Best Optimal

Management of T2DM :
Combined approach of
clinical experience,
personalisation,
and
application of the
information in the
guidelines as
clinically appropriate.
 ADA / EASD
Guidelines

Consensus Statement
Algorithm 2009 (First published 2006)

Evolved to
Position Statement 2012
- Best available evidence
- Experience
- Insight of writing group
- Extensive review by additional experts
ADA 2014 :
Position Statement
- Evidence Based Medicine
- Clinical Trials results
- Expert Opinion
 Evidence used for
position statements:

1. RCT
2. Rigorous protocols
3. Agent inclusion / exclusion criteria
 Real World

Heterogenous patient population

Should involve clinical experience

1984 - 2009 : Private and Government Hospital
2009 - 2015 : Private Practice ( SS Diabetes Care)
( + 4000 patients with comprehensive medical record)
 Diabetes Cost a Lot More Than 

Anybody Believed. Why?

A. Complications due to poor control

B. Limitations by the health care system
C. Poor access to care
D. Health education deficiencies
E. Chronic and complex condition
Establish Individual Goals
 Pathophysiology of Type 2 Diabetes:
The Ominous Octet

Insulin secretion β

Glucose production

Glucose uptake

α Glucagon secretion Hyperglycemia

Incretin effect

Lipolysis
Neurotransmitter function

Glucose reabsorption
 Pathophysiology of Type 2 Diabetes:
Therapies

GLP-1s
Insulin β
DPP-4s Insulin secretion
secretion
Insulin Sulfonylureas
Glucose Metformin
Glucose production
production
TZDs TZDs Glucose
Glucose uptake
Insulin uptake
Metformin

α Glucagon GLP-1s
Glucagon secretion
secretion Normoglycemia GLP-1s Incretin
DPP-4s Incretin effect
effect
DPP-4s

Lipolysis
Lipolysis TZDs
Neutransmitter
GLP-1s Neurotransmitter
function function

Glucose
Glucose reabsorption
reabsorption SGLT2s
Establish Individual Goals
16
 GLYCEMIC CONTROL ALGORITHM
LIFESTYLE MODIFICATION (Included Medically Assisted Weight Loss)

Entry A1c < 7.5% Entry A1c > 9.0%

Entry A1c ≥ 7.5%

MONOTHERAPY*

Metformin DUAL THERAPY* SYMPTOMS

✓
GLP-1 RA

✓ GLP-1 RA ✓ NO YES
SGLT-2i

✓ SGLT-2i ✓ TRIPLE THERAPY*

DPP-4i
✓ GLP-1 RA
✓ DPP-4i
MET
or other ✓
1st-line TZD SGLT-2i
DUAL
AGi
agent ✓ Therapy
✓ INSULIN
+ Basal Insulin
TZD
±
TZD MET
Colesevelam or other Basal Insulin OR Other
✓ 1st-line
Agents
SU/GLN agent +
Bromocriptine QR 2nd-line
✓ agent
DPP-4i
TRIPLE
✓
✓ AGi + Therapy
Colesevelam
SU/GLN
✓
Bromocriptine QR
✓
AGi
✓
If not a goal in 3 months SU/GLN
proceed to Double Therapy

If not a goal in 3 months ADD OR INTENSIFY INSULIN

proceed to Triple Therapy Refer to Insulin Algorithm
If not a goal in 3
months proceed
to or intensify
insulin therapy ✓ Few adverse events or
LEGEND possible benefits
Use with caution
*Order of medications listed represents a suggested hierarchy of usage

PROGRESSION OF DISEASE
 Position Statement
ADA / EASD

A Patient-Centered Approach
Personalization of treatment targets and treatment strategies

HbA1c Goal (7%)

More stringent Determined Based on Less stringent
Patient / Disease Factors
 dual en
s if i al h
i on
opt cated er init rapy w
se sid he
t h the raindi Con ation t >9%
wi t bin A1c
g i n i n con om
Be form c
met

n
i n suli 2%
l
i n itia >10-1
r C
n side en A1
Co y wh
rap
the
 Decision-Making Tree:
Individualising Glycemic Targets

