Diabetes

Melitus

Lita Septina
FK UMSU – RS Haji Medan
 Diabetes Historical Perspective
Egyptian Papyrus Ebres
• Hey – Ra (1552 –BC), passage of much urine
• Celces – (30 BC – 50 AD)
• Arateus of Cappadocia, siphoon – melting down of the flesh and limbs
into urine
• Galen of Pergamum (150 AD), disease of the kidney
• Scholars in China, Japan, India ( 3rd – 6th century AD), sweet and sticky
urine
Avicena (Ibnu Sina)

• Diabetes Mellitus (honey)

• Avicena 1000 AD
• Bouchard,1870 – disappearing of glucosuria during the rationing of food
• Paulo Langerhans, 1863; 1894 Contribution of microscopy anatomy of pancreas
• Frederic Banting (Father of Diabetes), October 311920 1921 Banting and Best,
canine pancreas extract
Permasalahan dan
Tantangan Saat ini
 Presentation of the new
IDF DIABETES ATLAS
WORLD DIABETES DAY
Peningkatan
> 54 Milyar Dolar (USD)
Pembiayaan Diabetes
> 10 juta penderita dibanding 2015
diabetes baru dibanding
2015
> 19 juta penderita diabetes
tidak terdiagnosa dibanding
2015
> 34 juta penduduk dewasa
resiko menjadi diabetes
dibanding 2015
1 diantara 6 kelahiran terpapar
hiperglikemia pada kehamilan

> 8 juta penderita > 1 juta anak dan dewasa

diabetes usia diatas 63 menderita diabetes mellitus tipe
tahun dibanding 2015 1
Diabetes : emergensi global
Jumlah penduduk diabetes berdasarkan region 2017 dan 2045 ( usia 20 – 79 tahun)
 Diabetes Melitus Type1 (T1DM)

Destruksi sel Beta, umumnya menyebabkan defesiensi insulin absolut.

Kejadian Diabetes anak – anak dan remaja di Eropa : >90% T1DM
Global IDF/ISPAD Guideline for Diabetes in Childhood and Adolescence. 2011.
Diabetes Melitus
Suatu keadaan terjadi TINGGINYA KADAR
GULA DARAH (hiperglikemia), akibat kurang
insulin yang beredar dalam pembuluh darah
(gangguan pengeluaran insulin), atau insulin
yang beredar dalam jumlah cukup (malahan
bisa berlebih) tetapi tidak mampu bekerja
efektif (gangguan aktifitas insulin / resistensi
insulin), atau kedua-duanya.
KLASIFIKASI DIABETES MELITUS
 Type 1 diabetes
 Immune-mediated diabetes.
 5–10% of those with diabetes;
 absolute insulin deficiency (insulin dependent
diabetes, type I diabetes, or juvenile-onset diabetes)
 cellular-mediated autoimmune destruction of the β-
cells of the pancreas.
 markers of the immune destruction of the -cell
include
 islet cell autoantibodies, autoantibodies to insulin,
 autoantibodies to glutamic acid decarboxylase (GAD65),
 autoantibodies to the tyrosine phosphatases IA-2 and IA-2.

 Idiopathic diabetes.
 no known etiologies
 Other specific types of diabetes
A. Genetic defects of -cell function
 Chromosome 12, HNF-1 (MODY3); Chromosome 7,
glucokinase (MODY2); Chromosome 20, HNF-4 (MODY1);
Chromosome 13, insulin promoter factor-1 (IPF-1;
MODY4); Chromosome 17, HNF-1 (MODY5);
Chromosome 2, NeuroD1 (MODY6); Mitochondrial DNA
B. Genetic defects in insulin action
 Type A insulin resistance; Leprechaunism; Rabson-
Mendenhall syndrome; Lipoatrophic diabetes.
C. Diseases of the exocrine pancreas
 Pancreatitis; Trauma/pancreatectomy; Neoplasia; Cystic
fibrosis; Hemochromatosis; Fibrocalculous pancreatopathy.
D. Endocrinopathies
 Acromegaly; Cushing’s syndrome; Glucagonoma;
Pheochromocytoma; Hyperthyroidism; Somatostatinoma;
Aldosteronoma.
 Other specific types of diabetes
E. Drug- or chemical-induced
 Vacor; Pentamidine; Nicotinic acid; Glucocorticoids; Thyroid hormone; Diazoxide;
adrenergic agonists; Thiazides; Dilantin; Interferon.
F. Infections
 Congenital rubella; Cytomegalovirus.
G. Uncommon forms of immune-mediated diabetes
 “Stiff-man” syndrome; Anti–insulin receptor antibodies.
H. Other genetic syndromes sometimes associated with diabetes
 Down’s syndrome; Klinefelter’s syndrome; Turner’s syndrome; Wolfram’s syndrome;
Friedreich’s ataxia; Huntington’s chorea; Laurence-Moon-Biedl syndrome; Myotonic
dystrophy; Porphyria; Prader-Willi syndrome
 Gestational diabetes mellitus (GDM)
 Any degree of glucose intolerance with onset during
pregnancy
 Return to normal glucose regulation after delivery is
common
 Increased perinatal morbidity and mortality if untreated

