SMF PENYAKIT DALAM

RS ABDUL MOELOEK
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 Islet-Cell Dysfunction
Glucagon
(alpha cell)

Pancreas

Insulin Insulin
(beta cell) resistance
Hepatic
glucose
Glucose uptake
output
Hyperglycemia

Liver Muscle Liver

Adipose
tissue

1. Kahn CR et al. In: Joslins Diabetes Mellitus. 14th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005:145168.

Glucose-
Ingesti Peripheral
dependent
Insulin from
on of glucose
food beta cells uptake
Pancreas (GLP-1 and
Release of
GI GIP) Blood glucose
active incretins
Beta cells in fasting and
tract GLP-1 and GIP Alpha cells postprandial
DPP-4 Glucose- states
enzym dependent Hepatic
e Glucagon
Inactive Inactive
from alpha glucose
GLP-1 GIP
cells production
(GLP-1) by the intestine throughout the day;
Incretin hormones GLP-1 and GIP are released
their levels increase in response to a meal.

DPP-4=dipeptidyl peptidase-4; GI=gastrointestinal; GIP=glucose-dependent insulinotropic polypeptide; GLP-1=glucagon-like peptide-1.

1. Drucker DJ. Diabetes Care. 2003;26(10):29292940. 2. Brubaker PL et al. Endocrinology. 2004;145(6):26532659. 3. Zander M et al. Lancet. 2002;359(9309):824930. 4. Ahrn B. Curr Diab
Rep. 2003;3(5):365372. 5. Buse JB et al. In: Williams Textbook of Endocrinology, 11th ed. Saunders; 2008:13291389.
 Progression of Type 2 Diabetes Mellitus

Insulin resistance
Hepatic glucose
production
Insulin level
Beta-cell function
47 years Postprandial
glucose
Fasting plasma
glucose

Development of Microvascular Complications

Development of Macrovascular Complications
Impaired Glucose Frank Diabetes
Tolerance Diabetes Diagnosis
aConceptual representation.

1. Reproduced with permission of Elsevier from Ramlo-Halsted et al. Primary Care. 1999; 26(4):771789.
 Type 1 DM
Lack of Insulin production
Destruction of pancreatic -Cell
Type 2 DM
Impaired sensitivity to insulin (insulin resistance)
Delayed or inadequate insulin release

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 Insulin Insulin Macrovascular
sensitivity secretion disease
30% 50% DM 50%
tipe 2

50% IGT
70-100% 40%
Impaired
glucose 10%
70% 150%
metabolism
Normal glucose
100% 100%
metabolism
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Cause dysfuction and failure of various organs

1. Eyes
2. Kidneys
3. Nerves
4. Heart
5. Blood vessels

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Diabetes Mellitus is a group of metabolic
disease characterized by hyperglycemia
resulting from defects in :

1. Insulin action (insulin resistance)

2. Insulin secretion
3. Or both

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Suatu sindrome metabolik yang disebabkan
oleh :
Resistensi Insulin (terutama penderita gemuk)
Defisiensi Insulin (pada berat badan normal atau
kurang)
Atau keduanya

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 Range from predominantly insulinresistance
with relative insulin deficiency to an insulin
secretory defect with insulin resistance

Keterangan diatas menunjukan bahwa

secara etiologik DM tipe 2 ada 2 penyebab
yaitu
Resistensi insulin dan
Defek sekresi insulin

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 HATI GLUKOSA SEL

Produksi Glukosa Defek Reseptor

Meningkat dan Postreseptor
PANKREAS

Sekresi berkurang

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1. Peripheral Insulin Resistance in muscle and
fat
2. Impaired pancreatic Insulin Secretion
3. Increased Hepatic Glucose Production

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 Jumlah insulin bisa normal atau malah lebih
akan tetapi reseptor insulin pada
permukaan sel yang kurang, sehingga
glukosa juga tidak dapat masuk kedalam
sel
Akibatnya glukosa darah juga meningkat
disamping insulin yang juga meningkat
dikenal dengan istilah resistensi Insulin.