Life
expectancy Co-morbidities

Disease Patient Attitude

duration

Hypoglycemia and Resources and

drug adverse support
effects system

HbA1c 7%

Decisions should be made in conjunction with the patient reflecting his or her
preferences, needs, and values.
The clinical decision-making process

As clinicians,
we have multiple options for therapeutic selection
 Current Antihyperglycemic Medications

TZDs
Sulfonylureas
Glinides
alpha- Generalized insulin Reduce peripheral Biguanide
Glucosidase Restore postprandial secretagogue insulin
inhibitors insulin patterns resistance Reduces hepatic
Delay CHO absorption insulin resistance

DPP-4
Inhibitors 12 Different groups with different SGLT-2 Inhibitors

mechanisms of action Block renal glucose

Restore GLP-1 reabsorption
Level

GLP-1 Analogs Bromocriptine

Stimulate beta-cells Insulin Colesevelam Hypothalamic pituitary

Suppress glucagon reset
Replacement Amylin Analog
Bile acid
Therapy
Suppresses sequestrant
glucagon
 Algoritme Pengelolaan DM Tipe 2 di Indonesia
KONSENSUS PERKENI 2015

Modifikasi Pola Hidup Sehat

HbA1c > 9.0%

HbA1c < 7.5% HbA1c > 7.5%

Gejala ( - ) Gejala ( + )
Monoterapi* dengan Kombinasi 2 obat dengan kombinasi 2 obat
salah satu dibawah ini mekanisme kerja yang berbeda

Insulin +/-
Obat jenis lain
• Metformin
Kombinasi 3 obat kombinasi 3 obat
Metformin / obat lini pertama yang lain +

• Agonis GLP-1
• Agonis GLP-1
• Penghambat DPP-IV
• Penghambat DPP-IV

Metformin / obat lini pertama yang lain +

• Penghambat Glikosidase Alfa
• Tiazolidindion • Agonis GLP-1
• Penghambat SGLT-2**
• Penghambat SGLT-2 • Penghambat DPP-IV
• Tiazolidindion
• Tiazolidindion Mulai atau intensifikasi insulin
•• Insulin basal

Obat lini kedua +

• Sulfonilurea
• SU/Glinid • Penghambat SGLT-2
• Glinid
• Kolesevelam** •• Insulin basal

• Kolesevelam** Keterangan
• Bromokriptin-QR
*Obat yang terdaftar pemilihan dan
penggunaannya disarankan
• Penghambat Glukosidase Alfa • Bromokriptin-QR mempertimbangkan faktor
Jika HbA1c > 6.4% dalam 3 bulan
keuntungan,kerugian, biaya dan ketersediaan
tambahkan obat ke 2 (kombinasi 2
• Penghambat Glukosidase Alfa sesuai tabel.
obat)
** Kolesevelam belum tersedia di Indonesia.
Bromocriptin QR umumnya digunakan pada
terapi tumor hipofisis.

Jika belum memenuhi sasaran

dalam 3 bulan, masuk ke
kombinasi 3 obat
Jika belum memenuhi sasaran dalam 3
bulan, mulai terapi insulin / intensifikasi
terapi insulin
 Algoritme Pengelolaan DM Tipe 2 di Indonesia
KONSENSUS PERKENI 2015
Modifikasi Pola Hidup Sehat

HbA1c > 9.0%

HbA1c < 7.5% HbA1c > 7.5%

Gejala ( - ) Gejala ( + )
Monoterapi* dengan salah Kombinasi 2 obat dengan kombinasi 2 obat
satu dibawah ini mekanisme kerja yang berbeda

Insulin +/- Obat

jenis lain
• Metformin
• Agonis GLP-1 Kombinasi 3 obat kombinasi 3 obat
Metformin / obat lini pertama yang lain +