• Risk assessment for GDM should be

undertaken at the first prenatal visit.
• Women with clinical characteristics
consistent with a high risk for GDM (those
with marked obesity, personal history of
GDM, glycosuria, or a strong family history
of diabetes) should undergo glucose testing
as soon as possible
 Gestational diabetes mellitus (GDM)
 Diagnostic criteria for the 100-g OGTT are as follows:
 ≥95 mg/dl fasting, ≥ 180mg/dl at 1 h, ≥ 155 mg/dl at 2 h, and ≥ 140
mg/dl at 3 h.
 Two or more of the plasma glucose values must be met or exceeded for
a positive diagnosis.
 The test should be done in the morning after an overnight fast of
8–14 h.
 Type 2 diabetes

Type 2 diabetes is characterised by:

 chronic hyperglycaemia with disturbances of
carbohydrate, fat and protein metabolism
 defects in insulin secretion (-cell dysfunction)
and insulin action (insulin resistance)

Definition, Diagnosis and Classification of Diabetes Mellitus and its Complications. Department of Noncommunicable
Disease Surveillance, World Health Organization, Geneva 1999.
 Pathogenic Mechanisms
of Diabetes Mellitus

Genetic and environmental risk

factors impact inflammation,
autoimmunity, and metabolic stress

Environmental Influences
Dietary factors, endocrine disruptors and
other environmental
polluters, and gut microbiome
composition

Jay S. Skyler,1 George L. Bakris,2 Ezio Bonifacio,3 Tamara Darsow,4 Robert H. Eckel,5
Leif Groop,6 Per-Henrik Groop,7,8,9 et al. Differentiation of Diabetes by Pathophysiology, Natural History,
and Prognosis Diabetes 2017;66:241–255 | DOI: 10.2337/db16-0806
 Insulin Resistance and -Cell Dysfunction
Produce Hyperglycemia in Type 2 Diabetes
-Cell Dysfunction Insulin Resistance
Increased
Pancreas Lipolysis

Elevated
Liver Plasma FFA

Islet -Cell Degranulation;

Reduced Insulin Content
+ -
Muscle Adipose Tissue
Increased Glucose Output

Reduced
Plasma Insulin
Decreased Glucose Transport
& Activity (expression) of GLUT4
Hyperglycemia

Courtesy of S. Smith, GlaxoSmithKline

 Role of Free Fatty Acids in Hyperglycemia
Adipose
tissue insulin
resistance
ADIPOSE TISSUE

MUSCLE
 Lipolysis LIVER

Muscle  FFA mobilization

insulin
resistance Liver insulin
resistance
 FFA oxidation  FFA oxidation

 Glucose utilization  Gluconeogenesis

Hyperglycemia

Boden G. Proc Assoc Am Physicians. 1999;111:241-248.

Insulin Resistance: An Underlying Cause of
Type 2 Diabetes
Aging
Obesity and Medications
inactivity

Genetic Rare
abnormalities disorders
INSULIN
RESISTANCE
Type 2
diabetes PCOS

Hypertension Atherosclerosis
Dyslipidemia
Reaven GM. Physiol Rev. 1995;75:473-486
Clauser, et al. Horm Res. 1992;38:5-12.
 Beta cells mass in people with type 2 diabetes
-cell mass is determined as the sum of replication, neogenesis and hypertrophy minus the rate
of apoptosis.

