DIABETES MELLITUS

Dr. SUHAEMI, SpPD, FINASIM

Diabetes Mellitus

Suatu Sindroma kelainan metabolik,

ditandai adanya hiperglikemia, akibat
defek sekresi insulin, defek kerja insulin,
atau kombinasi keduanya.
Classification of Diabetes

 Type 1 diabetes
 β-cell destruction
 Type 2 diabetes
 Progressive insulin secretory defect
 Other specific types of diabetes
 Genetic defects in β-cell function, insulin action
 Diseases of the exocrine pancreas
 Drug- or chemical-induced
 Gestational diabetes mellitus

ADA. I. Classification and Diagnosis. Diabetes Care 2011;34(suppl 1):S12.

Diabetes Mellitus :
a group of diseases characterized by high levels of blood glucose resulting from
defects in insulin production, insulin action, or both

 20.8 million in US ( 7% of population)

 estimated 14.6 million diagnosed (only 2/3)
 Consists of 3 types:
1) Type 1 diabetes
2) Type 2 diabetes
3) Gestational diabetes

 Complications :
- Stroke
- Heart attack
- Kidney disease
- Eye Disease
- Nerve Damage
Diabetes Mellitus
 Type 1 Diabetes
- cells that produce insulin are
destroyed
- results in insulin dependence
- commonly detected before 30
 Type 2 Diabetes
- blood glucose levels rise due to
1) Lack of insulin
production
2) Insufficient insulin
action (resistant cells)
- commonly detected after 40
- effects > 90%
- eventually leads to β-cell failure
(resulting in insulin dependence)
Gestational Diabetes
3-5% of pregnant women in the US
develop gestational diabetes
Diabetes Mellitus Type 1
 Results from inability of islet
cells to produce insulin
 Also known as insulin-
dependent or juvenile-onset
diabetes
 Cause is unknown, but likely
to have genetic, autoimmune
component
Diabetes Mellitus Type 2
 Results from decreased
insulin sensitivity and
decreased pancreatic beta-
cell function
Gestational Diabetes
 Diabetes that first presents
during pregnancy
 Occurs in 2-10% of
pregnancies
 30-60% chance of
developing T2DM
Pathophysiology of T1DM

antibodies
attack islets!
1986 NEJM “Stages” in Development of Type1Diabetes
(?Precipitating Event)

Genetic Overt
Predisposition immunologic
abnormalities Progressive
loss insulin
Beta cell mass

release
Normal insulin
release Overt
Glucose diabetes
normal

C-peptide
present
No
C-peptide

Age (years)
Stages Type IA Diabetes

 I Genetic Susceptibility
 II Triggering
 III Active Autoimmunity
 IV Progressive Metabolic Abnormalities
 V Overt Diabetes
 VI Insulin Dependence
 Environment

 Congenital Rubella
 Controversy re Enteroviruses/ other
virus
 Controversy re bovine milk

 Hygiene Hypothesis

 2 JAMA papers re early cereal

Etiology of Autoimmune Diabetes
 Genetic susceptibility
 Lifetime risk in general population: 0.4%
 Up to 50% concordance in monozygotic twins
 Sibling risk: 5%, Father to child risk: 6-12%, Mother to child risk: 4% if <25
years at delivery and 1% if >25 years (Risk doubles if parent/sibling was
younger than 11 at diagnosis.)
 Associated with HLA DR3/DR4 genes

 Environmental trigger
 Incidence more common in fall and winter - viral infection trigger?
 Possibly multiple potential triggers in early infancy: viruses, cows milk, toxins

 Auto-antibodies: 1 or more present in 85-90% at diagnosis:

 GAD 65, islet cell, insulin and tyrosine phosphatases (IA-2 & IA-2B) antibodies
 GAD 65 (glutamic acid decarboxylase) most common: protein found in the beta
cell which shares sequence homology with some viruses
 Natural History of Type 2 Diabetes

TLC Post-prandial
OAD glucose
Plasma ACEI
glucose AIIA
Fasting glucose

OADs Insulin resistance

-cell
function Insulin Rx
Insulin secretion

0 10 20 30
Years of Diabetes
Adapted from International Diabetes Center (IDC). Minneapolis, Minnesota
 RISKESDAS 2008

Indonesian Basic Health Diagnosed patients

Research (RISKESDAS)

Total DM = 5,7%
Diagnosed DM = 1,5%
Undiagnosed DM = 4,2%
IGT = 10,2 %
Undiagnosed patients

DM patients estimated (WHO)

