ROLE OF INCRETIN IN GLUCOSE HOMEOSTASIS

L i n
Focus :
a g l i
DIABETES MELLITUSp t i n
A Novel DPP IV inhibitor in
Clinical Practice

Dr. M a h a t m a SpPD
F.Kedokteran UMS
SURAKARTA

STANDING TOGETHER AGAINST DIABETES

Seminar/ pelatihan D M
Singapura Diabetes Up Date 2007
Japan : Diabetes Course 2008
Berlin, Jerman, EASD 2012
Chicago, USA ADA 2013
Singapure, Diabetes Up Date 2014
San Fransisco, USA ADA 2014
Endocrine/ Perkeni Indonesia
 OUTLINE
Pendahuluan
Anatomi, fisiologi, histologi, biokimia,
biomolekuler
Definisi, klasifikasi
Patofisiologi
Gejala, diagnosa
A1c
Penatalaksanaan
Komplikasi
 Urgent need for Action
Total Prevalence DM =
5,7%
1,5 Diagnosed
% patients
IGT = 10,2
%
(MDGs
Pre: 4,2% Undiagnosed
patients
DiabetesKIA
)
AIDS

TB
International Diabetes Federation. IDF Homepage. International Diabetes Federation 2011.
Available from: http://www.idf.org/.
 Jumlah Pengidap Diabetes
di Dunia 1995 - 2025
PA N D E M I
350 122%
Jumlah pengidap diabetes dewasa

300 1995 170%

2000
250 2025
200
41%
150
100
50 Negara Negara Dunia
0 maju berkembang
Wild S, et al. Diabetes Care 2004;27(5):10471053.
 Every 10 seconds... Two people develop
Diabetes
The number of patients with diabetes worldwide is expected to increase
from 366 million in 2011 to 552 million in 2030
Number of patients, millions 2011 2030

North South and Europe Indonesia India China RoW

America Central
and America
Caribbean

International Diabetes Federation. IDF Homepage. International Diabetes Federation 2011. Available from: http://www.idf.org/. 6
 In developing countries
Diabetes will affect people aged 4565 years

Developed Countries Developing Countries

Estimated number of people with diabetes
(millions)

2000 2030
Wild S, et al. Diabetes Care 2004;27(5):10471053.
 Type 2 diabetes is associated with
serious complications

Stroke
Diabetic 2- to 4-fold increase in
Retinopathy cardiovascular mortality
and stroke5
Leading cause
of blindness
in adults1,2 Cardiovascular
Disease
8/10 individuals with
diabetes die from
Diabetic CV events6
Nephropathy
Diabetic
Leading cause of Neuropathy
end-stage
Leading cause of
renal disease3,4 non-traumatic lower
extremity amputations7,8
1
UK Prospective Diabetes Study Group. Diabetes Res 1990; 13:111. 2Fong DS, et al. Diabetes Care 2003; 26 (Suppl. 1):S99S102. 3The Hypertension in Diabetes Study
Group. J Hypertens 1993; 11:309317. 4Molitch ME, et al. Diabetes Care 2003; 26 (Suppl. 1):S94S98. 5Kannel WB, et al. Am Heart J 1990; 120:672676.
6
Gray RP & Yudkin JS. Cardiovascular disease in diabetes mellitus. In Textbook of Diabetes 2nd Edition, 1997. Blackwell Sciences. 7Kings Fund. Counting the cost. The real im
 OUTLINE
Pendahuluan
Anatomi, fisiologi, histologi, biokimia,
biomolekuler
Definisi, klasifikasi
Patofisiologi
Gejala, diagnosa
A1c
Penatalaksanaan
Komplikasi
 PROINSULIN