Cho JH et al. J Diabetes Invest 2011; 2: 6-17

 -cell dysfunction
 Reduced ability of -cells to secrete
insulin
 Impaired ability of -cells to compensate
for insulin resistance
 Genetic
and environmental
pathophysiology

DeFronzo RA et al. Diabetes Care 1992; 15: 318–54.

Multiple factors may drive progressive decline of
b-cell function
Hyperglycaemia
(glucose toxicity)
Insulin resistance

Protein -cell “lipotoxicity”

glycation (genetic background) elevated FFA,TG

Amyloid
deposition
Kriteria diagnosis Diabetes Melitus
Kadar tes laboratorium darah untuk
diagnosis daibetes dan prediabetes
 Natural History of Type 2 Diabetes
Altered
Glucose Diagnosis Progression
Normal Metabolism IGT* of T2D of T2D Insulin
Resistance

Post-meal
glucose

Fasting
glucose

Insulin
concentration

-Cell
Dysfunction
Microvascular disease
Macrovascular disease

*IGT=impaired glucose tolerance

Ramlo-Halsted & Edelman. Clinical Diabetes,2000;18:80–85

 The principle of management
 Education of diabetes
 Lifestyle management
 Diet
 Exercise

 Interventional of pharmacology
 Oral treatment
 Insulin
 Sasaran glikemik penderita Diabetes

ADA 2015 PERKENI IDF NICE

A1c (%) < 7,0 < 7,0 6,2 - 7,5 ≤ 6,5 - 7,5

Glukosa Puasa
pra - prandial 80 - 130 80 - 110 91 - 120 72 - 144
(mg/dL)

Glukosa post
prandial (mg/dL)
< 180 < 180 136 - 160 < 180

ADA = American Diabetes Association; IDF = International Diabetes Federation; NICE = National institute of Health and Clinical Excellence

Petunjuk Praktis Terapi Insulin pada Pasien Diabetes Melitus, PERKENI 2015
 Penatalaksanaan”
Earlier Tradisional”
and Appropriate Diabetes
Intervention May Tipe 2:
Improve Patients’ Chances of Reaching
Pendekatan terhadap “Kegagalan Terapi” Goal1

Published Conceptual Approach

OAD +
multiple daily
Diet and OAD OAD OAD OAD + insulin
exercise monotherapy up-titration combination basal insulin injections

10

9
HbA1c,%

HbA1c goal of 7%
7

Mean HbA1c 6
Duration of Diabetes
of patients Conventional stepwise Earlier and proactive intervention
treatment approach approach

Adapted with permission from Del Prato S et al.1

OAD = oral antidiabetic agent.
1. Del Prato S et al. Int J Clin Pract. 2005;59:1345–1355. 29
 Lifestyle Management—Diet &
Exercise
 Diet -- Three important components
• Enough nutrition to meet energy demands
• Food intake distributed throughout the day
• Feeding pattern and amounts should be consistent
 Exercise
• Helps decrease blood glucose levels
• Have physician approve exercise program
• Adjust meals & medications accordingly
• 3-4 times per week usually recommended (30
minute)
 Mengapa Edukasi Diabetes Penting
• Pengelolaan diabetes yang sukses tergantung kepada : apakah
pasien memiliki gaya hidup sehat, memeriksa glukosa darahnya,
dan mematuhi pengobatan.
• Orang dengan diabetes harus menyediakan 95% atau lebih dari
kegiatan hariannya untuk diabetes.
• Kendali Glukosa yang belum memuaskan meskipun sudah
mendapat pengobatan.
Mengapa Edukasi Diabetes Penting
• Edukasi Diabetes sejak lama diketahui sebagai faktor yang vital dan
bagian penting dari pengelolaan diabetes yg sukses.
• Banyak penelitian menunjukkan bahwa edukasi sangat berperan
dalam promosi kesehatan yang dapat memperlambat atau menunda
terjadinya komplikasi 1,2,3 dan memperbaiki outcome biomedis dan
psikososial pasien
• Penelitian lain menunjukkan bahwa individu yang tidak pernah
mendapatkan edukasi empat kali lebih berrisiko untuk terjadi
komplikasi diabetes.