8 million >21
million

2000
2030
Epidemiology of Diabetes
 Diabetes in the World

Year
31.7 2000 20.8
China
India 17.7
USA
8.4 6.8
Indonesia millions Japan
Reference: Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes. Diabetes Care. 2004; 27(5): 1047-1053.
¡Viva la Vida con Salud!
 Diabetes in the World

Year
79.4 2030 42.3
China
India 30.3
USA
21.3 8.9
Indonesia Japan
millions
Reference: Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes. Diabetes Care. 2004; 27(5): 1047-1053.
¡Viva la Vida con Salud!
 Why is Diabetes on the
Increase?
 Ethnicity and family history are implicated
 Closely associated with overweight or obese
people
 Increased switch to Western diet and lifestyle
Obesity
Genetic component Western lifestyle

TYPE 2 DIABETES
International Diabetes Federation. Diabetes Atlas, 2nd Edition, 2003
Fast Food and Obesity
 200%  fast-food visits 1977-1995
 30% of US children (4-19 yrs) consume fast food
daily
Fast Food and Obesity
 Fast-foods  fat and energy
 Big Mac + medium fries = 83% daily fat intake
 Adversely affects dietary quality
 Less fiber, fruits, vegetables and milk
 Mega-meals
Mega – Meals
Super Size
 Each 12 oz soda has 10
tsp sugar (150 cal)
 One can of soda/day 
child’s risk obesity 60%
 Most popular Canadian
drink
 > 110 L/ person/yr
 1942-1998:
 US production increased 9X
Maharaja Mac ? Jumbo Vadapav? Double
Cheese Pizza?

DO NOT UPSIZE !!!

We Need To Minimize
Not Maximize
Oxidative Stress Damages Here
Endothelial lining Smooth muscle Collagen
 Diabetes
33

Metformin Approved Use

Single Therapy

Combined with Insulin

Children > 10 years
Metformin dose < 2000mg

POM Indonesia ; monotherapi or combination with insulin ;

- Glucophage 1000 mg film-coated tablet can be used in children from 10 years of age and adolescents.
- The maximum recommended dose of metformin hydrochloride is 2 g daily, taken as 2 or 3 divided doses.
Presentation title in footer | 00 Month 0000
Diabetes Today: An
Epidemic
Impact of DM
 25.8 million Americans have diabetes (8.3% of
population)
 The number of Americans treated for diabetes
doubled from 1996 to 2007.
 1 in 3 Americans born in 2000 will have diabetes
in their lifetime
 Annual costs -- $132 billion
 Leading cause of blindness, ESRD, amputations,
MI, strokes
 Relative Risk of Progression of
Diabetes Complications (DCCT)

15

13

11 Retinop

9
RELATIVE Neph
7
RISK
5 Neurop

1
6 7 8 9 10 11 12
Mean A1C

DCCT Research Group, N Engl J Med 1993, 329:977-986.

 Diabetes Melitus
Definisi :
- gangguan metabolisme
- kenaikan kadar glukosa darah kronis
- disebabkan oleh adanya gangguan produksi insulin akibat kerusakan
sel beta pankreas dan atau kerja insulin.

Kerusakan sel Diabetes Resistensi

Beta pankreas Tipe 2 Insulin

DeFronzo et al. Diabetes Care 1992;15:318-68

The Pathophysiology of Type 2 Diabetes
Includes Three Main Defects
Islet
Insulin deficiency

Pancreas Alpha cell

produces Beta cell
excess produces
glucagon less insulin
Excess Diminished
glucagon insulin

Diminished
insulin
Hyperglycemia Muscle and fat
Liver

Excess glucose output Insulin resistance (decreased

glucose uptake)
Adapted from Buse JB et al. In Williams Textbook of Endocrinology. 10th ed. Philadelphia, Saunders, 2003:1427–1483; Buchanan TA Clin
Ther 2003;25(suppl B):B32–B46; Powers AC. In: Harrison’s Principles of Internal Medicine. 16th ed. New York: McGraw-Hill, 2005:2152–2180;
Rhodes CJ Science 2005;307:380–384. 38
How does insulin decrease blood sugar levels?

Insulin activates a cell signaling pathway that results

in glucose transporters moving to the cell surface
Copyright © 2008 Dr. Salme Taagepera, All rights reserved.
http://www.fda.gov/fdac/graphics/2002graphics/insulin.jpg
Types of diabetes
1. Type 1 = autoimmune disease resulting in loss of
insulin production

2. Type 2 = associated with obesity, lack of cellular

response to insulin Type 2
Type 1

Copyright © 2008 Dr. Salme Taagepera, All rights reserved.