• Penghambat DPP-IV • Agonis GLP-1

• Penghambat Glikosidase • Penghambat DPP-IV

Metformin / obat lini pertama yang lain +

Alfa • Tiazolidindion
• Agonis GLP-1
• Penghambat SGLT-2** • Penghambat SGLT-2
• Penghambat DPP-IV
• Tiazolidindion • Insulin basal Mulai atau intensifikasi insulin
• Tiazolidindion

Obat lini kedua +

• Sulfonilurea • SU/Glinid
• Penghambat SGLT-2
• Glinid • Kolesevelam**
• Insulin basal
• Bromokriptin-QR
• Kolesevelam** Keterangan
• Penghambat *Obat yang terdaftar pemilihan dan
Jika HbA1c > 6.4% dalam 3 • Bromokriptin-QR penggunaannya disarankan
bulan tambahkan obat ke 2 Glukosidase Alfa mempertimbangkan faktor
• Penghambat keuntungan,kerugian, biaya dan
(kombinasi 2 obat) ketersediaan sesuai tabel-11.
Glukosidase Alfa
** Kolesevelam belum tersedia di Indonesia
Bromocriptin QR umumnya digunakan pada
terapi tumor hipofisis.

Jika belum memenuhi sasaran

dalam 3 bulan, masuk ke
Jika belum memenuhi sasaran
kombinasi 3 obat
dalam 3 bulan, mulai terapi insulin /
intensifikasi terapi insulin
 Diabetes Pathway
Non-insulin situations and
Clinical Scenario approaches

Incidental finding, or symptoms with

At diagnosis moderate hyperglycaemia:
lifestyle and metformin

Incidental finding, or symptoms with more

marked hyperglycaemia: lifestyle,
metformin, and sulfonylurea (for rapid onset
of effect)

Early after diagnosis Partial early response to lifestyle with

oral agents:
add or GLP-1 agonist

Obese and not controlled on

metformin and insulin secretagogue:
GLP-1 agonist or SGLT2 inhibitor

Multiple introductions of other approaches

Continuing Care
with continuing monitoring for deterioration
to above target levels: DPP4-
inhibitor, GLP-1 agonist, SGLT2 inhibitor

Continued poor metabolic control with

marked obesity:
bariatric surgery
 Algoritme Pengelolaan DM Tipe 2 di Indonesia
KONSENSUS PERKENI 2015
Modifikasi Pola Hidup Sehat

HbA1c > 9.0%

HbA1c < 7.5% HbA1c > 7.5%

Gejala ( - ) Gejala ( + )
Monoterapi* dengan salah Kombinasi 2 obat dengan kombinasi 2 obat
satu dibawah ini mekanisme kerja yang berbeda

Insulin +/- Obat

jenis lain
• Metformin
Kombinasi 3 obat kombinasi 3 obat
• Agonis GLP-1
Metformin / obat lini pertama yang lain +

• Penghambat DPP-IV • Agonis GLP-1

• Penghambat Glikosidase • Penghambat DPP-IV

Metformin / obat lini pertama yang lain +

Alfa • Tiazolidindion
• Penghambat SGLT-2** • Penghambat SGLT-2 • Agonis GLP-1
• Tiazolidindion • Insulin basal • Penghambat DPP-IV Mulai atau intensifikasi insulin

Obat lini kedua +

• Sulfonilurea • SU/Glinid • Tiazolidindion
• Glinid • Kolesevelam** • Penghambat SGLT-2

• Bromokriptin-QR • Insulin basal

Keterangan
• Penghambat • Kolesevelam** *Obat yang terdaftar pemilihan dan
• Bromokriptin-QR penggunaannya disarankan
Glukosidase Alfa mempertimbangkan faktor
Jika HbA1c > 6.4% dalam 3 • Penghambat keuntungan,kerugian, biaya dan
ketersediaan sesuai tabel-11.
bulan tambahkan obat ke 2
Glukosidase Alfa
(kombinasi 2 obat) ** Kolesevelam belum tersedia di
Indonesia. Bromocriptin QR
umumnya digunakan pada terapi
tumor hipofisis.

