INSULIN RESISTANCE

Divisi Endokrin-Metabolik
Departemen Ilmu Penyakit Dalam FK USU / RSUP HAM
Medan
 Other Names Used:

• Syndrome X
• Cardiometabolic Syndrome
• Cardiovascular Dysmetabolic
Syndrome
• Insulin-Resistance Syndrome
• Metabolic Syndrome
• Beer Belly Syndrome
• Reaven’s Syndrome
The concept has existed for an 80 ye

KYLIN 1923 KAPLAN 1989 (DEADLY

QUARTET)

VAGUE 1947

WHO 2001
WORKING GROUP ON
CREPALDI 1967 DIABETES

FERRANNINI 1991 8c
HAFFNER 1992
REAVEN 1988 (INSULIN RESISTANCE SYNDROME)

(SYNDROME X)

TheW I

Metabolic Syndrome
-r— ■... Institute
 Prevalence

• Affects as many as one in four American adults

(25%)
• For adults over the age of 40, more than 40%
• increased 61% over the past decade.
• Rates differ among races and genders.
 Definisi Insulin resistance:
• Impaired response to the physiological effects
of insulin (including on glucosa, lipid and protein
metabolisme) and the effect on endothelial
function.

• Glucose can no longer be absorbed by the

cells but remains in the blood, triggering the
need for more and more insulin
(hyperinsulinaemia).
 Pharmacodynamics of insulin

* Affects all major metabolic pathways

carbohydrate, fat, protein

* Major target tissues are

liver, adipose, and skeletal muscle *

* Decreases hepatic glucose production

decreases gluconeogenesis, glycogenolysis, ketogenesis,
(also glycogen synthesis)
A Insulin-sensitive | Glucose

f Glycogen
synthesis

Insulin I Liver

|
Glyco
{Gluconeogenesis
gen

^|FA
turnover-------------► T Ac-CoA

I Lipolysis t
Pyruvate - • {pc * - PEPCK G6Pase -activity \ ► {Glucose
production

•{Glycerol ■
turnover-------------------------► jDHAP

White
adipose tissue
 Insulin Resistance
B Insulin resistance/type 2 diabetes
|
Glycogen
synthesis
i

t
• Insulin \ Glycogen
1
1
1
1
\_ fGluconeogenesis
t E
FA

turnover
-► f Ac-CoA

| Lipolysis
Pyruvate - | PC - PEPCK -7— G6Pase v f Glucose
^I^ activity productio
n
^ Glycerol
fDHAP
| Adipose turnover
macrophages
 ance problem:

* Receptor:
Quantity /function

* Post-
receptor
Translocation
(mostly): of GL UT:
IRS (insulin receptor substance) / kinase
Synthesis of GLUT
 Stimulation of glucose
transport GLUT-4 Cell Insulin
membrane Insulin
receptor.

5'-AMP-activated
kinase Protein
kinase B Tyrosine phosphorylation
v <Akt) >

Translocation
to cell Phosphoinositide
membrane dependent kinases
Exercise-^
j .x'
responsive
GLUT-4- Phosphoinositide-3
containing Atypical kinase SH2
k vesicle ~ protein domai
kinase C ns

Insulin- Cytoplasm
responsive
GLUT-4-
containing
_ vesicle r*

Shepherd PR et al. Glucose transporters and insulin action. NEJM, July 22, 1999
 Insulin resistance - reduced
response to circulating insulin
Insulin J I
resistance
i
__3
Liver
1 Adipose
tissue

t Glucose output i Glucose uptake 4- Glucose uptake

 Causes of Insulin Resistance:
Inherited and Acquired Influences
Inherited Acquired

Rare Mutations: ■ Inactivity

■ Insulin Receptor ■ Overeating
■ Glucose Transporter ■Aging
■ Signaling Proteins
■ Medications
■
Common Forms: Hyperglycemia
■ Largely unidentified
■ Elevated
FFAS
 Hyperinsulinemia

Uric Acid Novel Risk

Dyslipidemia Hemodynamic
Metabolism Factors
▼
• 1 Uric acid
s • 1s TG 1s SNS activity CRP
Glucose • sL Urinary • 1s PP lipemia 1s Na retention PAI-1
intolerance uric acid • sL HDL-C Hypertension 1 Fibrinogen
s

clearance • sL PH LA
• Small, dense LDL

CORONARY HEART DISEASE

Adapted from Reaven G. Drugs. 1999;58 (suppl): 19-20
Insulin Resistance: Associated Conditions

Type 2 diabetes
Atherosclerosis Hypertension

Impaired
Dyslipidemia
glucose tolerance
Insulin
Resistanc
Decreased
e
Obesity (central)
fibrinolytic activity

Acanthosis Polycystic
nigricans ovary disease
Hyperuricemia

Adapted from Consensus Development Conference of the American

Diabetes Association. Diabetes Care. 1998;21:310-314.
 ©
Interrelationship Between Insulin
Resistance and Atherosclerosis
 MEASUREMENT INSULIN
_RESISTANCE_
• Euglycemic Clamp

• Fasting Plasma Insulin Concentration

• The Homeostasis Model Assessment (HOMA)
• Quantitative Insulin Sensitivity Check Index
(QUICKI)
• Continuous Infusion of Glucose with Model
Assessment (CIGMA)
• Oral Glucose Tolerance Test (OGTT)
• Insulin Tolerance Test (ITT)
CAUSE The Metabolic Syndrome:
a network of atherogenic factors
Genetic factors
Environmental the deadly quartet
factors
Hyperglycemia/IGT

Visceral obesity
Dyslipidemia
Hypertension/
Microalbuminuria

Atherosclerosis

McFarlane S, etal. J Clin Endocrinol Metab 2001; 86:713-718.