1.Singh N, Armstrong DG, Lipsky BA (2005). Preventing foot ulcers in patients with diabetes. JAMA 293(2):217-28. 2. Strine TW, Okoro
CA, Chapman DP, Beckles GL, Balluz L, Mokdad AH (2005a).The impact of formal diabetes education on the preventive health practices
and behaviors of persons with type 2 diabetes. Preventive Medicine 41(1):79-84. 3. Strine TW, Okoro CA, Chapman DP, Beckles GLA,
Balluz L, Mokdad AH (2005b). The impact of formal diabetes education on the preventive health practices and behaviors of persons with
type 2 diabetes. Preventive Medicine 41(1):79-84. 4. Brown SA (1988). Effects of educational interventions in diabetes care: a meta-
analysis of findings. Nursing Research 37(4):223-30. Brown SA (1990). Studies of educational interventions and outcomes in diabetic
adults: a metaanalysis revisited. Patient Education & Counseling 16(3):189-215. 5. Steed L, Cooke D, Newman S. (2003). A systematic
review of psychosocial outcomes following education, self-management and psychological interventions in diabetes mellitus. Patient
Education & Counseling 51(1):5-15.
 Apa itu Edukasi Diabetes ?
• Edukasi Diabetes adalah cara membantu individu dengan diabetes,
keluarganya dan orang yang merawatnya, dalam meningkatkan
pengetahuan, keterampilan, motivasi dan kepercayaan diri dalam mengelola
keadaannya.

• Edukasi Diabetes membantu individu dengan diabetes untuk : mengetahui

Apa yg harus dilakukan, Bagaimana melakukannya, Mau melakukan, dan
Mampu melakukan, dan tahu Kapan harus mencari pertolongan
 Apa itu Edukasi Diabetes ?

• Diabetes self-management education (DSME) diberikan untuk membantu

individu dengan diabetes menjaga pengelolaan yg efektif sejak terdiagnosis
sampai seterusnya begitupun saat mereka menerima kesempatan-
kesempatan baru dan adanya pengobatan-pengobatan terbaru .
 Terapi Gizi Medik :
Bagian integral dari :
• Pencegahan dan penatalaksanaan DM
• Komponen edukasi diabetes
• Upaya pencegahan komplikasi diabetes

Diabetes Care , Vol. 31, Suppl 1, 2008

 Sasaran TGM dlm pencegahan dan
penatalaksanaan DM :
I. Individu yg mempunyai risiko DM atau dg
pre-diabetes :
Menurunkan risiko DM dan PKV - melalui
promosi makanan sehat dan aktivitas fisik
untuk mempertahankan BB ideal.

Diabetes Care , Vol. 31, Suppl 1, 2008

 Sasaran TGM dlm pencegahan dan
penatalaksanaan DM :
II. Individu yg menyandang DM :
1. Mencapai dan mempertahankan :
- Gula darah , profil lipid dan TD
2. Mencegah/ memperlambat progresivitas
komplikasi kronik
3. Memenuhi kebutuhan gizi individu
4. Mempertahankan selera makan dgn hanya
membatasi jenis makanan tertentu sesuai
dgn bukti 2 ilmiah.

Diabetes Care , Vol. 31, Suppl 1, 2008

Prinsip pengaturan makan pada penyandang DM :

• Hampir sama dg masyarakat umum 

makanan seimbang sesuai dg kebutuhan
kalori dan zat2 gizi masing2 individu.
Yg penting ditekankan  3 J
- Jadwal
- Jenis
- Jumlah
Tugas Dokter dalam TGM
- Merujuk pasien ke dietisien
- Memberikan data pasien
- Mengkomunikasikan sasaran pengelolaan
- Memberikan Preskripsi Diet
- Memberikan keterangan mengenai
tingkat kegiatan jasmani yang diperkenankan
- Melakukan penyesuaian pengelolaan
sesuai hasil TGM
- Menekankan pentingnya pengaturan nutrisi
pada pasien
 Tugas Dietisien
• Memperoleh dan mengkaji data klinis,makanan, latihan jasmani,
sosial ekonomi, pengetahuan/keterampilan pasien
• Mengidentifikasi “ treatment goal ”
• Menerapkan preskripsi diet, edukasi perencanaan makan, latihan
jasmani, pemantauan glukosa darah sendiri (bila perlu).
• Mengevaluasi TGM : kontrol glikemik, lipid, tek.darah,BB,
perenc.makan, lat.jasmani.
• Memberikan laporan & saran pada dokter
 Physical exercise and insulin resistance
 Exercise 
 muscle glucose uptake
 whole body glucose disposal
} acute &
long-term

