Resistensi Insulin

Insulin Resistance dan
Pengaruhnya terhadap
Penanganan Diabetes Melitus
Sarwono Waspadji
Diabetes and Lipid Center,
Div. Endocrinology and Metabolism, Dept. of Medicine,
School of Medicine, University of Indonesia,
Salemba 6, Jakarta
Resistensi Insulin
Sindrom Resistensi Insulin
Kelainan Biomolekular Terkait Resistensi Insulin
Kelainan Klinis Terkait Resistensi Insulin
Implikasi Klinis Terkait Resistensi Insulin
Implikasi Klinis Khusus Pengelolaan Obat DM Tipe 2
Insulin Reseptor:
Suatu tirosin kinase
Glikoprotein Heterotetramerik transmembran
subunit alfa ekstraselular (723 a.a.)
subunit beta transmembran (620 a.a.)
Jumlah pada setiap sel bervariasi:
40 pd eritrosit
> 20.000 pd Adiposit
Dasar sistem signalling adalah:
fosforilasi tirosin kinase
modulasi serin/treonin kinase
treonin fosfat fosfatase
Cellular Mechanisms
of Insulin Action
C
-cell Insulin aS Sa
130K 130K
S

95K
Cell membrane
P
©1997
PPS
Intracellular
enzymes,
protein, RNA,
DNA synthesis
S
S
S

ATP
95K
ADP
P
-Tyr
Glucose
PP
Translocation
Mediators
and/or
phosphorylation
GLUT4
Kruszynska Y, Olefsky JM. J Invest Med. 1996;44:413-428.
s
Cell Membrane
s
S
s
s
a subunit
s
 subunit
ras
Tyr-P
SOS
raf
syp
Tyr-P
nck
?
Cell Growth
IRS-1
Tyr-P
IRS-2
Tyr-P
IRS-3 IRS-4
Tyr-P
Insulin Effects
grb
MEKK
PI-3
kinase
?
Metab.
Kinase
and
phosphatase
cascade
Transcript.
Insulin Effects
 Stimulate glucose transport
 Stimulate amino acid transport
 Stimulate lipid transport
 Activate or inactivate cytoplasm & membrane
enzymes
 Alter the rate of synthesis and degradation of
various proteins and specific mRNAs
 Influence the processes of cell growth and
differentiation

The multiple effects vary widely
- tissue to tissue
- dose response

Effect on glucose transport:
within seconds,
low insulin concentration

Action on cell growth in certain cells
require hours
high insulin concentration
Assessment of Insulin Resistance
 Determination of insulin level
 at fasting
 after OGTT
 Assessment of sequential plasma glucose after
i.v. administration of insulin (I.T.T.)
 Estimation of an index of insulin sensitively (Si) by
applying minimal model technique HOMA -IR
 Measurement of in vivo insulin mediated glucose
disposal by euglycemic / hyperinsulinemic clamp
technique
Resistensi Insulin
Sindrom Resistensi Insulin
Kelainan Biomolekular Terkait Resistensi Insulin
Kelainan Klinis Terkait Resistensi Insulin
Implikasi Klinis Terkait Resistensi Insulin
Implikasi Klinis Khusus Pengelolaan Obat DM Tipe 2
Syndrome X (Gerard Reaven 1988)
Resistance to insulin mediated glucose disposal
( hyperinsulinemia ) was a common finding in
patients with :
DM type 2 / IGT
Obesity
Hypertension
Hyper TG / Low HDL-chol
Deadly quartet
Metabolic syndrome
Insulin Resistance syndrome
Additional risk factors for the development of
cardiovascular complications / atherosclerosis :
- uric acid, PAI-1, etc --- Plurimetabolic syndrome
Cardio-metabolic syndrome
Cardiometabolic Risk
Resistensi Insulin
Sindrom Resistensi Insulin
Kelainan Biomolekular Terkait Resistensi Insulin
Kelainan Klinis Terkait Resistensi Insulin
Implikasi Klinis Terkait Resistensi Insulin
Implikasi Klinis Khusus Pengelolaan Obat DM Tipe 2