C-PEPTIDE
INSULIN
EAGLE FLIES ALONE, MHT
 Fisiologi

Distribusi Glukosa ke Jaringan

INS

INS

INS
INS

NO INSULIN
 Overview of Carbohydrate metabolism Biokimi
a

INS

INS INS INS

INS
INS
INS INS

INS

EAGLE FLIES ALONE, MHT

 Bio Molekuler
Insulin Glucose
transloca
tion
Insulin
receptor

Synthesis GLUT 4
PPAR mRNA
RXR

PPRE transcription
promoter Coding reg

EAGLE FLIES ALONE, MHT

 OUTLINE
Pendahuluan
Anatomi, fisiologi, histologi, biokimia,
biomolekuler
Definisi, klasifikasi
Patofisiologi
Gejala, diagnosa
A1c
Penatalaksanaan
Komplikasi
 Definisi
Apakah Diabetes itu ?
Faktor
Faktor Lingkungan/
keturunan Cara hidup Gaya hidup
berisiko:
Makan
berlebihan
Kurang sport
Insulin kurang jumlahnya
Stres
Insulin kurang baik kerjanya

Genetik
DIABETES = penyakit dengan Virus
kadar gula (glukosa) darah meningkat Bakteri
Bahan Toksik
Nutrisi
Insulin = Hormon pengatur kadar glukosa darah yang dikeluarkan oleh pankreas
 Klasifikasi
Destruksi sel beta, umumnya menjurus ke defisiensi
insulin absolut
Tipe 1 Autoimun
Idiopatik

Tipe 2
Mulai resistensi insulin
disertai defisiensi insulin
Defek genetik fungsi sel beta
Defek genetik kerja insulin
Tipe Lain
Penyakit eksokrin pankreas
Endokrinopati
Karena obat/zat kimia
Infeksi
Sebab imunologi yang jarang
Sindrom genetik lain yang berkaitan
dengan DM
Gestasional
 OUTLINE
Pendahuluan
Anatomi, fisiologi, histologi, biokimia,
biomolekuler
Definisi, klasifikasi
Patofisiologi
Gejala, diagnosa
A1c
Penatalaksanaan
Komplikasi
 IV
glycemic disorders
( Prediabetes )
<< HDL , >> LDL
Hypertriglyceridemia
Insulin resistance Hypertension
Endothel Disfunction V
III Hiperuricemia
Microalbuminuria
inflammation (hsCRP)
Impaired thrombolysis
PAI-1

DIABETES
II MELLITUS
HIPERTENSI VI
P C O S dan NAFLD
HIPERURICEMIA
DISLIPIDEMIA
ATHEROSCLEROSIS
Central Obesity ACANTHOSIS NIGRICANS

JARANG OLAHRAGA
PENUAAN
OBAT OBATAN I STROKE CHD
VII
SEBAB LAIN
 patofisiologi
Insulin deficiency

Hyperinsulinemia
to compensate for insulin
resistance1,2

Glucotoxicity2 Lipotoxicity3

Amyloid

deposit High circulating free

Chronic Pancreas
fatty acids
hyperglycemia

Lipolysis
HGP

Uptake Insulin resistance TNF

SlametS
 OUTLINE
Pendahuluan
Anatomi, fisiologi, histologi, biokimia,
biomolekuler
Definisi, klasifikasi
Patofisiologi
Gejala, diagnosa
A1c
Penatalaksanaan
Komplikasi
 Gejala

Klini
s
poliuria poliphagia polidipsia
(sering kencing)(cepat lapar) (sering haus) Cepat Lelah Berat badan
turun

Luka pada kesemutan mata kabur impotensia gatal-gatal

Kaki Sukar
Sembuh
 Review Diagnosis

23 May 2017 PLEASE INSERT Presentation title 22

T T G O : 75 g Anhydrous Glucose in Water
 MASALAH DIAGNOSA

Komplikasi
CardioMetabolik +++
DM
Rata rata Px DM
terdiagnosa
PREDIABETIK

8 6 4 2 0 2 4 6 10

EAGLE FLIES ALONE, MHT

 OUTLINE
Pendahuluan
Anatomi, fisiologi, histologi, biokimia,
biomolekuler
Definisi, klasifikasi
Patofisiologi
Gejala, diagnosa
A1c
Penatalaksanaan
Komplikasi
Januari, 27 Februari,27 Maret, 27 April, 27

Blood Glucose
HbA1c mg/dl

200

8%

160
7%
130
6%
100
On target = 7%
 Lowering HbA1c
Reduces The risk of complications

