Glycogen synthesis,
Protein synthesis

MAP-K IRS 1,2 PI3K  Akt  eNOS  NO

Proliferation ET 1 Anti-apoptosis Vasidilatation Anti-inflamation Anti-oxidative stress


VSMC,
PAI-1
Vasoconstriction

(Atherogenic) (Antiatherogenic)
Increased Decreased
More than 80% of patients progressing to
type 2 diabetes are insulin resistant
Insulin sensitive;
low insulin secretion
(16%)

Insulin sensitive;
good insulin Insulin resistant;
secretion (1%) low insulin secretion (54%)

83%
Insulin resistant;
good insulin secretion
(29%)

Haffner SM, et al. Circulation 2000; 101:975–980.


Pathogenesis of type 2

This may be due to deposition of amylin as


amyloid deposites the latter is cosecreted
with insulin in high amount due to insulin
resistance.

Amylin is toxic to beta cells >>> will lead to


B cell exhaustion& DM
Hubungan resistensi insulin dan
disfunksi sel b-pankreas
Resistensi insulin

Ambilan glukosa di otot dan


jaringan lemak menurun Liipolisis meningkat
Pelepasan glukosa dari hati
meningkat

Hiperglikemia Asam lemak bebas


meningkat

Disfungsi sel b
Leal AMO,Voltarelli JC. Rev Bras Hemator
2010;32(4)
BOTH ISLET DYSFUNCTION AND INSULIN RESISTANCE
CONTRIBUTE TO THE ONSET AND PROGRESSION OF
TYPE 2 DM

Unhealthy Insulin Normal pancreatic Healthy


lifestyle and resistance islet function
Pancreas
environmental =
factors Insulin Normal
X Glucose
Sufficient Appropriate Tolerance
Insulin Glucagon (NGT)

Pancreatic islet
Reduced dysfunction Unhealthy
Glucose uptake Pancreas
More Insulin =
needed to Impaired GT
compensate which likely
progresses to
Insufficient Excess
More work Insulin Glucagon Type 2 DM
Central Obesity
for b-cells

GT = glucose tolerance; NGT = normal glucose tolerance; T2DM = type 2 diabetes mellitus
Type 2
Obesity IGT Complications Disability
diabetes

Preclinical state Clinical Death


disease

The natural history of type 2 diabetes

Crandall J, Shamoon H. Therapy for Diabetes Mellitus and Related Disorders.


4th edition, Lebovitz HE edit,2004
The Pathophysiology of Type 2 DM
Pancreas

LIVER
GLYCOGENOLYSIS

Insulin supply or action


G LYCOGEN

-
HGP +
+ GLUCOSE G L UC O S E

GLUCONEO FFA
GENESIS
LIPOLYSIS Lactic Acid

ADIPOSE TISSUE
The progressive nature of type 2 diabetes

Normal Impaired Type 2 Late type 2


glucose diabetes diabetes complications
tolerance

Insulin
sensitive
Hyperglycaemia

Normal insulin
secretion Insulin
resistance

Normoglycaemia
β-cell exhaustion

Insulin resistance

Fasting plasma glucose


Insulin sensitivity Adapted from Bailey CJ et al. Int J Clin Pract 2004;58:867–876.
Insulin secretion Groop LC. Diabetes Obes Metab 1999;1 (Suppl. 1):S1–S7.
30
Natural history of T2DM
Progressive loss of b-cell function
Diabetes
diagnosed

Beta-cell function (%)

Diabetes prevention

Years from diagnosis

By extrapolation, the loss of b-cell function has already started


10 to 12 years before type-2 DM is diagnosed, with a deterioration
rate of 4 %/ year.
β-cell function continues to decline regardless of intervention in
T2DM

Progressive Loss of β-cell Function Sulfonylurea (n=511)


100 Occurs prior to Diagnosis Diet (n=110)
Metformin (n=159)

80
β-cell Function (%)*

60

40

20

0
–5 –4 –3 –2 –1 0 1 2 3 4 5 6
Years since Diagnosis
T2DM=type 332 diabetes mellitus.
*β-cell function measured by homeostasis model assessment (HOMA).
Adapted from UKPDS Group. Diabetes. 1995; 44: 1249–1258.
β-cell Function Progressively Deteriorates and
Glycated Haemoglobin Levels Increase
• In this study, following an increase after initial therapy with metformin, glibenclamide or
rosiglitazone, β-cell function continued to decline
• It was also shown that glycated haemoglobin levels showed a time-dependent increase following
treatment

Annualized slope (95% CI) Annualized slope (95% CI)


Rosiglitazone -2.0 (-2.6 to -1.3) Rosiglitazone 0.07 (0.06 to 0.09)
Metformin -3.1 (-3.8 to -2.5)* Metformin 0.14 (0.13 to 0.16)*
Glibenclamide -6.1 (-6.8 to -5.4)* Glibenclamide 0.24 (0.23 to 0.26)*
100 8.0

Glycated haemoglobin (%)


7.6
90
β-cell function (%)

7.2
80
6.8
70
Treatment difference (95% CI) 6.4 Treatment difference (95% CI)
Rosiglitazone vs. metformin, Rosiglitazone vs. metformin,
60 5.8 (1.9 to 9.8); p=0.003
6.0
-0.13 (-0.22 to -0.05); p=0.002
Rosiglitazone vs. glibenclamide, Rosiglitazone vs. glibenclamide,
-0.8 (-4.7 to 3.1); p=0.67 -0.42 (-0.50 to -0.33); p<0.001
0 0
0 1 2 3 4 5 0 1 2 3 4 5
Years Years
No. of pts
3652 3227 2796 2353 1918 776 4012 3308 2991 2583 2197 822

Kahn SE et al. N Engl J Med 2006;355:2427-43.