 risk of developing Type 2 DM

 GLUT4 is recruited to the plasma membrane
independently of insulin
 Effective in Type 2 diabetics because muscle GLUT4
expression is normal
 Regular exercise has been shown to improve blood
glucose control, reduce cardiovascular risk factors,
contribute to weight loss, and improve well-being.
Recommendations of physical activity
 Initial physical activity recommendations should
be modest, based on the patient’s willingness
and ability, gradually increasing the duration and
frequency to 30 – 45 min of moderate aerobic
activity 3–5 days per week, when possible.
 Greater activity levels of at least 1 h/day of
moderate (walking)or 30 min/day of vigorous
(jogging) activitymay be needed to achieve
successfullong-term weight loss.
 Terapi antihiperglikemi pada Diabetes Tipe 2
Rekomendasi ADA (American Diabetic Association) dan EASD (European Association for the Study of Diabetes ) 2015

Monotherapy

Dualtherapy
Tripletherapy
Combination Injectable

Polonsky KS , Williams Text Book of

Endocrinology. 2016 : 1386 – 1450.
ADA, Diabetes Care 2016;39(Suppl.
1):S52–S59
 Algoritme Pengelolaan DM Tipe 2 Konsensus PERKENI 2015

Modifikasi pola hidup sehat

HbA1c < 7,5% HbA1c ≥ 7,5% HbA1c ≥ 9,0%
Gejala (-) Gejala (+)

Monoterapi dengan salah satu Kombinasi 2 obat* dengan
dibawah ini mekanisme kerja yang berbeda
Metformin Agonis GLP - 1
Agonis GLP - 1 Penghambat DPP-IV
Penghambat DPP-IV Tiazolidindion
Penghambat Glikosidase Penghambat SGLT-2**
Alfa
Insulin Basal
Penghambat SGLT-2**
SU / Glinid
Tiazolidindion
Kolsevelam **
Sulfonilurea
Bromokriptin - QR
Glinid
Penghambat Glikosidase
Alfa
Jika HbA1c > 6,4%
dalam 3 bulan Jika belum memenuhi
tambahkan obat ke 2
sasaran dalam 3 bulan
(kombinasi 2 obat) masuk ke kombinasi 3
obat
Kombinasi 3 obat
Agonis GLP - 1
Penghambat DPP-IV
Tiazolidindion
Penghambat SGLT-2**
Insulin Basal
Kolsevelam **
Bromokriptin - QR
Penghambat Glikosidase
Alfa
Jika belum memenuhi
sasaran dalam 3 bulan
mulai terapi insulin atau
intensifikasi terapi
insulin
Kombinasi 2 obat
Insulin +/- obat
jenis lain
Kombinasi 3 obat
Mulai atau intensifikasi
insulin
Keterangan
* Obat yang terdaftar pemilihan dan
penggunaannya disarankan
mempertimbangkan faktor
keuntungan dan kerugian biaya
dan ketersediaannya
* ** Kolseveam belum tersedia di
Indonesia. Bromokriptin QR
umumnya digunakanpada terapi
tumor hiposis

Konsensus Pengelolaan dan Pencegahan DMT2 di Indonesia, PERKENI 2015

 Oral Therapy for Type 2 Diabetes
Target Sites of Action
Sulfonylureas
Pancreas
Repaglinide Gut
Adipose
 Insulin secretion
tissue
 Glucose Acarbose
uptake
Miglitol
 FFA output
 Glucose
Rosiglitazone  Hyperglycemia absorption
Pioglitazone

Liver Muscle
Metformin Rosiglitazone
Rosiglitazone  Hepatic Pioglitazone Glucos
Pioglitazone glucose Metformin e uptake
output
 Biguanides
 First Generation- Phenformin
Phenethylbiguanide
Adverse Effects
Lactic acidosis
Risk of cardiovascular disorder

 Second Generation- Metformin

 1,1-Dimethylbiguanide
 Rarely produces lactic acidosis except
under predisposing conditions
 SEVERAL ALGORHYTHMS PUT METFORMIN
AS THE FIRST DRUG OF CHOICE

NICE
20021

Asian
20092 Pacific4
Metformin

IDF
20053

1. UK National Clinical Guidelines for T2DM 2002. Rev 2005

2. Nathan DM et al. Diabetes Care 2009;31(1):193-203
3. IDF Clinical Guidelines Task Force. Diabet Med 2006;23:579-93
4. Asian Pacific Type 2 Diabetes Practical Targets & Treatment. 4th Ed
Algorithms made by Diabetes Associations such as the ADA, EASD, IDF,
AACE is revised every year.
Metformin is always put as the first drug of choice.