21% Deaths related

Base on treatment target to diabetes

HbA1c

Microvascular
37% complications
1%

14% Myocardial
infarction

Insulin : 1,5 - 3.5%

Stratton IM, et al. BMJ . 2000; 321:405412

 Expected HbA1c reduction according to intervention

Intervention Expected in HbA1c (%)

Lifestyle interventions 1 to 2%
Metformin 1 to 2%
Sulfonylureas 1 to 2%
Insulin 1,5 to 3.5%
Glinides 1 to 1.5%1
Thiazolidinediones 0.5 to 1.4%
-Glucosidase inhibitors 0.5 to 0.8%
GLP-1 agonist 0.5 to 1.0%
Pramlintide 0.5 to 1.0%
1. Repaglinide is more effective than nateglinide
DPP-IV
Adapted from Nathan DM, inhibitors
et al. Diabetes Care 2009;32:193-203. 0.5 to 1.2%
 Majority of patients with type 2
diabetes remain far above glycaemic
goals

10.0 10.2% have HbA1c > 10

9.0 10.4% have HbA1c 9

8.0 37.2% have

HbA1c 8%3
57.8% of patients
ADA/EASD target (< 7%)4
with type 2 7.0
diabetes Japan target (< 6.9%)5
have HbA1c > Korea target ( 6.5%)6
7.0%1* AACE/ACE target ( 6.5%)7
6.0
China target (< 6, 7%)4

HbA 1c
AACE, American Association of Clinical Endocrinologists; ACE, American College of Endocrinology; ADA, American Diabetes
Association.
1. Dodd AH, et al. Curr Med Res Opin. 2000;291:16051613; 2. Oluwatowoju I, et al. Diabet Med. 2010;27:354359; 3. Sydah SH, et
al. JAMA. 2004;291:335342; 4. Inzucchi SE et al; Diabetes Care (2012), 35 (6), 1364-1379 5. JDS Guidelines 2011.
Two thirds of individuals do Are We Reaching
not achieve target HbA1c HbA1c Target?

HbA1c <6.5% 7.0% <7.0% <7.0% <7.0%

Target Europe1 Canada2 United Latin Asia4
States3 America4

Saydah SH, et al. JAMA 2004; 291:335342., Liebl A, et al.

 OUTLINE
Pendahuluan
Anatomi, fisiologi, histologi, biokimia,
biomolekuler
Definisi, klasifikasi
Patofisiologi
Gejala, diagnosa
A1c
Penatalaksanaan
Komplikasi
 Penatalaksanaan
Treatment :
stepwise approach
( dulu )
+
+ 5
Insulin
+ 4 Combination
3 oral
3 Combination of
2 oral medicines
2 One oral
medicine
Education
1 Exercise
Diet
 The New Paradigm of Diabetes Treatment
Aggressive Treatment :
Driven by Target A1C < 7 %
Early Insulinisation :
Treat
Combination Oral insulin

to A1C < 7 %
Target

At diagnosis of type 2 diabetes & Current management

50% of patients already have complications1

< 50% of -cell function has already been lost2

2/3 of patients do not achieve target HbA1c3,4

The majority of patients require polypharmacy to meet glycaemic goals across time5
1. UKPDS Group. Diabetologia. 1991;34:877890; 2. Holman RR. Diabetes Res Clin Prac. 1998;40:S21S25;
Stages of Diabetes in Relationship to -cell Function

Diabetes is a progressive Disease Aggressive Treatment

Insulin
 ADA/EASD consensus algorithm
Tier 1: Call to action if HbA1c is 7%
well-validated therapies
Lifestyle + Metformin Lifestyle + Metformin
+ Basal insulin + Basal Insulin
At diagnosis: + Intensive insulin
Lifestyle +
Metformin
Lifestyle + Metformin
+ Sulfonylurea

STEP 1 STEP 2 STEP 3

Tier 2:
Less well validated Lifestyle + Metformin
therapies + Pioglitazone Lifestyle + Metformin
No hypoglycaemia + Pioglitazone
Oedema/CHF + Basal Insulin
Bone loss