Physiology: Role of Insulin
Normal
Patho: DM Type 1

No Insulin
Patho-Cont.:DM Type 2
History of DM

Diabetes Mellitus “Ebers Papyrus”

Greek for Latin for (Egyptian, 1500 B.C.)
“passing water “sweetened first depiction of diabetes mellitus
- urination of excess amounts
like a siphon” with honey”
- manipulation of diet therapy
 Sudah dikenal sejak zaman Ebers Papyrus 1550 SM
 Willis : mencatat ada rasa manis pada urine
 IBNU SINA : Gangren Diabetic
 Matthew Dobson : Rasa manis karena gula
 1815 : Chevreul (ahli Kimia) membuktikan bahwa gula
dalam urine adalah glukosa
 1921 : Frederic Grant Banting, Charles Best berhasil
mengekstraksi insulin pertama kali dari pankreas anjing
 11 Jan 1922 : Leonardo Thompson, remaja merupakan
pasien pertama yang mendapat insulin di RS Toronto
Kanada
 1979 : Goedde menghasilkan human insulin dengan
rekayasa genetik
Faktor Resiko untuk Terjadinya DM

 Kelompok Usia > 45 tahun

 Gemuk : BB > 120% BBI (IMT > 27 kg/m2)
 Hypertensi
 Riwayat Keluarga DM
 Riwayat melahirkan bayi > 4 kg.
 Riwayat DM pada waktu hamil (DM Gestasi)
 Dislipidemia : HDL < 35 mg/dl, Trigliserida > 250
mg/dl
 Pernah mengalami gangguan toleransi glukosa
Etiologi
 Herediter, diperlukan faktor lain yang disebut faktor
risiko atau faktor pencetus
 Virus
 Pada DM tipe 1 dijumpai HLA gen yang rentan
terhadap infeksi virus tertentu.
 Virus yang selalu menimbulkan insulitis adalah : Coxackie,
Mumps, Rubella, Cytomegalovirus, Herpes, dll.
 Obesitas
 Kadar Insulin cukup tetapi tidak efektif (Resistensi Insulin )
 Memakai obat-obatan yang menyebabkan Kadar
Gula Darah meningkat
 Causes of Mortality in Diabetic Patients

Myocardial infarction 34.7

Stroke 22
Tumors 10
Infections 6.7
Diabetic coma 3.1
Renal insufficiency 2.9
Gangrene 2.7
Accident / suicide 2.1
Tuberculosis 0.9
Others 11.4
Not specified 3.4 % deaths in diabetics
0 10 20 30 40

Panzram G. Diabetologia 1987; 30: 120-31

Pankreas

 Terletak dibelakang lambung

 Berat : 200 – 250 gram
 Bentuk : Kerucut terbaring
 Bagian yang lebar : Kepala (Caput)
 Bagian yang kecil : Ekor (Cauda)
 Terdapat kumpulan sel disebut pulau-pulau Langerhans yang
berisi sel Beta dan mengeluarkan hormon Insulin.
 Disamping sel Beta terdapat sel Alfa yang mengeluarkan
Glukagon yang bekerja berlawanan dengan insulin yaitu
meningkatkan kadar gula darah. Juga ada sel Delta yang
mengeluarkan Somatostatin
 INSULIN

Definisi :
Insulin adalah hormon yang
dikeluarkan oleh sel beta
pankreas yang berperanan
dalam mengatur kadar glukosa
darah

Insulin diibaratkan sbg anak

kunci yang membuka pintu
masuknya glukosa ke dalam sel
 KERJA FISIOLOGIS INSULIN
& PENGLEPASAN INSULIN

 Insulin dibentuk dari pro insulin  distimulasi dg pe

glukosa darah  menghasilkan insulin & C-peptide yg
akan masuk ke dlm aliran darah & akan me kan kadar
glukosa darah
 Insulin membantu meningkatkan sintesa protein,
meningkatkan penyimpanan lemak, menstimulasi
mesuknya glukosa ke dlm sel utk sumber energi dan
membantu penyimpanan glikogen dlm lemak dan hati
 Insulin : endogen & eksogen
 Insulin
NORMAL
Insulin Insulin