Why ?
The explanation for that is:
Metformin acts against hyperglycemia and to the core
of T2DM, that is the insulin resistance, and against
dyslipidemia and other cardiometabolic risks.
Metformin is relatively safe and cheap ……
 Effect on the Liver
Reducing Gluconeogenesis
and Glycogenolysis
↓
Inhibiting hepatic glucose output

Effect on ß – cell
METFORMIN ↓
•Potentiation of first phase insulin secretion
in response to glucose
CARDIOVASCULER •Exerts a protective effect against
RISK FACTORS gluco-and lipotoxicity
→ preserve ß – cell function

Effect on peripheral tissue

Increased insulin receptor tyrosine kinase activity Effect on Adipose tissue

Enhanced glycogen synthesis ↓Concentration and oxidation
Augmented GLUT 4 transporter number and of plasma FFA
activity  Improves glucose utilization
Triglyceride
 Efek Metformin lainnya : anti–atherogenic
In addition to amelioration of insulin resistance, improved
fibrinolysis and improved lipid profile

Action Potential effect

 Oxidation  Apoptosis, oxidative damage

 Advanced glycation end-  Inflammation, oxidative

products stress/apoptosis

 Endothelial adhesion molecules  Atherogenesis

 Monocytes → macrophages  Atherogenesis

 Lipid uptake by macrophages  Atherogenesis

Improved microcirculation  Nutritive blood flow

Kurukulasuriya R et al. Diabetes 1999;48 Suppl:A315; Beisswenger P et al. Diabetes Metab 2003;29:
6S95-103; Pavlović D et al. Diabetes Obes Metab 2000;2:251-6; Mamputu JC et al. Diabetes Metab 2003;29:6S71-6.
Wiernsperger NF et al. Diabetes Metab 2003;29:6S77-87
 Sulfonylureas

 First Generation - rarely used today: Tolbutamide, Chlorpropamide

 Second Generation: Glibenclamide, Glipizide, Gliclazide, Gliquidone

 Third Generation: Glimepiride

Cheng and Fantus. CMAJ 2005; 172: 213-226
 Issue with SU treatment
 Beta cells apoptosis
– Gliclazide is less likely to induce B-cells failure as compared
to conventional SUs
 Beta cells de-differentiation
– Account for reduced B-cell mass and insulin secretion
– Glimeperide enhanced B-cell secretory capacity
 Weight gain
– Glimeperide, ER glipizide, Gliclazide MR: ≈netral;
Glibenclamide: increased body weight
 Hypoglycemia
– Glimeperide < Glibenclamide
 Cardiovascular safety
– Modern SUs (Gliclazide MR, glimeperide) < risk of all cause
CV-related mortality compared to conventional SUs
Adopted from Kalra S et al. Place of sulfonylureas in the management of type 2 diabetes mellitus in South Asia: A
consensus Statement. Indian J Endocrinol Metab 2015; 20: 577-596
 Sulphonil Urea as an option

For Against
 Good Glucose Lowering:  Safety and Tolerability:
Efficacious & rapid onset of – Hypoglycemia
action – Weight Gain
 Time tested & clinical experience – CV Safety ?

 Durability, Beta cell failure

 Efficacy in Late Diabetes

S. Kalra, Indian Journal of Endocrinology and Metabolism / Sep-Oct 2015 / Vol 19 | Issue 5
 First Generation Sulfonylureas
Name Daily Max daily Doses/day
dose dose
range (mg/day)
Tolbutamide* 500-3000 3000 2-3
Chlorpropamide 100-500 500 1
Tolazamide * 100-1000 1000 1-2
Acetohexamide* 250-1500 1500 1-2

*not available
 Second Generation Sulfonylureas
Name Daily Max daily Doses/day
dose dose
range (mg/day)
(mg/day)
Glibenclamide 1.25-2.50 20 1-2
Glipizide 2.5-40 40 1-2
Glipizide XL 5-20 20 1
Gliclazide 40-320 320 1-2
Glimepiride 4-8 8 1
 Adverse Effects of Sulfonylureas
 Severe hypoglycemia
 Overdose
 Early in treatment
 Most common with glybenclamide
 Weight gain
 Erythema, skin reactions
 Blood dyscrasias (abnormal cellular elements)
 Hepatic dysfunction and other GI disturbances
 Contraindications for Sulfonylureas
 Pregnancy
 Surgery
 Severe infections
 Severe stress or trauma
 Severe hepatic or renal failure