Jika belum memenuhi sasaran

dalam 3 bulan, masuk ke Jika belum memenuhi sasaran
kombinasi 3 obat dalam 3 bulan, mulai terapi insulin /
intensifikasi terapi insulin
HbA1c < 7.5%
 HbA1c < 7.5%

Monoterapi* dengan
salah satu dibawah ini

• Metformin

• Agonis GLP-1
• Penghambat DPP-IV
• Penghambat Glikosidase Alfa
• Penghambat SGLT-2**
• Tiazolidindion
• Sulfonilurea
• Glinid MONO THERAPY*
HbA1c > 7.5%
 HbA1c > 7.5%

Kombinasi 2 obat dengan

mekanisme kerja yang berbeda

• Agonis GLP-1
Metformin / obat lini pertama yang lain +

• Penghambat DPP-IV
• Tiazolidindion
• Penghambat SGLT-2

• • Insulin basal
• SU/Glinid
• Kolesevelam**
• Bromokriptin-QR DUAL THERAPY*
• Penghambat Glukosidase Alfa
 HbA1c > 7.5%

KOMBINASI 3 OBAT

• Agonis GLP-1

• Penghambat DPP-IV
Metformin / obat lini pertama yang lain +

• Tiazolidindion
Obat lini kedua +

• Penghambat SGLT-2

• • Insulin basal

• Kolesevelam**
TRIPLE THERAPY*
• Bromokriptin-QR

• Penghambat Glukosidase Alfa

HbA1c > 9%
 HbA1c > 9%

GEJALA

Tidak Ada

kombinasi 2 obat

Insulin +/-
Obat jenis
lain

kombinasi 3 obat

Mulai atau intensifikasi insulin

 Profil obat antihiperglikemia oral yang tersedia di Indonesia

Efek Samping
Golongan Obat Cara Kerja Utama Penurunan HbA1c
Utama

Meningkatkan
Sulfonylurea BB naik hipoglikemia 1,0-2,0%
sekresi insulin

Meningkatkan
Glinid BB naik hipoglikemia 0,5-1,5%
sekresi insulin

Menekan produksi
glukosa hati & Dispepsia, diare,
Metformin menambah 1,0-2,0%
asidosis laktat
sensitifitas terhadap
insulin
Penghambat Alfa- Menghambat
Flatulen, tinja lembek 0,5-0,8%
Glukosidase absorpsi glukosa

Menambah
Tiazolidindion sensitifitas terhadap Edema 0,5-1,4%
insulin
Meningkatkan
Penghambat DPP-IV sekresi insulin, Sebah, muntah 0,5-0,8%
menghambat sekresi
Menghambat Dehidrasi, infeksi
Penghambat SGLT-2 penyerapan kembali 0,8-1,0% 47
saluran kemih
glukosa di tubuli
 Keuntungan, kerugian dan biaya obat anti hiperglikemik

Kelas Obat Keuntungan Kerugian Biaya

• Efek samping gastrointestinal

• Tidak menyebabkan • Risiko asidosis laktat Defisiensi vit B12
Bigunanide Metformin hipoglikemia • Kontra indikasi pada CKD, asidosis, hipoksia, Rendah
• Menurunkan kejadian CVD dehidrasi

• Glibenclamide
• Efek hipoglikemik kuat
• Glipizide • Risiko hipoglikemia
Sulfonylurea • Menurunkan komplikasi berat badan naik Rendah
• Gliclazide •
mikrovaskular
• Glimepiride

• Repaglinide Menurunkan glukosa • Risiko hipoglikemia

Metiglinides Berat badan naik Sedang
• Nateglinide postprandial •

• Tidak menyebabkan
• Berat badan meningkat
hipoglikemia
• Edema, gagal jantung
TZD Pioglitazone • ↑ HDL
• Risiko faktur meningkat pada wanita Sedang
• ↓ TG
menopause
• ↓ CVD event 48