Pintu Insulin Insulin

Insulin
terbuka

Tenaga

Glukosa dibakar

Glukosa darah Pintu masuk sel pembawa glukosa

 Insulin
DIABETES Glukosa darah

Pintu
tertutup

Tenaga

Tak ada yang dibakar

Glukosa darah Pintu masuk sel Pembawa glukosa

 60 ng/ml
Individu normal

Insulin
plasma FAS E 1 FAS E-2

3-5 mnt 50-60 menit

waktu

Penderita DM tipe-2

Insulin (Tumpul) (Lebih tinggi dan lama)

plasma
FAS E- 1 FAS E-2

Waktu
(Delayed Insulin secretion)
KERJA FISIOLOGIK INSULIN
 MEMASUKKAN GLUKOSA DARI DALAM DARAH KE:
 Hati:
 Glukosa di robah jadi glikogen (Glikogenesis)
 Glikogen hati menjadi cadangan gula dalam tubuh
 Otot:
 Glukosa di robah jadi Glikogen (Glikogenesis)
 Glikogen otot dibakar menjadi sumber kalori.
 Adiposa:
 Glucosa dirobah (?) jadi trigliserida
 Mencegah pemecahan lemak (Antilipolisis)
 Mengaktifkan Lipoprotein Lipase di sel sel endotel P.darah
 Jaringan lain: Meningkatkan sintesa protein dari A.Amino
 INSULIN MENURUNKAN KADAR GLUKOSA DARAH
 Strategy to Prevent the Deterioration
of Type 2 Diabetes

Insulin with
Oral Hypo(s) or without
Life Style Monotherapy
Combination Oral Hypo
Glycemic agent

Beta Cell
Function
(%)
IGT Postprandial T2 DM T2DM phase III
Hyperglycemiaphase I T2DM
phase II

-12 –10 -6 -2 0 2 6 10 14
Years from Diagnosis
Lebovitz H. Diabetes Review 1999;7:139-53
 Hyperglycemia

AGE formation Glucose autoxidation Sorbitol pathwayr

 Antoxidants
 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

59 SlametS
 Effect of Hyperglycemia

Sorbitol DAG-PKC Hexosamine AGE

pathway pathway pathway pathway

Oxidative stress

Increase of : Increase of pro- Decrease of Increase of

• Extracellular matrixcoagulant proteins proliferation, apoptosis
• Collagen • von Willebrandt factor migration,
• Fibronectin • tissue factor
and fibrinolytic
potential

Vascular complications Stehouwer CDA et al. 2004

INSULIN DALAM JUMLAH YANG NOR
MAL TIDAK DAPAT BEKERJA SECARA
OPTIMAL DI JARINGAN SASARAN NYA
SEPERTI DI OTOT, HATI DAN ADIPOSA.

Sel sel β pancreas mengkompensasi keadaan ini

dengan meningkatkan produksi insulin dan me
nyebabkan HIPERINSULINEMIA
Insulin Resistance
The Ominous Octet of DM2
Islet -cell

Decreased
Incretin Effect Increased
Impaired Lipolysis
Insulin Secretion

Islet a-cell

Increased Increased Glucose

Glucagon Secretion Reabsorption

Increased
HGP
Neurotransmitter Decreased Glucose
Dysfunction Uptake

DeFronzo RA. Banting Lecture 2008. “From the triumvirate to the ominous octet: a new
paradigm for the treatment of type 2 diabetes mellitus.”
Glucose Transporters

 GLUT – 1 : Endothelium
 GLUT – 2 : Liver, B-cells of Pancreas
 GLUT – 3 : Neurons
 GLUT – 4 : Muscle, Adipose Tissue
 GLUT – 5 : Intestine
 Insulin Action
Insulin Glucose

Insulin
receptor

PPARg RXR
Synthesis GLUT 4
mRNA

PPRE transcription
promoter
Coding reg

Modified from Howard L. Foyt et al. Thiazolidinediones. Diabetes Mellitus: a Fundamental and Clinical Text, 2nd Ed.
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.
 Physiological Serum Insulin Secretion
Profile
Breakfast Lunch Dinner
Plasma insulin (µU/ml)

50

25

4:00 8:00 12:00 16:00 20:00 24:00 4:00 8:00

Time
 Type 2 Diabetes is NOT a mild disease
Microvascular Macrovascular
Stroke
Diabetic 1.2- to 1.8-fold increase
retinopathy in stroke3
Leading cause
of blindness
in working-age
adults1 Cardiovascular
disease
75% diabetic patients
die from CV events4

Diabetic
nephropathy Diabetic
Leading cause of neuropathy
end-stage renal disease2 Leading cause of non-
traumatic lower
extremity amputations5

1Fong DS, et al. Diabetes Care. 2003; 26 (Suppl. 1): S99–S102. 2Molitch ME, et al. Diabetes Care. 2003; 26 (Suppl. 1): S94–8.
3Kannel WB, et al. Am Heart J. 1990; 120: 672–6. 4Gray RP & Yudkin JS. In Textbook of Diabetes 1997.
5Mayfield JA, et al. Diabetes Care. 2003; 26 (Suppl. 1): S78–S79.
Chronic Complications-Microvascular :