Environment Influences
Genetic Influences
Insulin Resistance
+
Hyperinsulinemia
Glucose
Uric acid
Dyslipidemia Hemodynamic Hemostatic
Metabolism Metabolism
Glucose
Intolerance
Uric Acid
Urinary
uric acid
Clearance
TG
SNS Activity
PP Lipemia
Na Retention
HDL Chol
Hypertension
PHLA
Small Dense LDL
Coronary Heart Disease
PAI-1
Fibrinogen
Resistensi Insulin
Sindrom Resistensi Insulin
Kelainan Biomolekular Terkait Resistensi Insulin
Kelainan Klinis Terkait Resistensi Insulin
Implikasi Klinis Terkait Resistensi Insulin
Implikasi Klinis Khusus Pengelolaan Obat DM Tipe 2
Insulin Resistance:
Causes and Associated Conditions
Aging
Obesity and
inactivity
Medications
Rare
disorders
Genetics
INSULIN
RESISTANCE
Type 2
DM
Hypertension
©1998
PPS
PCOS
Atherosclerosis
Dyslipidemia
C
Etiology of Type 2 Diabetes Mellitus:
Insulin Resistance and Diminished Insulin Secretion
Genes
Insulin Resistance
Lifestyle and
Diet
Normal
Abnormal
Beta Cell Function
Beta Cell Function
Compensatory
Hyperinsulinemia
Normoglycemia
Relative Insulin Deficiency
Hyperglycemia
Type 2 Diabetes Mellitus
Natural History of Type 2 Diabetes
IFG*
Uncontrolled Hyperglycemia
Obesity
Diabetes
350
Post-meal Glucose
(mg/dL)
Glucose
300
250
200
Fasting Glucose
150
100
Relative
Function (%)
50
250
Insulin Resistance
200
150
100
-cell Failure
50
-10
*IFG = impaired fasting
glucose
Insulin Level
-5
0
5
10
15
20
25
Years of Diabetes
Adapted from International Diabetes Center (IDC), Minneapolis, Minnesota.
30
Resistensi Insulin
Sindrom Resistensi Insulin
Kelainan Biomolekular Terkait Resistensi Insulin
Kelainan Klinis Terkait Resistensi Insulin
Implikasi Klinis Terkait Resistensi Insulin
Implikasi Klinis Khusus Pengelolaan Obat DM Tipe 2
Clinical Implications
1. Awareness : IRS has many clinical manifestations.
When 1 clinical manifestation is found,
as clinicians, we should actively
look for other manifestations of IRS
holistic approach
DM --- hypertension,
lipid abnormalities,
fibrinolytic activity,
obesity,
PCOS
others
Global cardiometabolic risk
Clinical Implications
2. Healthy life style is very important
to reduce the IR state
healthy, balance diet
regular physical exercise
prevention of obesity
stop smoking
etc.
ESC guidelines for CVD prevention:
nutrition
33
A healthy diet is recommended as the cornerstone of CVD prevention
Saturated fatty acids to account for < 10% of total
energy intake, through replacement of polyunsaturated
fatty acids
Trans-unsaturated fatty acids: as little as possible,
preferably no intake from processed food, and < 1%
total energy intake from natural origin
< 5 g salt per day
0.5 cup raw
brown rice (5.5
g fiber)
Two servings
of fruit
30–45 g of fiber per day, from wholegrain products,
fruits and vegetables
200 g of fruit per day (2–3 servings)
Two servings
of vegetables
200 g of vegetables per day (2–3 servings)
Fish at least twice a week, one of which to be oily fish
Consumption of alcoholic beverages should be limited
to 2 glasses/day (20 g/day of alcohol) for men and 1
glass/day (10 g/day) for women
One short
mackerel
CVD, cardiovascular disease.
ESC Committee for Practice Guidelines. Euro Heart J. 2012 (published online; doi:10.1093/eurheartj/ehs092).