• Tidak menyebabkan • Efektivitas penurunan A1C sedang

Penghambat alfa- hipoglikemia
glucosidase acarbose • Efek samping gastrointestinal Sedang
• ↓ Gula darah postprandial • Penyesuaian dosis harus sering dilakukan
• ↓ CVD event
 Keuntungan, kerugian dan biaya obat anti hiperglikemik

• sitagliprin • Tidak menyebabkan • Infeksi urogenital

• Poliuria
Penghambat • vidagliptin hipoglikemia
↓ berat badan
• Hipovolemia/hipotensi/pusing Tinggi
DPP-4 • saxagliptin •
• ↓ tekanan darah • ↑ LDL
• linagliptin • Efektif untuk semua fase DM • ↑ creatinin (transient)

• Efek samping gastrointestinal (mual/muntah/

• liraglutide diare)
Agonis • exenatide* • Tidak menyebabkan • ↑ heart rate
hipoglikemia • Hyperplasia c-cell atau tumor medulla tiroid
reseptor • albiglutide* pada hewan coba Tinggi
• ↓ Gula darah postrandial
GLP-1 • lixisenatide* • ↓ beberapa faktor risiko CV • Pankreatitis akut?
• dulaglutide* • Bentuknya injeksi
• Butuh latihan khusus

Rapid-acting analogs
• lispro
• aspart
• glulisine
• Hipoglikemia
Short-acting
• berat badan meningkat
• human regular • Responnya universal • efek mitogenik?
Intermediate-acting • Efektif menurunkan
Insulin • Dalam sediaan injeksi Bervariasi
• Human NPH glukosa darah • Tidak nyaman
Basal insulin analogs • ↓ komplikasi mikrovaskuler (UKPDS)
• Perlu pelatihan pasien
• glargine 49
•
• detemir
• degludec*
Premixed (beberapa
tipe)
 Sasaran Pengendalian DM

Parameter Sasaran

IMT (kg/m2) 18.5 - < 23*

Tekanan darah sistolik (mmHg) < 140 (B)

Tekanan darah diastolik (mmHg) < 90 (B)

Glukosa darah preprandial kapiler (mg/dL) 80-130**

Glukosa darah 1-2 jam PP kapiler (mg/dL) < 180**

HbA1c (%) <7 (atau individual) (B)

<100 (<70 bila risiko KV sangat

Kolesterol LDL (mg/dL)
tinggi) (B)

Kolesterol HDL (mg/dL) Laki-laki: >40; Perempuan: >50

(C) 50

Trigliserida (mg/dL) <150 (C)

Keterangan: KV = Kardiovaskular, PP = Post prandial 50
*The Asia-Pasific Perspective: Redefining Obesity and Its Treatment, 2000
** Standards of Medical Care in Diabetes, ADA 2015
 Pemantauan

Pemeriksaan HbA1 dilakukan untuk melihat

hasil terapi dan rencana perubahan terapi.

Diperiksa setiap 3 bulan atau tiap bulan pada

keadaan HbA1c sangat tinggi (> 10%)
 What period is measured?
Total influence of
monthly blood
Test at end May glucose on HbA1c

May May May

May May
6.25% 8.33% 52%
12.5% 25.0%
April
April 27%
April
March
March April 14.5%

March Feb
Feb 6.5%

February March April May

Month red blood cell produced
 Sharing
Experience
Mechanism of Mitochondrial Dysfunction.
Polymorphism Overloaded FFA Hyperglycemia

ROS

Mutations Mitochondrial Aging

Biogenesis

Mitochondrial
Dysfunction

Beta-Oxidation ROS ATP

Insulin Resistance
Cardiovascular Diseases
Diabetes
Kim J et al. Circulation Research. 2008;102:401-414 Copyright © American Heart Association, Inc. All rights reserved.
 Insulin Signaling Pathway.
Insulin Receptor