 1. Diabetic Retinopathy
Chronic Complications-Microvascular

2. Nephropathy
Chronic Complications-Microvascular

 Gastroparesis

Nerve damage to the digestive

system most commonly causes
constipation. Damage can also
cause the stomach to empty
too slowly
Chronic Complications-Microvascular

3. Diabetic Neuropathy
 Clinical assessment

• symptoms and signs

may be obvious or subtle
- history of rest pain at night
- gangrene

• colour
- white
- red (hyperaemic skin)

• temperature
- cool

• Pulses and ABPI

 Effects on Blood Vessels

Blood Vessel
Lumen
 Chronic Complications-Microvascular

 Sexual problems for men

erectile dysfunction
retrograde ejaculation

 Sexual problems for women

decreased vaginal lubrication

decreased sexual response

 Urologic problems for men and

women

urinary tract infections

neurogenic bladder
Endocrine System Control Feedback
Regulation of Blood Sugar
insulin
body liver stores reduces
cells take sugar appetite
pancreas up sugar
from blood

high
blood sugar level
liver
(90mg/100ml)
low

liver
triggers releases
hunger sugar pancreas

liver glucagon
GEJALA KLASIK DM
 4P

 1. POLI DIPSIA
 2. POLIFAGIA
 3. POLI URIA
 3. PENURUNAN BERAT BADAN
Signs and Symptoms
Klinis Diabetes Melitus :

 Polifagia : sel mengalami starvasi karena cadangan KH,Lemak,

Protein berkurang ( tdk ada pengisian depot yg biasanya dilakukan
oleh Insulin )

 Polidipsia : glukosuria (diuresis osmotik) → dehidrasi intraselular

dan stimulasi pusat haus di hipotalamus) kompensasi: penderita
banyak minum

 Poliuria : glukosuria (diuresis osmotik) → penderita banyak kencing

 Penurunan BB : cairan tubuh berkurang karena diuresis osmotik,

protein dan lemak berkurang karena dipecah sbg sumber energi.

 Lelah : Metabolisme tdk berjalan sebagaimana mestinya.

Kriteria Diagnosa DM
 Gejala Klasik DM + Kadar Gula Darah Sewaktu >
200 mg/dl
 Gejala Klasik DM + Kadar Gula Darah Puasa > 126
mg/dl
 Kadar Gula Darah 2 jam TTGO > 200 mg/dl

 Puasa diartikan tidak mendapat kalori tambahan

sedikitnya 8 jam TTGO dengan standar WHO,
menggunakan beban glukosa yang setara dengan 75
gram glukosa anhidrous yang dilarutkan dalam air
Diabetes

 Fasting Plasma Glucose ≥ 7.0mmol/l(126mg/dl)

 Or
 2 hour plasma glucose ≥ 11.1 mmol/l (200mg/dl)
GEJALA KLINIS DIABETES MELLITUS TIPE-2

GEJALA KHAS GEJALA TIDAK KHAS

Poliuria Kesemutan
Polidipsia Gatal di daerah genital
Polifagia Keputihan
BB turun cepat Infeksi sukar sembuh
Bisul hilang timbul.
Penglihatan kabur
Cepat lelah
Mudah mengantuk
 KARAKTERISTIK
DM TIPE 1DAN DM TIPE 2
 DM TIPE 1
 Mudah terjadi ketoasidosis
 Pengobatan harus dgn insulin
 Onsetnya akut
 Biasanya kurus /Umur muda
 Terkait dgn HLA-DR3 & DR4
 ICA; GADA; & IAA selalu (+)
 Riwayat keluarga (+) pd 10%
 30-50% kembar identik terkena
 DM TIPE 2
 Jarang ketoasidosis (HONK bisa)
 Tidak mesti diberi insulin
 Onsetlambat (pelan-pelan)
 Gemuk atau tak gemuk / > 45 thn
 Tak ada kaitan dengan HLA
 Tak ada autoantibodi
 Riwayat keluarga (+) pada 30%
 ± 100% kembar identik terkena
 Kriteria Pemantauan Diabetes Mellitus