ESC guidelines for CVD prevention:
physical activity
Participation in regular physical activity and/or aerobic exercise training
is
associated
a ages
decrease
inspend
CV mortality
Healthy
adultswith
of all
should
2.5–5.0 hours/week on physical
activity or aerobic exercise training of at least moderate intensity, or 1.0–2.5
hours/week on vigorous intense exercise
Sedentary subjects should be strongly encouraged to start light-intensity
exercise programs
Physical activity/aerobic exercise training should be performed in multiple
bouts, each lasting ≥ 10 min and evenly spread throughout the week, i.e.
on 4–5 days a week
Patients with previous acute myocardial infarction, CABG, PCI, stable
angina pectoris, or stable chronic heart failure should undergo moderateto-vigorous intensity aerobic exercise training ≥ 3 times a week and 30 min
per session
Sedentary patients should be strongly encouraged to start light-intensity
exercise programs after adequate exercise-related risk stratification
CABG, coronary artery bypass graft; CV, cardiovascular; CVD, cardiovascular disease; PCI, percutaneous coronary intervention
ESC Committee for Practice Guidelines. Euro Heart J. 2012 (published online; doi:10.1093/eurheartj/ehs092)
34
Clinical Implications
3. Awareness : as clinicians, when we treat certain
component of IRS, we should be aware of
the possible impairment of other components
of IRS, as the undesireble effect of
the drug in use
R/ Hypertension
R/ DM type 2
effect on glucose tolerance ?
effect on lipid profile ?
effect on blood coagulation ?
Obese / Non obese
ADA and EASD position statement:
patient-centered approach to managing
hyperglycaemia in T2DM
Patient-centered care is defined as an
approach to ‘providing care that is respectful of and responsive to individual
patient preferences, needs, and values and ensuring that patient values guide all
clinical decisions’1
 Glycaemic targets and glucose-lowering therapies must be individualised
 Diet, exercise and education remain the foundation of any T2DM treatment
program
 Where possible, all treatment decisions, should be made in conjunction with
the patient, focusing on his/her preferences, needs and values
 Comprehensive CV risk reduction must be a major focus of therapy
 Engaging patients in healthcare decisions may enhance adherence to therapy
ADA, American Diabetes Association; CV, cardiovascular; EASD, European Association for the Study of Diabetes; T2DM,
type 2 diabetes mellitus
1. Committee on Quality of Health Care in America: Institute of Medicine, 2001. The National Academies Press,
Washington. 2. Inzucchi SE, et al. Diabetes Care. 2012;35(6):1364–79.
36
Steno-2: Multifactorial Intervention and
Cardio Vascular Disease in patients with T2DM
Conclusion
The intensified intervention aimed
at multiple risk factors reduces
the risk of cardiovascular and
microvascular events by about 50 %
Primary composite
endpoint* (%)
60
50
40
Conventional treatment
P = 0.007
Intensive treatment
30
20
10
0
0
12
24
36
48
60
72
84
96
44
61
41
59
13
19
Follow-up (months)
Number at risk
Conventional
Intensive
80
80
72
78
70
74
63
71
* Composite endpoint = CV death and amputation
(with either therapy), and relative risk for organ damage
(with intensive therapy)
59
66
50
63
Gaede P et al. N Engl J Med. 2003; 348: 383–93.
Clinical Implications
4. When we found a drug / a measure
which has been proven to be effective
to reduce the IR state,
it might also be effective for
the treatment of other components
of IRS
Metformin for PCOS ?, for lipid ?
Thiazolidinedione for PCOS ?
Treatment of Obesity for Metabolic syndrome
Resistensi Insulin
Sindrom Resistensi Insulin
Kelainan Biomolekular Terkait Resistensi Insulin
Kelainan Klinis Terkait Resistensi Insulin
Implikasi Klinis Terkait Resistensi Insulin
Implikasi Klinis Khusus Pengelolaan
Obat DM Tipe 2
Natural History of Disease Progression
Aggressive treatment of established cardiovascular risk factors
Macrovascular complications
Microvascular complications
Aggressive glycemic control
-cell function
Insulin
resistance
Blood
glucose
–10
Prevention
IGT/IFG
Prevention of IGT
0
Diagnosis
Treatment
10
Years
Type 2 diabetes
Prevention of progression of IGT to Type 2 DM
Adapted from Bergenstal RM, et al. Diabetes mellitus, carbohydrate metabolism and lipid disorders. In Endocrinology. 4th
ed. 2001.