Ominous Octet
DPP-4 inhibitors improve glucose control by
increasing incretin levels in type 2 diabetes8,17
Meal

Increased insulin
from beta cells Muscle Peripheral
(GLP-1 and GIP) glucose
Adipose
uptake
tissue
Release of
incretins from
Gut the gut
Pancreas Physiological
glucose
DPP-4 control
enzyme
Decreased glucagon
Liver Glucose
From alpha cells
production
(GLP-1)
Inactive
incretins
GLP-1=glucagon-like peptide-1; GIP=glucose-dependent insulinotropic polypeptide.
8. Porte DJr, Kahn SE. Clin Invest Med 1995;18:247-254.
17. Drucker DJ. Cell Metabolism 2006;3:153-165. 36
Glucose Reabsorption Occurs
Familial renal
in the Proximal Tubule
S1 segment of proximal
GLUCOSURIA
tubule
90% glucose less/or lack
reabsorbed Facilitated by
SGLT2 of SGLT2

Proximal Tubule

SGLT2

glucose
glucose-
reabsorption
glucose-
via SGLT1
Filtration (10%)
Minimal or NO
SGLT, sodium-glucose co-transporter
Glucose-excretion
1. Wright EM. Am J Physiol Renal Physiol. 2001;280:F10–18.
2. Lee YJ et al. Kidney Int Suppl. 2007;106:S27–35.
3. Hummel CS et al. Am J Physiol Cell Physiol. 2011;300:C14-21.
PROGRESSIVE

AGGRESSIVE
CHARACTERISTIC
TYPE 2 DM
MULTIPHARMACY

CARDIOVACULAR
DISEASE
INDIVIDUALIZED PATIENT
TREATMENT STRATEGIES
Poorly managed diabetes leads to serious
Complications

ACUT CHRONIC

39
Hypoglycaemia in T2DM: a possible link
to increased CV risk/events
Possible mechanisms1,2 Hypoglycaemia as link to tissue ischaemia3

• Haemodynamic changes: *
20
‒ activation of autonomic nervous system

Episodes accompanied by
‒ 10-50 fold increased secretion of

cardiac symptoms (%)


adrenaline & noradrenaline 15
*
• ECG changes: 10
‒ longer QT interval
‒ hypokalaemia
5

• Haemorheological changes:
‒ platelet activation 0
‒ increased viscosity

Study of 72-h continuous glucose monitoring and


simultaneous cardiac Holter monitoring in patients with
T2DM treated with insulin and history of frequent
hypoglycaemia and coronary artery disease (n=19)
*P <0.01 vs episodes during hyperglycaemia and normoglycaemia
54 episodes of hypoglycaemia reported (BGL <70 mg/dl)
1Desouza CV et al. Diabetes Care 2010;33:1389–1394; 59 episodes of hyperglycaemia reported (BGL >200 mg/dl)
2RobertTC et al. Diabetes 2003;52:1469–74;
3Desouza C et al. Diabetes Care 2003; 26:1485–1489
Chronic Complications in Newly Diagnose
Diabetes Mellitus
50% of patients had ≥ 1 complications
Retinopathy:
Stroke or TIA: 21%
1%
NEWLY
DIABETES
Hypertension:
35%
Plasma
creatinine Abnormal ECG :
>120mol/l: 3% 18%

Intermittent Erectal Dysfuntion :


Claudicasio: 3% 20%

Foot skin ischemia : Pedal pulse (-) :


6% 13%

UKPDS 6, Diabetes Res. 1990 Jan;13(1):1-11. J Hypertens 1993 Jun;11(6):681.


Acta Medica Iranica, 44(6): 415-419; 2006 International Journal of Diabetes Mellitus, 2010 April; 2(1):61-3
Hemodialisis krn Gagal
Ginjal pada pasien DM Tipe 2
Pasien DM Tipe 2
dirawat di CVCU
karena Infark Miokard.
Kaki diabetes pada
pasien DM Tipe 2
yang menolak
amputasi
Impact of Intensive Therapy for Diabetes: Summary
of Major Clinical Trials

Study Microvasc CVD Mortality


UKPDS      
DCCT /
EDIC*      

ACCORD   
ADVANCE   
VADT   
Kendall DM, Bergenstal RM. © International Diabetes Center 2009
Initial Trial
UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:854.
Holman RR et al. N Engl J Med. 2008;359:1577. DCCT Research Group. N Engl J Med 1993;329;977. Long Term Follow-up
Nathan DM et al. N Engl J Med. 2005;353:2643. Gerstein HC et al. N Engl J Med. 2008;358:2545.
Patel A et al. N Engl J Med 2008;358:2560. Duckworth W et al. N Engl J Med 2009;360:129. (erratum:
Moritz T. N Engl J Med 2009;361:1024) * in T1DM
RINGKASAN

Diabetes melitus adalah sekelompok penyakit metabolik yang


disifati oleh adanya hiperglikemi sebagai akibat defek sekresi
insulin, kelainan kerja insulin, atau keduanya.
Patogenesis utama terjadinya diabetes melitus tipe 2 adalah
resistensi insulin dan disfungsi sel beta.
Resistensi insulin adalah penurunan respon fisiologi terhadap
insulin walaupun kadarnya cukup.
Disfungsi sel beta pankreas adalah ketidak mampuan sel tersebut
memproduksi insulin dalam mengkompensasi resistensi insulin.
Penurunan fungsi sel beta berkelanjutan tanpa melihat intervensi
yang diberikan, hal ini menunjukkan bahwa diabetes tipe 2 bersifat
progresif