Insulin therapy should be used in all of these

 Repaglinide and Nateglinide
 Mechanism of action:
 decrease ATP-sensitive K+ conductance
 Additional high affinity binding site identified in
mouse ß-cells for repaglinide
 Action is glucose dependent
 High potency
 Elicited insulin release is rapid and brief
 Taken with meals for postprandial hyperglycemia
 Reduced risk of long-lasting hypoglycaemia
 Thiazolidinediones
CH3
 Antihyperglycemic N N
O
S O

 Do not increase NH
ROSIGLITAZONE O
 insulin secretion
 Increase insulin
 sensitivity in liver N O
S O

and muscle PIOGLITAZONE O

NH

 Reduce hepatic glucose output

 Improve lipid profiles
 Thiazolidinediones: Mechanism of
Action
Ligands for PPARg:
(Peroxisome proliferator-activated receptorg)
 Nuclear hormone receptor superfamily
 Expressed primarily in fat, regulates differentiation
 More limited expression in muscle, heart, liver,
kidney, gut, macrophages
 Heterodimerizes with RXR, binds to hormone
response elements, regulates gene transcription
Known natural ligands (low affinity)
 Prostanoid 15-deoxy12,14PG J2
 Polyunsaturated fatty acids, such as linoleic acid
 a glucosidase inhibitors (Acarbose)
Mechanism of action: competitive and reversible
inhibitors of a glucosidase in the small intestine
Delay carbohydrate digestion and absorption
Smaller rise in postprandial glucose

 Clinical use
For mild to moderate fasting hyperglycemia with significant
postprandial hyperglycemia
Taken with the first bite of a meal

 Adverse effects:
Gastrointestinal
disturbances; Flatulence, nausea, diarrhea
Use gradual dose titration
Tipe dan Sediaan Insulin
 Sediaan Insulin
Insulin Type Conventional Analogue

Rapid - acting
Short - acting regular human insulin
Novorapid®(Aspart)
Prandial Actrapid®
Humalog®(Lispro)
Humulin R®
Apidra®(Glulisine)

Intermediate - acting or Neutral Protaminated Hagerdon (NPH)

Long - acting
Insulin
Basal Lantus®(Glargine)
Insulatard®
Levemir®(Detemir)
Humulin N®

Combination of short & intermediate - acting :

Combination of rapid - acting & protaminated analogue
30%regular insulin + 70% NPH
Premixed Novomix 30® (30% aspart + 70% aspart protamine)
Mixtard® 30
Humalog Mix® 25 (25% lispro + 75% Lispro protamine)
Humulin® 30/70
 Pharmacokinetic profiles of various types of insulin

Brand (Generic) Name Onset Peak (hr) Duration (hr) Timing of Insulin

a) Short - acting, regular

Actrapid® 30 min 1-3 8 30 mins before meal
Humulin R® 30 min 2-4 6-8

b) Rapid - acting analogue

Novorapid® (Aspart) 10 - 20 min 1-3 3-5 5 - 15 mins before or
Humalog® (Lispro) 0 - 15 min 1 3,5 - 4,5 immediately after meals
Apidra® (Glulisine) 5 - 15 min 1-2 3-5

c) Intermediate - acting, NPH

Insulatard® 1,5 hr 4 - 12 18 - 23 Pre - breakfast / pre bed
Humulin N® 1 hr 4 - 10 16 - 18

d) Long - acting analogue

same time everyday at
Glargine® 2 - 4 hr peak less 20 - 24
anytime of the day
Detemir® 1 hr peak less 17 - 23

e) Premixed human (30% regular Insulin +

70% NPH)
30 min dual 18 - 23 30 - 60 mins before meals
Mixtard 30® 30 min dual 16 - 18
Humulin 30/70®

f) Premixed analogue
Novomix 30® (30% aspart + 70%
10 - 20 min dual 18 - 23
aspartprotamine) 5 - 15 mins before meals
Humalog Mix® 25 (25% lispro + 75% 0 - 15 min dual 16 - 18
lispro - protamine