Pathogenesis of T2DM: the Ominous Octet
TZDS
GLP1
DPP4i
GLP1
DPP4i
TZDs
SGLT2 i
TZDs,GLP1
TZDs, MET
GLP1,DPP4i
DeFronzo RA. Diabetes. 2009;58:773-95.
GLP1
DM tipe 2
Gemuk
•Edukasi
•Diet
•Olahraga
Dekompensasi
Metab. Berat
Evaluasi 4-8 mgg
Biguanid / Acarbose
Biguanid / Acarbose
+ Sulfonil urea
Biguanid + Acarbose
+ Sulfonil urea
INSULIN atau
INSULIN + OHO
Konsensus Pengelolaan Diabetes Melitus di Indonesia 1998
DM tipe 2
Tidak Gemuk
•Edukasi
•Diet
•Olahraga
Dekomp.
metabolik
berat
Evaluasi 4-8 mgg
Sulfonilurea / Acarbose
Sulfonil urea
+ Biguanid / Acarbose
Sulfonil urea
+ Biguanid + Acarbose
INSULIN atau
INSULIN + OHO
Konsensus Pengelolaan Diabetes Melitus di Indonesia 1998
AACE Comprehensive Diabetes Management Algorithm. Endocrine Practice. 2013;10(2):332
ADA/EASD. Diabetes Care. 2012;35(6):1364-79
ADA. Approach to Glycemic Treatment. Diabetes Care.2015; 38(suppI. I):S43
51
Thai Diabetes Treatment Guidelines
Lifestyle modification (1–3 months, if
uncontrolled)
FPG < 180 mg/dL and
HbA1c < 8%
Monotherapy
FPG 180–250
mg/dL
FPG 250–350
mg/dL or HbA1c > 9%
(consider 2 OADs)
FPG > 300 mg/dL or
HbA1c > 11%
(hyperglycaemia)
Lifestyle
modification
and
begin therapy
Receive treatment but FPG
> 300 mg/dL or HbA1c >
11% ± underlying condition
or complication
Metformin
Sulfonylurea
Insulin-resistant:
• BMI ≥ 23 kg/m2 or waist
circumference above average
• Acanthosis nigricans
• BP ≥ 130/85 mmHg (or receive antihypertensive drugs)
• Elevated TG, low HDL-C
Insulin-deficient
• BMI < 23 kg/m2 or waist
circumference not above
average
• Hyperglycaemia
Optional therapy: Glitazone or repaglinide or AGI or DPP-4 inhibitor
Combination therapy
Metformin +
Sulfonylurea +
1.
2.
3.
4.
1.
2.
3.
4.
Sulfonylurea or glinide
Thiazolidinedione
DPP-4 inhibitor
Basal insulin
Metformin
Thiazolidinedione
DPP-4 inhibitor
Basal insulin
Optional therapy: AGI
Triple oral therapy
Combination OADs + premixed insulin or premixed
insulin analogue (before breakfast or dinner)
AGI; α-glucosidase inhibitor; BMI, body mass index;
BP, blood pressure; DPP-4, dipeptidyl peptidase-4;
FPG, fasting plasma glucose; HbA1c, glycated
haemoglobin; LAA, long-acting analog; NPH, neutral
protamine Hagedorn; OAD, oral anti-diabetic agent;
RAA, rapid-acting analog; RI, regular insulin.
Combination OADs + insulin NPH before
bed (21:00–23:00) or LAA
Premixed insulin or premixed insulin analogue
(before breakfast and dinner) + metformin
Multiple insulin injections
Start LAA insulin injection before bed (or before breakfast) OR insulin
NPH before bed or insulin RI OR RAA before meals. Monitor blood sugar
after meal and adjust insulin dose OR refer to endocrinologists
AACE Guidelines 2013. Endo Prac . 2013;19:327-36
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