Insulin Resistance Syndrome
The Metabolic Syndrome: Genes &
Environment Interacting

Early Life Low Adult life

birth weight Sedentary lifestyle
Poor nutrition Dietary factors

Metabolic
Syndrome

\
CARDIOVASCULAR
DISEASE
The Metabolic Syndrome (“Deadly
Quartet”)
" A cluster of risk factors for diabetes and
cardiovascular disease” consisting of:
Central (abdominal) obesity Diabetes,
IFG and IGT
Hypertension
Dyslipidaemi
a
 Risk Factors

Age The prevalence of metabolic syndrome increases with age, affecting

less than 10% of people in their 20s and 40% of people in their 60s.
Race Metabolic syndrome is generally more common among blacks and
Mexican-Americans than among Caucasians.
Obesity A body mass index (BMI) greater than 25 increases your risk of
metabolic syndrome and abdominal obesity increase the risk of MS.
Abdominal obesity refers to having an apple shape rather than a pear.
History of
diabetes Having a family history of type 2 diabetes or diabetes during pregnancy
(gestational diabetes) increases the risk for developing metabolic
Other syndrome.
diseases A diagnosis of hypertension, cardiovascular disease (CVD) or
polycystic ovary syndrome (a hormonal disorder in which a woman’s
body produces an excess of male hormones) also increases the risk for
metabolic syndrome.
Effect of Insulin Resistance
 Clinical Symptom Insulin
Resistance; A Metabolic Time Bomb
 Signs and Symptoms

Metabolic syndrome
(Syndrome X)

• Central obesity

• High blood pressure

• High triglycerides

• Low HDL-cholesterol
Insulin resistance

Li */YDAJVI.
 Criteria for diagnosis:

• World Health Organization

• International Diabetes Federation (IDF)

• European Association for the Study

of Diabetes (EASD)
• National Cholesterol Education
Project, Adult Treatment Panel (NCEP-
ATP III)
• Others
WHO EGIR ATPIII
Main criteria 1) Abdominal
Main criteria Insulin resistance obesity
Insulin resistance
OR 2(High triglycerides
3)Low HDL
DM / IGT / IFG cholesterol
Other components 4)Blood pressure
Other
1) Blood
components
pressure 1 )Hyperglycemia >130/85
>140/90 2) Blood pressure 5)High fasting
2) Dyslipidemia >140/90 glucose
3) Dyslipidemia (three or more)
3) Central obesity
4) 4) Central
Microalbuminura obesity (two or
more)
International Diabetes Federation (IDF) Consensus
Definition 2005
Central Obesity
Waist circumference - ethnicity specific*
- for Europids: Male > 94 cm (90 Cm

Female > 80 cm (80 cm)

plus any two of the following:
Raised triglycerides > 150 mg/dL (1.7 mmol/L)
or specific treatment for this lipid abnormality
Reduced HDL < 40 mg/dL (1.03 mmol/L) in males
cholesterol < 50 mg/dL (1.29 mmol/L) in females
or specific treatment
for this lipid abnormality Raised blood pressure
Systolic : > 130 mmHg or
Diastolic: > 85 mmHg or
Treatment of previously diagnosed
hypertension
Raised fasting plasma Fasting plasma glucose >
TEST INSULIN RESISTANCE
Tests Recommended for Research: May Be Added
To Definition Later
 MANAGEMENT:

Life-Style Modification

• Exercise
- Improves CV fitness, weight control, sensitivity to
insulin,
reduces incidence of diabetes
• Weight loss
- Improves lipids, insulin sensitivity, BP levels, reduces
incidence of diabetes
• Goals: Brisk walking - 30 min./day
10% reduction in body wt.
 Drug Treatment of The
Metabolic Syndrome

• Achieve LDL-C targets

• Correct atherogenic dyslipidemia
• Non-HDL-C target goal is second
priority
• Consider HDL-C raising
• Control diabetes mellitus if present

NCEP ATP III. Circulation. 2002;106:3143-3421.

Drug Therapy of The Metabolic Syndrome
• Decrease small, dense LDL particles
- Statins
- Nicotinic acid (niacin)
- Fibrates
(statins may be more effective in reducing total number of LDL particles)
• Decrease triglycerides
- Fibrates
- Omega-3 fatty acids
- Nicotinic acid (niacin)
- Statins
• Increase HDL-C
- Nicotinic acid (niacin)
- Fibrates, especially if hypertriglyceridemia is present
NCEPATP III. Circulation. 2002;106:3143-3421.
Summary of The Metabolic Syndrome

• Diagnosis indicates a high-risk patient

beyond that classically defined by risk factor
assessment
• Achieve LDL-C target goals
• Control atherogenic dyslipidemia
• Weight loss and increased physical activity
deserve a high priority

NCEP ATP III. Circulation. 2002;106:3143-3421.

Insulin Resistance - Hidden Dangers

• Hyperinsulinemia
• IGT
• Dyslipidemia
• Hypertension
• Coagulation
abnormality
IGT = impaired glucose tolerance