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1. DEFECT INSULIN SECRETION
2. INSULIN RESISTANCE
 Insulin resistance

Insulin secretion

Onset Diabetes
The onset of diabetes occurs only after a significant decline in cell function
Appropriate therapy for type 2 DM must be taken into account both mechanism
of pathogenesis insulin deficiency and insulin resistance UKPDS
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 DM tipe 2 adalah suatu kondisi yang
heterogenus jadi mekanisme kausal tidak
satu
Ditandai sejumlah abnormalitas metabolik
Meliputi gagal fungsi sel Beta dan resistensi
insulin diotot, jaringan lemak dan hati dan
ini berlanjut menjadi hiperglikemia kronis

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 Insulin resisten menyebabkan gangguan
uptake glukosa di jaringan perifer dan
overproduksi glukosa oleh hati
Pada phase awal terjadi hiperinsulin akan
tetapi belum ada hiperglikemia
Pada tahap berikutnya gagal mekanisme
kompensasi sel Beta maka timbul DM tipe 2

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 Sel beta berkurang sampai 50-60%
Jumlah sel alfa meningkat
Jaringan amiloid pada sel beta bertambah
disebut amilin

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Beberapa hal dianggap sebagai penyebab :
Deposit amylin-amyloid di sel beta
Glukosatoksisitas
Lipotoksisitas

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 Changes insulin production
- insulin production reduces and
proinsulin
secretion increased in circulation
Changes B cell response to glucose level as
a result of glucose toxicity
- GLUT 2, phosphorilation process
(hexokinase and glucokinase)

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 Ca 2+ Voltage Dependent
ATP Sensitive
Ca2+ Channel
K+ channel depolarisation
Islet Cell
Open
Closed
Ca2+
ATP
ADP
Glucokinase
Proinsulin
Glucose
mtch
Metabolism
Insulin
Am.acid
C-peptide
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 Insulin resistance is defined as an impaired
biological response to insulin
Insulin resistance is primary defect in type 2
diabetes
In non-diabetic individuals, insulin
resistance in combination with
hyperinsulinemia has a strong predictive
value for the future development of type 2
diabetes

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 Insulin resistance in muscle
- GLUT 4 , glycogen synthetase
Insulin resistance in liver
- GLUT 2 decreased and gluconeogenesis
increased

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Mobilization of GLUT-4 from Intracellular Store to Cell Surface

Intracellular
Insulin Plasma membrane
pool
receptor

Intracellular signaling
Insulin
cascades

GLUT-4
vesicles
glucose glucose

Integration into plasma membrane

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Insulin resistance
Insulin Glucose

Translocation
Insulin
receptor
X

X Synthesis GLUT 4
PPARg +RXR mRNA

PPRE transcription
promoter Coding reg
Muscle
Cells

Modified from Howard L. Foyt et al. Thiazolidinediones. Diabetes Mellitus: a Fundamental and Clinical Text, 2nd Ed.
AVANDIA reduce insulin resistance
Insulin Glucose

Insulin
receptor

Synthesis GLUT 4
PPARg + RXR mRNA

PPRE transcription
promoter Coding reg
Muscle
Cells

Modified from Howard L. Foyt et al. Thiazolidinediones. Diabetes Mellitus: a Fundamental and Clinical Text, 2nd Ed.
 Penyebab pasti belum diketahui
Ada faktor yang berperan :
1. Obesitas sentral
2. Diet tinggi lemak rendah KH
3. Kurang gerak badan
4. Herediter ( keturunan )

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 Obesity Aging Drugs Exercise
Genetics Others

INSULIN RESISTANCE

PCOS

Type-2 DM Atheroschlerosis
Hypertension Dyslipidemia

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 cell dysfunction and insulin resistance