Lifestyle + metformin
+ GLP-1 agonist / Lifestyle + metformin
DPP4 Inhibitors + DPP4 Inhibitors
No hypoglycaemia + Basal insulin
Weight loss
Nathan DM, et al. Diabetes Care 2009;32Nausea/vomiting
193-203.
 HbA1c Level
<7% 7-8% 8-9% 9-10% 9-10% >10%
Lifestyle Lifestyle
Modification Modification
Lifestyle
PERKENI
+
Monotherapy
Modification Consensus 2011
Met, SU, AGI, + Lifestyle
Glinid, TZD, 2 OADs Modification
DPP-IV Combination

Met, SU, AGI,

+
3 OADs
Glinid, TZD, Combination
Lifestyle
DPP-IV Modification
Met, SU, AGI,
Glinid, TZD, +
DPP-IV 2 OADs
Combination

Met, SU, AGI,

Glinid, TZD,
DPP-IV Lifestyle
Notes :
Fail : not achieving A1c target < 7% + Modification
after 2-3 months of treatment.
(A1c = average blood glucose Basal +
conversion, ADA 2010) Insulin
Intensive
Insulin
 THERAPEUTIC OPTIONS & SITES OF ACTION
LIVER ADIPOSE TISSUE & MUSCLE

Introduction
or
Liver Skeletal Muscle Medications
Adipose Tissue FDA
Decreased Glucose Increased approval
PERIPHERAL
Decreased Lipolysis
GLUCOSEProduction
PRODUCTION GLUCOSEGlucose
UPTAKE Uptake
Insulin 1921
Biguanides Thiazolidinediones Inhaled insulin 2007
Thiazolidinediones (Biguanides) Sulfonylureas 1946
Biguanides 1957
INTESTINE PANCREAS
Glycosidase inhibitors 1995
TZDs Troglitazone 1997
Pancreatic Beta Cells Pioglitazone 1999
Small Intestine Increased Insulin Rosiglitazone 1999
GLUCOSE INSULIN Secretion
Secretion
Inhibition Glucose Meglitinides 1997
ABSORPTION Sulfonylureas
Absorption
Meglitinides GLP analogues 2006
alpha-glucosidase
inhibitors Insulin Amylin analogues 2005
Amylin DPP - IV inhibitors 2008

Intestine Cells INTESTINAL HORMONES

Increased Incretine Incretin
Secretion
 Intervensi Farmakologik
(1)
Obat Hipoglikemik Oral
Pemicu Meningkatkan sekresi insulin oleh sel beta Sulfonilurea
Sekresi Insulin Pilihan utama untuk pasien dengan BB Glinid
normal/kurang namun masih boleh diberikan
untuk BB lebih
Penambah Menurunkan resistensi insulin dengan Tiazolidindion
meningkatkan jumlah orotein pengangkut (Rosiglitazon,
sensitivitas glukosa shg meningkatkan pengambilan glukosa pioglitazon)
insulin perifer
Kontra indikasi pada pasien gagal jantung
TZD tidak digunakan sebagai obat tunggal
Penghambat Menurunkan glukoneogenesis disamping Metformin
memperbaiki ambilan glukisa perifer
Glukoneogene
sis Penggunaan terutama pada orang gemuk
Kontra indikasi pada pasien dengan gangguan fs
ginjal (kreatinin serum > 1.5)
Penghambat Mengurangi absorbsi glukosa di usus halus shg Acarbose
mempunyai efek menurunkan kadar glukosa
Glukosidase darah setelah makan
alpha Tidak menimbulkan efek samping hipoglikemi EAGLE FLIES ALONE, MHT
 Mekanisme Kerja, Efek samping
utama dan pengaruh terhadap
penurunan
Cara Kerja A1c
Efek Samping Penurunan A1c
Utama Utama
Sulfonilure Meningkatkan sekresi BB naik, hipoglikemi 1.5 2 %
insulin
a
Glinid Meningkatkan sekresi BB naik, hipoglikemi
insulin

