Husaini Umar
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
80
60
Fungsi pankreas
40
= 50% dari normal
20
0
―10 ―8 ―6 ―4 ―2 0 2 4 6
Waktu (tahun)
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
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
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 (%)
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
11
GLUCOSE HOMEOSTASIS:
three mechanisms
• 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.
GLUT 4 Translocation
Insulin Receptor
Glycogen synthesis,
Protein synthesis
Anti-lipolysis
MAP-K IRS 1,2 PI3K Akt eNOS NO
(Atherogenic) (Antiatherogenic)
PATHOGENESIS OF TYPE 2 DIABETES
Much less in known–multifactorial complex disease.
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 )
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
(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%)
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
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
LIVER
GLYCOGENOLYSIS
-
HGP +
+ GLUCOSE G L UC O S E
GLUCONEO FFA
GENESIS
LIPOLYSIS Lactic Acid
ADIPOSE TISSUE
The progressive nature of type 2 diabetes
Insulin
sensitive
Hyperglycaemia
Normal insulin
secretion Insulin
resistance
Normoglycaemia
β-cell exhaustion
Insulin resistance
Diabetes prevention
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
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
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
• Haemorheological changes:
‒ platelet activation 0
‒ increased viscosity
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