BAIK LUMAYAN BURUK

KGD puasa 80-109 110-139 > 140
KGD 2 jam pp 110-159 160-199 > 200
HbA1c* 4 - 5.9% 6 – 8% > 8%
Kolesterol total* < 200 200-239 > 240
Kolest. LDL (PJK-)* < 130 130-159 > 160
Kolest.LDL (PJK+)* < 100 100-129 > 130
Trigliserida (PJK-)* < 200 200-249 > 250
Trigliserida (PJK+)* < 150 150-199 > 200
* = diperiksa tiap 3 hingga 6 bulan
Glycated Hemoglobin (HbA1c) 1
 PADA TIAP KUNJUNGAN HARUS
DIPANTAU

 KGD Sewaktu
 Tekanan darah (diukur dalam keadaan duduk)
 Indeks Massa Tubuh = BB (kg) / TB (M)2

PEMERIKSAAN BAIK LUMAYAN BURUK

TD sistolik (mmHg) < 130 130-150 >150
TD diastolik < 80 80-85 >85
IMT Pria (Kg/M2) 20-24.9 25- 27 < 20 atau >27
IMT wanita (Kg/M2) 18.5-22. 9 23- 25 < 18.5 atau >25
 Tujuan Pengelolaan
Diabetes Mellitus
 Menghilangkan gejala
 Mempertahankan rasa sehat
 Memperbaiki kualitas hidup
 Mencegah komplikasi (akut dan kronis)
 Mengurangi laju komplikasi yang sudah ada
 Menurunkan jumlah kematian
 MANAGEMENT OF DM
 Regular Blood Glucose Monitoring

Drug Therapy Diet

Exercise
91
The Ominous Octet of DM2
Islet -cell

Decreased
Incretin Effect Increased
Impaired Lipolysis
Insulin Secretion

Islet a-cell

Increased Increased Glucose

Glucagon Secretion Reabsorption

Increased
HGP
Neurotransmitter Decreased Glucose
Dysfunction Uptake

DeFronzo RA. Banting Lecture 2008. “From the triumvirate to the ominous octet: a new
paradigm for the treatment of type 2 diabetes mellitus.”
 Site & Mode of Action of OADs
Site of action MOA Agents
Sulfonylureas
 Insulin Repaglinide
secretion
Nateglinide
 HGO Biguanides
production Glitazones

Slow CHO a- glucosidase

Digestion inhibitors
 Peripheral Glitazones
insulin sensitivity Biguanides

Adapted from DeFronzo R. Ann Intern Med 1999;131:281

93 www.drsarma.in
 Sites of Action of Currently Available
Therapeutic Options
ADIPOSE MUSCLE
LIVER
TISSUE

PANCREAS

GLUCOSE
PRODUCTION PERIPHERAL
Metformin GLUCOSE
Thiazolidinediones UPTAKE

INSULIN SECRETION Thiazolidinediones

Sulfonylureas: Glyburide, Gliclazide, Metformin
INTESTINE Glimepiride
Non-SU Secretagogues: Repaglinide,
GLUCOSE Nateglinide
ABSORPTION
Alpha-glucosidase inhibitors
 Current Therapeutic Targets
BRAIN PANCREA LIVER
S

Insulin
GLP-1 Agonists
Dopamine Analogs DPP-4 Inhibitors Metformin
Pramlintide Sulfonylureas Thiazolidinediones (TZD)
Pramlintide (α cells only)
Meglitinides
GI TRACT MUSCLE/FAT
?? KIDNEY ??

Metformin
GLP-1 Agonists Thiazolidinediones
Alpha Glucosidase (TZD)
Inhibitors
SU’S: Mechanism of action

Others:
•Dec glucagon
Secretion
•Binding to
Extrapancreatic
SU receptors
in K channels
Actions of Metformin

Dr.Sarma@works
REPAGLINIDE:
Mechanism of action

Meglitinides: have 2 common binding sites

w/ SU and 1 unique binding site
THIAZOLIDINEDIONES: MOA

 PPAR-g activators
LIVER, MUSCLE, FAT
 Insulin sensitizers Activate insulin-responsive genes
regulating
- Glc and lipid metab

- Insulin signalling
- Adipocyte differentiation
GLP-1 MIMETIC:
EXENATIDE

 SC injections: absorbed equally from arm,

abdomen, thigh
 Peak: 2 hrs
 Duration: up to 10 hrs
DPP-IV INHIBITORS

Sitagliptin
COMBINATION PILLS AVAILABLE

- improve compliance
 Glibenclamide + Metformin (Glucovance)
 Glipizide + Metformin (Norsulin)
 Metformin + Rosiglitazone (Avandamet)
 Glimepiride + Metformin (Solosamet)
 Sitagliptin + Metformin (Janumet)
 Pioglitazone: Metformin ( ActosMet)
Sejarah Insulin
 1921 Insulin ditemukan
oleh Banting dan Best