IRS-1/2

PI 3-Kinase

PDK-1
Akt

eNOS PKC
FOXO
NO GLUT4
G6Ptase/PEPCK
Vasodilation Glucose uptake
Gluconeogenesis

Heart Adipose Tissue

Liver Vascular Skeletal Muscle
Endothelium Heart
Insulin Resistance
 Natural History of Type 2 Diabetes

Altered
Glucose Diagnosis 
 Progression of
Normal Metabolism IGT* of T2D T2D Insulin
Resistance

Post-meal
glucose

Fasting
glucose
Insulin
concentration

β-Cell
Dysfunction
Microvascular disease

Macrovascular disease

*IGT=impaired glucose tolerance

Ramlo-Halsted & Edelman. Clinical Diabetes,2000;18:80–85
Insulin Signaling
Metabolic link : Insulin Resistance and Diabetes
 Lipotoxic Hypothesis of Insulin Resistance

LCCoA: Long chain acyl-CoA Savage et al, Hypertention, 200560

DAG: diacylglycerol
 New Point of View

61
Muoio et al, Science, 2004
Adipose tissue infiltration by macrophages in obesity

J. Clin. Invest. 2006;116:33-35

J. Intern. Med. 2007;262:422-430
 Cellular Origin of the Peptides Secreted
by Human Adipose Tissue
Stromavascular fraction cells
Adipocytes - Adipokines
— cytokines & chemiokines

Monocyte chemoattractant protein 1 (MCP1)

Leptin Macrophage inflammatory protein (MIP)
Adiponectin Tumor necrosis α (TNFα)
Serum amyloids Interleukins 1β, 6, 8, 10, ….
Retinol binding protein 4 (RBP4) Chemiokines
Apelin Resistin
etc Apelin
…
 Obesity + Inflammatory Infiltration of Fat Tissue

Lean with normal …… Obese with full

metabolic function metabolic dysfunction

Adipocyte Necrotic
adipocyte

……

CD4+T cell
Macrophage (M2) Crown-like structure
Proinflammatory cytokines
Leptin CCL2 TNF
CXCL5 IL-6 IL-18

Modified from Ouchi N et al., Nat Rev Immunol 2011

 Overview of Fatty Acid Metabolism

Alternate fuel source

for brain and other organs Liver
TG NEFA
Ketone bodies
and CO2
Adipose tissue
VLDL
LPL TG
Lipases

Chylomicrons NEFA
(lymphatic circulation) LPL
TG

Intestinal absorption FA Muscle,

CO2 myocardium,
kidney cortex,
etc.
Essays Biochem. 2006;42:89-103.
 Role of Fatty Acids in Obesity complications
Subcutaneous adipose tissue
Visceral adipose tissue Vessels
Thrombosis

Heart
Portal and visceral FA Abdominal FA Myocardial
performance
FA hepatic flux
Liver Skeletal
muscle
Non alcoholic Hepatic Glucose
steatohepatitis glucose utlization
production Pancreas
Increased synthesis
of TG-rich VLDL Glucose intolerance Hyperinsulinemia
Insulin resistance
Hyperlipidemia

Obesity complications
Fatty acid and Glucose Metabolism in White Adipocytes

IR

β1- β2- β3- α2-AR Glucose VLDL CL

ASP LPL
AR NH2 NH2

GLUT4
AC CD36
FAT
Gs Gi IRS
CO

CO
OH
OH

GLUT4
ATP PDE 3B PI3-K

cAMP Glucose 6-P

5' AMP PKB
PKA Pyruvate

Acetyl-CoA
Fatty acids
ALBP
ATGL Glycerol 3-P
HSL HSL Fatty acids
P
Perilipins DGAT

Triglycerides Fatty acids

 Diabetes therapies
Insulin Resistance

■ Metformin (biguanide) inhibits hepatic glucose

release.

■ Thiazolidinediones (TZDs) increase insulin

sensitivity by acting at PPAR gamma.