Metformin Menekan prod glukosa Diare, dispepsis, asidosis 1.5 2 %

& menambah laktat
sensitivitas thd insulin

Penghamb Menghambat absorbsi Flatulens, tinja lembek 0.5 1 %

glukosa
at alpha
glukosidas
e
TZD menambah sensitivitas Edema 1.3%
thd insulin

Insulin Menekan prod glukosa BB naik, hipoglikemi Potensial sampai

hati, stimulasi normal
pemanfaatan glukosa EAGLE FLIES ALONE, MHT
 Benefits and Limitations of T2DM Treatment Options
DPP-4 Sulfo GLP-1
inhibit nilure Biguanid Glini analog
or a e de TZD AGI ues Insulin
Neutr
Neutral ++ ++ + ++ Neutral +++
FPG al
PPG +++ ++ + +++ + +++ +++ +++
Level of Risk
Moderat
Modera Neutr
Hypoglyca Neutral Neutral Mild Neutral
te al
Neutral
e to
emia severe
Mild to
Neutr Benefi
Weight Neutral Mild Benefit Mild Moderate Moderat
al t
gain e
Contrain Contrain
Neutra Neutr Neutr
Neutral dicated dicated Neutral Neutral
l al al
CV event in CHF in CHF
Drug-
Limitations Oral Antidiabetic Agents :
drug Modera Mode Neutr
Neutral te
Limited Efficacy
Neutral - Neutral
Weight gain Neutral Neutral
interactio rate al
n Hypoglycaemia - Non-adherence

1. Liebl A, et al. Diabetologia. 2002;45:S23-S28;

SULFONILUREA Generasi 1 Generasi 2 Generasi 3
Paling banyak digunakan Glimepiride
dalam praktek
(Generasi 3)
Potensi ekstra pankreas
Memacu sekresi insulin
Memperbaiki Glucose > efektif
Clearance Kerja cepat & tahan lama
Memperbaiki profil lipid
Dosis kecil
BB Normal
Mencegah angiopati
Glukosa darah puasa
140 mg/dl membersihkan
Diit, OR biguanid gagal radikal bebas
Belum butuh Insulin Memperbaiki
Mulai dosis kecil tunggal fungsi trombosit
dosis Memacu
terbagi/berulang
fibrinolisis
Ditelan 30 mnt AC
 MEKANISME KERJA SULFONILUREA

K - ATP Channel Berikatan

dengan
glimipirid K+ Ca++ reseptor 65
e kDa
SU lain140 65 kDa
Depolarisasi
+ Pengeluaran K
kDa dihambat
reseptor SU
_

Sel beta pankreas

K+ + Depolarisasi
[Ca++]i
Metabolism

Saluran Ca++
cAMP
Glukosa [ATP] +
terbuka
&
[ADP] ADP
Asam Amino

[Ca++] intrasel
Pro-insulin meningkat

Sekresi Insulin Sekresi insulin

 Farmakokinetik dari
Bermacam-macam Sulfonilurea

Waktu Jangka Dosis/

Obat Paruh Waktu hari Tablet/ Metabolit
( Jam ) Kerja ( mg ) hari Aktif
( Jam )
ACETOHEXAMIDE 0.8 - 2.4 12 - 18 250 - 1500 2 -

CHLORPROPAMIDE 24 - 48 24 - 72 100 - 500 1 -

GLICLAZIDE 6 - 15 10 - 15 40 - 320 1-2 -

GLIPIZIDE 1-5 14 - 16 2.5 - 20 1-2 -

GLIBURIDE 2-4 20 - 24 2.5 - 20 1-2 -

TOLBUTAMIDE 3 - 28 6 - 10 500 - 3000 2-3 -

TOLAZAMIDE 4-7 16 - 24 100 - 1000 1-2 -

 Combination
Cardioprotective

Ischemic Preconditioning
IP adalah suatu mekanisme
(IP) endogen jantung untuk
melindungi dirinya dari
suatu kejadian iskemik
yang mematikan (parah)