 1922 Leonard Thompson

adalah pasien pertama yang
mendapat suntikan insulin

 1923 Novo Nordisk mulai

produksi Insulin Hewan
(Sapi dan Babi)

 1973 Insulin Hewan

Monokomponen

 1987 Insulin Human

 1990 Insulin Analog
 Insulin is Discovered!
 1921 – Ontario Canada
 Frederick Banting and his
assistant Charles Best
administer canine pancreas
extract to a diabetic dog and
keep it alive for 70 days.
 1923
 Frederick Banting and J.J.
Macleod win the Nobel Prize
for Medicine for their
discovery of insulin.
 J. L. Age 3 yrs. Weight 15 lbs,
December 15, 1922. Courtesy of Eli
Lilly and Company Archives." / "J. L.
Weight 29 lbs, February 15, 1923.
Courtesy of Eli Lilly and Company
Archives
 INDIKASI PENGGUNAAN INSULIN
1. DM tipe 1
2. Penurunan berat badan yg cepat
3. Hiperglikemia yg berat disertai dg ketosis
4. Ketoasidosis diabetik
5. Hiperglikemia hiperosmolar non ketotik
6. Hiperglikemia dg asidosis laktat
7. Gagal dg kombinasi OAD dosis hampir max
8. Stress berat
9. Kehamilan dg DM atau DM Gestasional
10. Gangguan fs. ginjal atau hati yg berat
11. Kontraindikasi dan atau alergi thp OAD
KAPAN INSULIN DIPERLUKAN?

Data UKPDS :
 50% DMT2 perlu insulin setelah 6
tahun
 Fungsi B-cell yg rendah pd saat
diagnosis  risiko kegagalan OHO
lebih tinggi

Marre M. Int J Obesity (2002) ; 26 (Suppl 3) : S25-S30

Modern "Aggressive" Rx of Type 2 DM
from Time of Diagnosis
HbA1c > 10 %


 or
IMMEDIATE
 FPG >260 mg/dl INSULIN
 or

 Symptomatic
 or

 Ketotic
Modern "Aggressive" Rx 4
HbA1c not < 7% by 6
Start

months

Insulin
INSULIN ANALOGS

Glu

Asn
Lys

RAPID-ACTING /
ULTRASHORT-ACTING INSULINS LONG-ACTING INSULINS

Insulin glulisine

Alterations in pharmacokinetic properties

Long-acting insulins
 Insulin analogs:
 Insulin glargine
 Insulin detemir

 Can’t be mixed with other insulins so need to use

different syringes
 Used as BASAL insulin (fasting, between meals,
overnight)
Insulin glargine

 Absorption less variable day to day and not site nor

dose dependent
 Peakless insulin (broad plasma concentration plateau)
– IDEAL once daily (usually) basal insulin
 Acidic pH (4.0)
Insulin detemir
Myristic acid Thr removed at
B30
Tipe insulin berdasarkan puncak dan
jangka waktu kerjanya :
1. Insulin kerja sangat cepat : NovoRapid, Humalog,
Apidra
2. Insulin kerja pendek : , Humulin R
3. Insulin kerja sedang : , Humulin N
4. Insulin campur : , Humulin 30/70, NovoMix 30,
Humalog 25
5. Insulin kerja panjang : Levemir, Lantus
 Kendala Terapi Insulin
Adanya anggapan :
 Sekali dimulai, tidak pernah bisa berhenti
 Akan membatasi aktivitas sehari-hari
 Memulai terapi Insulin berarti:
Saya telah gagal
DM-nya sudah menjadi serius
 Suntikan insulin akan sangat sakit/nyeri
 Suntikan insulin menyebabkan kebutaan
 Frank’s story: “Jika anda tidak bekerja keras, anda
akan saya suntik insulin lho”
Prinsip Terapi
 Insulin Basal  menurunkan gula darah
puasa

 Insulin Bolus  menurunkan gula darah

post prandial (setelah makan)

 Insulin Premixed  menurunkan GD

puasa dan GD 2 jam PP
Macam-macam Rejimen Insulin

 Basal Bolus
4 suntikan per hari (3 bolus dan 1 basal)

 Satu kali suntikan insulin basal pada malam

hari ditambah dengan obat oral

 Premixed Insulin, sekali sampai 3 kali sehari,

sebelum makan.