DeWitt DE et al. J Am Med Assoc. 2003; 289: 2254-64

 Insulin Preparations
Ultra fast/ultra
Lispro/aspart
short-acting

Short-acting regular

Plasma [Insulin]
Intermediate- NPH
acting

lente
Long-acting ultralente

Ultra long-acting glargine

0 4 8 12 16 20 24
 Selecting initial insulin regimen based on blood sugar profile

Blood Glucose Profile

Preferred insulin regiment

Pre - breakfast Daytime

High Normal Pre - bed intermediate / long acting insulin (Basal)

Pre - bed intermediate / long acting insulin and

later add on prandial short / rapid acting insulin
High High
(Basal —> basal Plus / Basal Bolus) or (Pre -
Breakfast and Pre - Dinner Premixed Insulin)

Prandial short / rapid acting insulin and later add

Normal High on basal insulin
(Prandial —> Basal Plus / Basal Bolus)
 Clinical Uses of Insulin
 Type 1 diabetes mellitus
 Type 2 diabetes mellitus uncontrolled on maximal
combination therapy with oral agents
 Gestational diabetes
 Hyperglycemic emergencies
 Total pancreatectomy patients
 Acute or chronic hyperglycemia provoked by:
 Infection or trauma
 Steroid therapy
 Endocrinopathies such as hyperthyroidism
 Other types of secondary diabetes
 Yakinkan pasien bahwa pemberian insulin bukan hanya karena kesalahannya
Beri penekanan patofisiologi DMT2, progresifitas DM membutuhkan terapi insulin
Perhatian Personal Penjelasan tentang pemberian insulin pada saat yang tepat dapat mengontrol gula darah dan
menghambat progresifitas selanjutnya

Beri informasi yang benar dan jelas

Mengatasi ketakukan pasien dengan sabar dan beri informasi tentang insulin menyeluruh
Insulin menyebabkan
Diskusikan tentang pemberian insulin tidak berarti kondisi kesehatan pasien sedang
komplikasi dan kematian memburuk, dimana pemberian insulin merupakan langkah efektif mencegah progresivitas dan
komplikasi Diabetes
S
A
H Jelaskan kelebihan penyuntikan menggunakan sediaan pulpen / sediaan lainnya.
Nyeri saat penyuntikan Beri contoh teknik penyuntikan secara subkutan dengan menggunakan sediaan pulpen. Beri
penekanan lokasi penyuntikan.
R
insulin
A Beri kesempatan pasien mencoba menyuntikkan menggunakan plasebo
A
M Kekhawatiran akan
Yakinkan pasien ada beberapa strategi untuk mencegah, waspada, mengenali gejala awal dan
cara mengatasi hipoglikemia, dan hal ini dapat menghindarkan keadaan yang serius yang tidak
N
hipoglikemia diharapkan.
&
B Insulin basal memiliki resiko minimal

Merubah gaya hidup :

D
A 1. Dapat dilakukan sendiri Beri informasi dan diskusikan tentang insulin dan sediaan pulpen :
Merupakan alat suntik mutakhir (insulin pen), mudah dalam penggunaannya. I
(independent) Penggunaan insulin sesuai / tidak menyulitkan dengan kegiatan sehari - hari
2. Tetap menyuntik insulin Pilihan tipe dan jenis insulin memiliki fleksibelitas maksimal tersendiri
T walau ditempat umum S
K
A Beri penjelasan bahwa diabetes merupakan penyakit yang berhubungan dengan insulin, dan
insulin yang digunakan sangat mirip / menyerupai insulin yang dihasilkan tubuh.
Ajukan “penawaran” mencoba insulin dalam 3 bulan, untuk melihat respon dan pendapat U
Insulin tidak efektif
N pasien
Sekali pasien mencoba memakai insulin, sangat jarang mereka akan merubahnya akibat S
keberhalisan terapi
I
Insulin meningkatkan berat Konsultasi dengan ahli gizi dan diskusikan strategi mencegah peningkatan berat badan
badan Intervensi gaya hidup kontinyu melalui diet dan olahraga (hal yang penting)

Juliana Chan et al. Diabetes Car e 2009; (32):227-233.

Terima kasih
History of diabetes medications

White JR. Diabetes Spectrum Volume 27, Number 2, 2014