IP : kanal/saluran KATP
di
jantung terbuka
Oklusi/hambatan Oklusi/hambatan yang
secara otomatis
yang singkat dan berulang- menyusul kejadian iskemik
berkepanjangan ulang pada pembuluh miokard yang singkat
pada arteri darah yang sama
epicardial akan menyusul oklusi yang
menyebabkan berkepanjangan akan Obat-obatan yang
infark miokard menghasilkan luas infark
yang lebih kecil menghambat terbukanya
KATP di jantung dapat
(ischemic
preconditioning) membahayakan kondisi
iskemik miokard
 Metformin

Improved Reduced
Insulin sensitivity Hypertriglyceridaemia
Fibrinolysis AGE formation
Nutritive capillary flow Cross-linked fibrin
Haemorrheology Neovascularisation
Postischaemic flow Oxidative stress

Reduced cardiovascular risk

AGE : advanced glycation end-products

Vascular benefits of metformin

 AMPK 51 1 INSULIN RESISTANCE 2 1 h PP ( PmH)
-Endorphin 50 3 FPG
ADMA 49 4 VAT

Apn 48 5 WC

Resistin 47 6 Glucose Absorption

Leptin 46 56 FOXO1/ FABP4 7 Glycogenesis
NFKB 45 8 Insulin Rec. Binding
Cytosolic Ca++ 44 9 GUT : GLUT-5 Expression
SMC Fibroblast 43 10 Post-Receptor Effect
Plaque Regression 42 11 Glucolipotoxicity
NO ( HSP-90, eNOS) 41 METFORMIN 12 Oxidative Stress
Capillary Permeability 40 MIRACLE 13 Inflammation
MMP-9 39 14 FFA
Peripheral A. Blood Flow 38 15TG, HDL-C, Tot-C, LDL-C
56
PTEN 37 16 Synthesis & Secretion of GLP-1
EFFECTS
HT-29 36 17 AGE
LNCaP 35 18 Fibrinogen
PC-3 34 19 Factor-VII (TF)
DU 145 33 20 PAI-1
cyclin D1 32 21 Factor-XVIIIA
TSC2 31 22 TSH
TSC1 30 23 Respiratory Complexl
mTORC1 29 24 Erythrocyte Deformability
LBK1 28 25 Platelet Aggregation
p53 27 26 Hyperinsulinemia

FIGURE-4 MET with 56

Metabolic-Cardiovascular-Carner (MMC) Protective Effects

(MMC : Metabolic Cardiovascular Cancer protector IIIustrated : Tjokroprawiro 1994-2011

 What are incretins? INtestine seCRETion INsulin

Ileum Duodenum -
Colon Jejunum

Hormones produced by the gastrointestinal tract in response to

incoming nutrients, and have important actions that contribute
to glucose homeostasis.
Two hormones:
- Gastric inhibitory polypeptide / Glucose dependent
Insulinotropic polypeptide(GIP)
- Glucagon-like
Published peptide-1 (GLP-1).
by American Osteopathic Association

Freeman J. J Am Osteopath Assoc 2007;107:S6-S9

 ROLE OF INCRETINS IN GLUCOSE HOMEOSTASIS

Ingestion of food
Pancreas2,3
Glucose-dependent
Insulin from beta cells Glucose
Release of gut uptake by
(GLP-1 and GIP) muscles
hormones :
Incretins
Beta cells
Active Alpha cells
Ileum, Colon :GLP-1
Glucose
Duodenum, Jejunum :GIP
production
Glucose dependent by liver
DPP-4 Glucagon from
enzyme alpha cells
(GLP-1)
Inactive Inactive
GLP-1 GIP

DPP-4 = dipeptidyl-peptidase 4
Sources :1. Kieffer TJ, Habener JF. Endocr Rev. 1999;20:876913. 2. Ahrn B. Curr Diab Rep. 2003;2:365372.
3. Drucker DJ. Diabetes Care. 2003;26:29292940. 4. Holst JJ. Diabetes Metab Res Rev. 2002;18:430441.
GLP-1 has wide-ranging biological activity