Cell Insulin signalling

dysfunction defect

Loss of early phase

Insulin release
Insulin resistance

Postprandial Increased basal

Glucose spikes glucose levels

glucotoxicity
Hyperglycaemia
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 Sulfonylureas Acarbose
Repaglinide Miglitol

PANCREAS GUT

Insulin Deficiency CHO Metabolism

HYPERGLYCEMIA
Insulin
HGP Resistance

LIVER MUSCLE

Glitazone
Metformin smf p dalam
1. FASTING HYPERGLYCEMIA
2. POSTPRANDIAL HYPERGLYCEMIA
 Mekanisme kerja :
1. Merangsang pelepasan insulin yang
tersimpan
2. Menurunkan ambang sekresi insulin
3. Meningkatkan sekresi insulin sebagai akibat
rangsangan glukosa

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 Yang masih beredar metformin :
Memperbaiki tingkat seluler (reseptor) dan
menurunkan produksi glukosa hati
Juga meningkatkan pemakaian glukosa
diusus
Disangka juga mnurunkan serapan glukosa
diusus setelah makan

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 Improving peripheral sensitivity to insulin
Reducing gastrointestinal glucose
absorption
Reducing hepatic glucose production
Not stimulate insulin secretion
Not cause hypoglycemia

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 Kombinasi rasional
SU/Gliben
clamide Metformin

Restores phase Counters IR HGP

Insulin release and glucose uptake

PPG FPG

HbA1c

Microangiopathy
Macroangiopathy
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 HbA1c Goa
6.5% a

HbA1c 6.5%7.5% b HbA1c 7.6%9.0% HbA1c >9.0%

Drug Naive Under Treatment

Symptoms No Symptoms

Monotherapy Dual Therapy l

MET c DPP-4 d GLP-1 TZD e AGI f GLP-1 or DPP-4
d GLP-1
g or TZD e or DPP-4 d SU j
23 Months MET + INSULIN INSULIN
Other MET + TZD e Other
Dual Therapy SU or Glinide h,i Agent(s) k Agent(s) k
d g GLP-1
GLP-1 or DPP-4
23 Months TZD e
or DPP-4 d
MET + TZD e
Triple Therapy m
Glinide or SU h

TZD + GLP-1 or DPP-4 d GLP-1

+ TZDe a May not be appropriate for all patients
or DPP-4 d b For patients with diabetes and HbA1c <6.5%, pharmacologic Rx may be
Colesevelam considered
MET + MET + GLP-1 c Preferred initial agent
f
AGI
or DPP-4 d d DPP-4 if PPG and FPG or GLP-1 if PPG
g + SU j e TZD if metabolic syndrome and/or NAFLD
23 Months AGI if PPG
TZD e f
g If HbA1c goal not achieved safely
Triple Therapy
g h Low-dose secretagogue recommended
23 Months Glinide if PPG or SU if FPG
MET + TZD e i
j Decrease secretagogue by 50% when added to GLP-1 or DPP-4
GLP-1 or +
k a) Discontinue insulin secretagogue with multidose insulin
DPP-4 d Glinide or SU i,j b) Can use pramlintide with prandial insulin
INSULIN
23 Months
g Other Agent(s) k l If HbA1c <8.5%, combination Rx with agents that cause hypoglycemia
should be used with caution
m If HbA1c >8.5%, in patients on dual therapy, insulin should be
INSULIN considered
Other Agent(s) k

AACE=American Association of Clinical Endocrinologists; ACE=American College of Endocrinology; AGI=-glucosidase inhibitor;

DPP-4=dipeptidyl peptidase-4; FPG=fasting plasma glucose; GLP-1=glucagon-like peptide-1; MET=metformin;
NAFLD=nonalcoholic fatty liver disease; PPG=postprandial glucose; SU=sulfonylurea; TZD=thiazolidinedione.
1. Reproduced with permission of American Association of Clinical Endocrinologists from Rodbard HW et al. Endocr Pract. 2009;15(6):540559.