68
69
 Effects of Tyrosine and Serine Phosphorylation
Site of Insulin Binding
Alpha Sub Unit Tyrosine Kinase
Receptor

α α Cell Membrane
Insulin Sensitivity β β
Cellular Response
Tyrosine
IRS

Inlacin Phosporylation

Serine
P Tyrosine: Increase Insulin
Sensitivity
Beta Sub Unit Tyrosine Kinase
Receptor
P Serine: Causes Insulin
Insulin Resistance Resistance
 Inlacin
• Inhibit Serine Phosphorylation
• Reducing TNF Alpha
• Reducing FFA
• Increasing Insulin Sensitivity
Inlacin (DLBS3233) increases
GLUT-4 in Adipocytes
Summary of Research on Inlacin
in
Indonesia

1. Padang (Asman Manaf)

2. Surabaya (Askandar Tjokroprawiro
3. Denpasar (Ketut Suastika)
4. Manado (Karel Pandelaki)
5. Multicenter PCOS (Suhartono DS)
80
81
 Conclusion

Inlacin has been 5 years in clinical

practice in Indonesia

Clinical trials are still going on

Inlacin 50 & 100 mg DLBS3233
DLBS3233 adalah fraksi bioaktif yang mengandung Lagerstroemia
speciosa dan Cinnamomum burmannii.
Herbal-herbal tersebut dikembangkan melalui proses tertentu,
yang menghasilkan fraksi bioaktif dengan karaktek khusus dan
aktivitas biologi tertentu.
Kombinasi dari kedua herbal ini bekerja secara sinergis sehingga
efek yang dicapai pada diabetes lebih baik dibandingkan dengan
hanya menggunakan satu komponen saja.
Uji pra-klinis DLBS3233 menunjukkan efeknya dalam mengurangi
kadar gula dalam darah.
Hasilnya secara khusus menggambarkan bahwa fraksi bioaktif ini
meningkatkan ekspresi dari PI3 Kinase, Akt, GLUT-4, PPAR γ dan
PPAR δ pada level mRNA pada sel-sel 3T3 Swiss Albino Pre-
adipocyte.
Fraksi bioaktif ini juga mampu mengurangi ekspresi gen resistin
dan meningkatkan Glut-4 dan adiponectin pada level mRNA.
Adipose tissue secretes proteins which may influence insulin sensitivity. Among them,
tumour necrosis factor (TNF)-alpha has been proposed as a link between obesity and
insulin resistance because TNF-alpha is overexpressed in adipose tissue from obese
animals and humans, and obese mice lacking either TNF-alpha or its receptor show
protection against developing insulin resistance. The activation of proinflammatory
pathways after exposure to TNF-alpha induces a state of insulin resistance in terms of
glucose uptake in myocytes and adipocytes that impair insulin signalling at the level of
the insulin receptor substrate (IRS) proteins. The mechanism found in brown adipocytes
involves Ser phosphorylation of IRS-2 mediated by TNF-alpha activation of MAPKs. The
Ser307 residue in IRS-1 has been identified as a site for the inhibitory effects of TNF-
alpha in myotubes, with p38 mitogen-activated protein kinase (MAPK) and inhibitor kB
kinase being involved in the phosphorylation of this residue. Moreover, up-regulation of
protein-tyrosine phosphatase (PTP)1B expression was recently found in cells and
animals treated with TNF-alpha. PTP1B acts as a physiological negative regulator of
insulin signalling by dephosphorylating the phosphotyrosine residues of the insulin
receptor and IRS-1, and PTP1B expression is increased in peripheral tissues from obese
and diabetic humans and rodents. Accordingly, down-regulation of PTP1B activity by
treatment with pharmacological agonists of nuclear receptors restores insulin sensitivity
in the presence of TNF-alpha. Furthermore, mice and cells deficient in PTP1B are
protected against insulin resistance induced by this cytokine. In conclusion, the absence
or inhibition of PTP1B in insulin-target tissues could confer protection against insulin
resistance induced by cytokines.