Glucose uptake
Glucose storage

23 May 2017 PLEASE INSERT Presentation title 50

Freeman J. J Am Osteopath Assoc 2007;107:S6-S9
 Actions of GLP-1 & GIP
The Problem
Unfortunately, GLP- 1 is rapidly broken down
By the DPP- IV enzyme ( Very short half-life in plasma )

Duodenum -
Jejunum

Ileum
Colon
Seino Y et al.B.
Zinman J Diabetes
Am Invest 2010: 1:
J Med 8-23
2011; 124 (1 Suppl): S19-S34
Actions of GLP-1 & GIP
The Problem
Unfortunately, GLP- 1 is rapidly broken down By the DPP- IV enzyme
( Very short half-life in plasma )
 The solution
Two options:
Incretin mimetics are glucagon-like peptide-1 (GLP-1) analogues/ agonist :

- Exenatide, Exenatide once weekly , Liraglutide, Taspoglutide, Albiglutide, Lixinatide

Dipeptidyl peptidase-IV (DPP-IV) inhibitors :
- Sitagliptin, Saxagliptin, Vildagliptin, Alogliptin, Linagliptin
- Exenatide - Liraglutide
- Taspoglutide - Albiglutide

DPP-4
- Sita GLIPTIN - Saxa GLIPTIN
- Vilda GLIPTIN - Alo GLIPTIN
Lina GLIPTIN
 OUTLINE
Pendahuluan
Anatomi, fisiologi, histologi, biokimia,
biomolekuler
Definisi, klasifikasi
Patofisiologi
Gejala, diagnosa
A1c
Penatalaksanaan
Komplikasi
 Komplikas
KOMPLIKASI DIABETES MELLITUS i
Akut : Kronik :

- Hipoglikemia - Mikroangiopati :
- Koma Asidosis Dia- - Nefropati D M
betika - Retinopati DM
- Hiperosmoler Non - Kardiomiopati DM
Ketotik - Neuropati DM
- Koma Laktat Asi- - Makroangiopati :
dosis - PJK + hipertensi
- CVA
- Ulkus/ ganggren
- Neuropati DM
- Rentan Infeksi :
- TB Pulmo, dll.
 KOMPLIKASI AKUT DM

LIFE THREATENING METABOLIC DISORDERS

(KEGAWATAN)

HIPERGLIKEMI HIPOGLIKEMI

Edema cerebri
Kerusakan SSP
KETOASIDOSIS LAKTOASIDOSIS HIPEROSMOLER

Kontraktilitas miokard Syok hipovolemi

Cardiac output Trombo-emboli
Tensi
Perfusi ke organ2
Respons vaskuler thd katekolamin
Syok hipovolemi
 Poliuri, Polidipsi Diagnosis laborat
Nausea, Vomitus Hiperglikemi berat
Kulit & Mukosa kering Glukosuri berat
Ketonuri berat
Nafas kuszmaul
pH darah
Dehidrasi syok PO O2
Lemah, Depresi, Kejang Tekanan osmose plasma
Kesadaran koma
50% i.v m
0.3 0.4 unit/KgBB gra
pr o
50% s.c ri
I A
S sd a
N
LA dosi
Banyak diminati
efek terapi cepat
Continous komplikasi minimal
Hipoglikemi

infusion Hipokalemi

0.1 u/kgBB/jam me insulin plasma memenuhi

(100 200 u/mL) kapasitas maksimal
reseptor insulin
 KALIUM Indikasi
K+ < 5.5 mEq/L

KCL ( 2/3 )
Preparat
KPO4 ( 1/3 )

BIKARBONAT Indikasi
pH < 7,1 (darah arteri)
HCO3 < 5.0 mEq/L
K+ > 6.5 mEq/L
Hipotensi respon ( - )
thd pemb. cairan
Payah jantung kiri
Depresi pernafasan

ANTIBIOTIKA Indikasi
infeksi akut
 Data Laboratorium klinik

LABORATORIUM KAD HONK

Glukosa plasma (mg/dl) > 250 > 600
pH < 7.3 > 7.3
HCO3 serum (mEq/L) < 15 > 20
Keton urine 3+ 1+
Keton serum (+) pengenceran 1:2 (-) pada pengenceran 1:2
Osmolalitas serum (mOsm/Kg) Bervariasi 330
Natrium serum (mEq/L) 130 140 145 155
Kalium serum (mEq/L) 56 45
BUN (mg/dl) 18 - 25 20 - 40

