INSULIN RESISTANCE

Dharma Lindarto
Divisi Endokrin-Metabolik
Departemen Ilmu Penyakit Dalam FK USU / RSUP HAM
Medan

The concept has existed for more than 80 years

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).
ADA. Diab Care 1988

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
Dyslipidaemia

Other Names Used:

Syndrome X
Cardiometabolic Syndrome
Cardiovascular Dysmetabolic Syndrome
Insulin-Resistance Syndrome
Metabolic Syndrome
Beer Belly Syndrome
Reavens Syndrome
etc.

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.

National Health and Nutrition

Examination Survey III, 1988-1994.

Risk Factors
Apple

Pear

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
syndrome.

Other
diseases

A diagnosis of hypertension, cardiovascular disease (CVD) or

polycystic ovary syndrome (a hormonal disorder in which a womans
body produces an excess of male hormones) also increases the risk
for metabolic syndrome.

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)

Insulin Signaling: Stimulation

of Glucose Uptake
Insulin

Insulin resistance reduced

response to circulating insulin
Insulin
resistance

Liver

IR
Adipose
tissue

Muscle

Glucose output

Glucose uptake

Glucose uptake

Hyperglycemia

Insulin Resistance: Associated

Conditions

The Metabolic Syndrome Is

A Metabolic Time Bomb

Causes of The Metabolic Syndrome

Overweight/obesity
Physical inactivity
Genetics
Closely associated with insulin resistance
Underlying cause of diabetes

Reduced HDL-C
Elevated triglycerides
Hypertension
Abdominal obesity

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

CAUSE The Metabolic Syndrome:

a network of atherogenic factors
Genetic factors
Environmental
factors

the deadly quartet

Hyperglycemia/IGT
Visceral obesity
Insulin Resistance

Dyslipidemia
Hypertension/
Microalbuminuria

Atherosclerosis
McFarlane S, et al. J Clin Endocrinol Metab 2001; 86:713718.

Insulin Resistance Syndrome

Genetic
Influences

Insulin
Resistance

Environmental
Influences

Hyperlipidemia

Glucose
Intolerance

Increase
Triglycerides

Decreased
HDL
Cholesterol

Increased
Blood
Pressure

Small Dense
LDL

PAI-1
Coronary Heart
Disease

The Metabolic Syndrome: Genes &

Environment Interacting
Early
EarlyLife
Life
Low
Low birth
birthweight
weight
Poor
Poor nutrition
nutrition

Adult
Adult life
life
Sedentary
Sedentarylifestyle
lifestyle
Dietary
Dietaryfactors
factors
Metabolic
Metabolic
Syndrome
Syndrome

Genes
Genes

CARDIOVASCULAR
CARDIOVASCULAR
DISEASE
DISEASE

Causes (molucular):
Multiple level: genetic and acquired
Prereceptor (eg: high level antibodies, FFA)
Receptor: (eg; genetic alteration: Robson
Mendenhal Syndrome)
Post receptor; (alteration pathway insulin
signal)

Pathogenesis of the Metabolic Syndrome

Abdominal Adiposity
Enlarging adipocytes

Liver

glucose

Increased adipocytokines
and FFA
Inflammatory

Insulin resistance

(IL-6, coagulation factors)

Metabolic Syndrome

The Metabolic Syndrome:

Current Perspective
Body
BodySize
Size

BMI
BMI

Central
CentralAdiposity
Adiposity

Insulin
Insulin Resistance
Resistance

Hyperinsulinemia
Hyperinsulinemia
Glucose
Glucose
Metabolism
Metabolism

Glucose
intoleran
ce

Uric
UricAcid
Acid
Metabolism
Metabolism

Uric

acid
Urinary
uric
acid
clearance

Dyslipidemia
Dyslipidemia

TG
PP lipemia
HDL-C
PHLA
Small, dense
LDL

Hemodynamic
Hemodynamic

SNS activity
Na retention
Hypertension

CORONARY
CORONARY HEART
HEART DISEASE
DISEASE
Adapted from Reaven G. Drugs. 1999;58 (suppl):19-20

Novel
Novel Risk
Risk
Factors
Factors

CRP
PAI-1

Fibrinogen

Signs and Symptoms

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

The Metabolic Syndrome Proposed definitions

________________________________________________

WHO

EGIR

ATPIII

Main criteria
Insulin resistance
OR
DM / IGT / IFG

Main criteria
Insulin resistance

Other components
1)Blood pressure
140/90
2)Dyslipidemia
3)Central obesity
4)Microalbuminura
(two or more)

Other components
1)Hyperglycemia
2) Blood pressure
140/90
3)Dyslipidemia
4)Central obesity
(two or more)

1)Abdominal
obesity
2)High triglycerides
3)Low HDL
cholesterol
4)Blood pressure
130/85
5)High fasting
glucose
(three 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
cholesterol

< 40 mg/dL (1.03 mmol/L) in males

< 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
glucose

Fasting plasma glucose > 100 mg/dL (5.6 mmol/L) or

Previously diagnosed type 2 diabetes
If above 5.6 mmol/L or 100 mg/dL, OGTT is strongly recommended
but is not necessary to define presence of the syndrome.

Tests Recommended for Research: May Be Added

To Definition Later
CRP

Adiponectin

BP

Insulin
Resistance*

TG
Abdominal
IFG &
Obesity

Microalb

Diabetes

HDL
PAI-1

Apo B
Little LDL

* HOMA, euglycemic clamp, fasting insulin etc

OGTT

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.

Management (cont)

Obesity
Glucose Intolerance
Insulin Resistance
Lipid Disorders
Hypertension

Goals: Minimize Risk of Type 2 Diabetes and

Cardiovascular Disease

Drug Treatment of
The Metabolic Syndrome

Achieve LDL-C targets

Correct atherogenic dyslipidemia
NonHDL-C target goal is second priority
Consider HDL-C raising

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

 Correct insulin resistance

Weight reduction
Increased physical activity
Drugs which decrease insulin resistance
have not been proven to reduce CHD risk
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
NCEP ATP 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

Type 2 Diabetes
Hyperinsulinemia
IGT
Dyslipidemia
Hypertension
Coagulation
abnormality
IGT = impaired glucose tolerance

Thank You for Your Attention

Joslin ; Diabetes Mellitus 14th Edit