 Premixed dikombinasi dengan short acting

4 Suntikan per Hari
3 Short + 1 Intermediate/Long Acting
(Basal Bolus)

6 7 8 9 10 11 12 1 2 3 4 5 6 7 8 9 10 11 12 1 2 3 4 5
time

Breakfast Lunch Evening Meal Sleep

 Dua kali Suntikan Premixed Insulin Per Hari

6 7 8 9 10 11 12 1 2 3 4 5 6 7 8 9 10 11 12 1 2 3 4 5
time

Breakfast Lunch Evening Meal Sleep

Tempat Penyuntikan Insulin Subkutan :
Searah Jarum Jam

75 -90 1 -15

61 -75 16 -30

45 -60 31 -45
 Continuous IV insulin infusion
 Used to maintain glycemic control in
hospitalized patients with high blood
glucose levels; in DKA and HHNS

 Regular insulin may be used IV

 May also be given preoperatively or

postoperatively

 More frequent BS monitoring ( q1-2 hours

per agency protocol)
Efek Samping Insulin
 Hipoglikemia (kadar glukosa darah terlalu
rendah)
 Peningkatan berat badan
 Reaksi Alergi (kemerahan, gatal-gatal di tempat
penyuntikkan)
 Lipodistrofi
DIABETES
DAN PERAN INSULIN DALAM PENANGANANNYA

Dr. SUHAEMI, SpPD, FINASIM

 Insulin is Discovered!
 1921 – Ontario Canada
 Frederick Banting and his
assistant Charles Best
administer canine pancreas
extract to a diabetic dog and
keep it alive for 70 days.
 1923
 Frederick Banting and J.J.
Macleod win the Nobel Prize
for Medicine for their
discovery of insulin.
 J. L. Age 3 yrs. Weight 15 lbs,
December 15, 1922. Courtesy of Eli
Lilly and Company Archives." / "J. L.
Weight 29 lbs, February 15, 1923.
Courtesy of Eli Lilly and Company
Archives
Leonard Thompson

1922 – 1923

Meninggal tahun 1935

 1969
 Ames Diagnostics releases the first portable glucose
meter

 1979
 First insulin pump marketed

 First Hba1c test devised

Perkembangan Terakhir Injeksi Insulin
Insulin Delivery Devices 3
Inhaled Insulin
 Exubera
Inhaled Insulin

1-1-08
voluntary discontinuation
4-6-08
Cancer Warning
Exubera (Inhaled Insulin)

Insulin Blisters
for Aerosol
www.drsarma.in 136
Other Injectable Drugs 1

 Exenatide (Byetta)
 insulin secretagogue
 peptide

 gila monster saliva

 use with other drugs

 no hypoglycemia

 bid
 Exenatide (Byetta)

www.drsarma.in 138
Bolus Wizard Calculator : meter-entered

Paradigm 512™

Paradigm Link™

 Monitor sends BG value to pump via radio waves : No

transcribing error
 Enter carbohydrate intake into pump
 “Bolus Wizard” calculates suggested dose
Smart Insulin Pumps
CGMS
More New Technology
SMBG
 Value in Type 2 DM
not established
 Useful for titrating
insulin
Glycated Hemoglobin (HbA1c) 2
 Insulin
 Acute
Complication:
Hypoglycemia

 Tx: (15/15 or 20/20

Rule)
Give 15/20 g simple
carb and recheck
BG in 15/20 minutes
Insulin – Acute Complication
Hypoglycemia
How to prevention
Complications of Diabetes ?
1. Weight reduction, Exercise
2. Strict control hyperglycemia
3. Achieving lipid profile targets
4. Smoking cessation
5. Rx. of Hypertension with ACEi/ ARB
6. Low dose aspirin therapy
7. Statin therapy for all T2DM
8. ACEi or ARB for all with MAU
9. Early detection and evaluation

www.drsarma.in 148
AACE/ACE Diabetes Algorithm
for Glycemic Control

American Association of Clinical Endocrinologists. AACE/ACE Diabetes Algorithm for Glycemic Control.
Available at https://www.aace.com/publications.
 KRITERIA PENGENDALIAN DM
Konsensus PERKENI 2006

BAIK SEDANG BURUK

Gula Darah Puasa 80 - 100 100 - 125 > 126

Gula Darah 2 JSM 80 - 144 145 - 179 > 180

HbA1C (%) < 6,5 6.5 - 8 >8

Kolesterol Total < 200 200 - 239 > 240

Kolesterol LDL < 100 100 - 129 > 130

Kolesterol HDL > 45

Trigliserida < 150 150 - 199 > 200

BMI 18,5 - 22,9 23 - 25 > 25

Tekanan Darah < 130 / 80 130-140/ 80-90 > 140 / 90