Panduan klinik praktis untuk membedakan KAD & HONK

Dengan pengertian sekitar 30% penderita KAD dapat
Tampil dalam kondisi HONK
 Hyperglycemia

AGE formation Glucose auto oxidation Sorbitol pathway

Antioxidants
Oxidative Sress

Lipid peroxidation Endothelial dysfunction Hypercoagulability

Leukocyte adhesion NO Endothelin Fibrinolysis
Foam cell formation Prostacyclin Coagulability
TNF a TXA2 Platelet reactivity

Vascular complications

Retinopathy Nephropathy Neuropathy

SlametS
 Vascular Complications
Diabetes
FPG PPG

Microangiopathy Macroangiopathy

Nephropathy C V D
Retinopathy S N H
Neuropathy
P A D

EAGLE FLIES ALONE, MHT

 When Macrovascular & Microvascular Complication in T2DM?
Saat terdiagnosis Diabetes Mellitus
komplikasi telah terjadi
DIAGNOSIS
350
300 Post-meal
Glucose (mg/dl)

250 glucose Fasting

200 glucose
150
100
50

250 Insulin resistance

200
150 Insulin
level
Relative -cell

100
function (%)

50 -cell failure
0
Obesity IGT Diabetes Uncontrolled hyperglycaemia

Predia Type 2 diabetes

Clinical Macrovascular complications
betes
features
Microvascular complications
Years -10 -5 0 5 10 15 20 25

Adapted from Type 2 Diabetes BASICS. 62

Minneapolis, Minn: International Diabetes Center; 2000.
 Dasar
Cardioprotective
Reaching glucose goals is important to reduce
complications
Overall, 75%
of people with type 2 diabetes will die

cardiovascular
from

disease 1,2

Gray RP & Yudkin JS. Cardiovascular disease in diabetes mellitus. In Textbook of Diabetes 2nd Edition, 1997. Blackwell
1

Sciences.
63
2
Kannel WB, et al. Am Heart J 1990; 120:672676.
Pro-oxidant effects of glucose
leading to increased CV risks
AGEs Glucose

Glycolysis Autoxidation Glycation Sorbitol

Pathway ?
Reactive intermediates
Mitochondrial resp. chain GSH reduction
Reactive intermediates

NAD(P)H
Oxidase
Generation of reactive
oxygen species
RAGE
ROS

Ca signalling Protein kinase C NFkB

Vascular disease
 Perjalanan nefropati diabetik
Perubahan fungsi
GFR Incipiens Nephropathy
Albuminuria reversible
Hiperfiltrasi
Ginjal membesar
Mikroalbuminuria
Hyperfiltration
Hipertensi

0 2 5 Waktu (tahun) 15 20 25

Awal DM ESRD
ACE Inhibitor
Perubahan struktur Overt nephropathy
Penebalan membrana basalis Makroalbuminuri/ gross prote
Ekspansi mesangium
Hyperperfusion
Kreatinin
120 60 < 10
GFR ml/mnt 150
Serum 1 > 2,0 >5
creat mg/dl 0,8
Penyakit Paling Mahal
 Patofisiolog
y
Mekanisme Rentan Infeksi Pada
DM
Keadaan Nutrisi intra sel berkurang
(malnutrisi, dehidrasi)
Insufisiensi Vaskular
( makro dan mikroangiopati )
Neuropati
Fungsi Leukosit Berkurang
- Penurunan kemampuan Intracelluler Killing PMN, MN
- Defisiensi Komplemen
- Berkurangnya jumlah T- helper
- Disfungsi Makrofag
Disfungsi Makrofag
Penurunan kemampuan Intracelluler Killing PMN, M

Kemotaksis
Perlekatan

Fagositosis
H2O2, spesies oksigen aktif

Intracellular Killing

Eksositosis
Thank You