INSULIN RESISTANCE

Santi Syafril

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

• etc.

The concept has existed for more than 80 yearsThe concept has existed for more than 80 years

Definition 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 • Diabetes, IFG and IGT

• Hypertension

• Dyslipidaemia

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)

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Shepherd PR et al. Glucose transporters and insulin action. NEJM, July 22, 1999

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* Receptor:* Receptor:* Receptor:* Receptor:� Quantity / function

* Post* Post* Post* Post----receptor receptor receptor receptor (mostly)::::* Post* Post* Post* Post----receptor receptor receptor receptor (mostly)::::� Translocation of GLUT:

IRS (insulin receptor substance) / kinase

� Synthesis of GLUT

Insulin resistance – reduced

response to circulating insulin

Insulinresistance

Liver Muscle Adipose

tissue

IR

↑↑↑↑ Glucose output ↓↓↓↓ Glucose uptake ↓↓↓↓ Glucose uptake

Hyperglycemia

tissue

Insulin Resistance: Associated

Conditions

The Metabolic Syndrome Is

A Metabolic Time Bomb

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. • increased 61% over the past decade.

• Rates differ among races and genders.

National Health and Nutrition

Examination Survey III, 1988-1994.

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

Apple Pear

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 woman’s

body produces an excess of male hormones) also increases the risk

for metabolic syndrome.

Clinical Causes of The Metabolic

Syndrome

• Overweight/obesity

• Physical inactivity

• Genetics• Genetics

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

CAUSE The Metabolic Syndrome: CAUSE The Metabolic Syndrome: a network of atherogenic factorsa network of atherogenic factors

Genetic factors

Environmentalfactors

Insulin Resistance

Hyperglycemia/IGT

Visceral obesity

Dyslipidemia

the deadly quartet

Atherosclerosis

McFarlane S, et al. J Clin Endocrinol Metab 2001; 86:713–718.

Insulin Resistance Dyslipidemia

Hypertension/ Microalbuminuria

Insulin Resistance Syndrome

Genetic

Influences

Insulin

Resistance

Environmental

Influences

Hyperlipidemia

Glucose

Intolerance

Increase

Triglycerides

Decreased

HDL

Cholesterol

Small Dense

LDL

Increased

Blood

PressurePAI-1

Coronary Heart

Disease

The Metabolic Syndrome: Genes &

Environment Interacting

The Metabolic Syndrome: Genes &

Environment Interacting

Adult life

• Sedentary lifestyle

• Dietary factors

Adult life

• Sedentary lifestyle

• Dietary factors

Early Life

• Low birth weight

• Poor nutrition

Early Life

• Low birth weight

• Poor nutrition

MetabolicMetabolicSyndromeSyndromeMetabolicMetabolicSyndromeSyndrome

GenesGenesCARDIOVASCULAR CARDIOVASCULAR

DISEASEDISEASECARDIOVASCULAR CARDIOVASCULAR

DISEASEDISEASE

The Metabolic Syndrome:

Current PerspectiveBody SizeBody Size�������� BMIBMI

�������� Central AdiposityCentral Adiposity

Insulin ResistanceInsulin Resistance

HyperinsulinemiaHyperinsulinemia++

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

GlucoseGlucoseMetabolismMetabolism

Uric AcidUric AcidMetabolismMetabolism

DyslipidemiaDyslipidemia HemodynamicNovel Risk

Factors

CORONARY HEART DISEASECORONARY HEART DISEASE

���� TGTG���� PP lipemiaPP lipemia���� HDLHDL--CC���� PHLAPHLA��Small, dense LDLSmall, dense LDL

��±± GlucoseGlucose

intoleranceintolerance

���� Uric acidUric acid���� Urinary uricUrinary uricacid clearanceacid clearance

���� SNS activitySNS activity���� Na retentionNa retention��HypertensionHypertension

���� CRPCRP���� PAIPAI--11���� FibrinogenFibrinogen

Signs and Symptoms

Criteria for diagnosis:

• World Health Organization

• International Diabetes Federation (IDF)

• European Association for the Study of • European Association for the Study of

Diabetes (EASD)

• National Cholesterol Education Project, Adult Treatment Panel (NCEP-ATP III)

• Others

________________________________________________

The Metabolic Syndrome Proposed definitions

WHOMain criteria

Insulin resistance

OR

DM / IGT / IFG

ATPIII1)Abdominal

obesity

2)High triglycerides

3)Low HDL

EGIRMain criteria

Insulin resistance

DM / IGT / IFG

Other components

1)Blood pressure

≥140/90

2)Dyslipidemia

3)Central obesity

4)Microalbuminura

(two or more)

3)Low HDL

cholesterol

4)Blood pressure

≥130/85

5)High fasting

glucose

(three or more)

Other components

1)Hyperglycemia

2) Blood pressure

≥140/90

3)Dyslipidemia

4)Central 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 abnormalityor 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.

TEST INSULIN RESISTAN

����TG

IFG &AbdominalObesity

���� BP

Adipo-nectin

InsulinResistance*

CRP

Microalb

Tests Recommended for Research: May Be Added

To Definition Later

OGTTIFG &

DiabetesObesity

����HDL

Apo BLittle LDL

PAI-1

* HOMA, euglycemic clamp, fasting insulin etc

Microalb

MANAGEMENT:

Life-Style Modification

• Exercise

– Improves CV fitness, weight control, sensitivity to insulin, reduces incidence of diabetesreduces 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• 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• 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• 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• Hyperinsulinemia

• IGT

• Dyslipidemia

• Hypertension

• Coagulation

abnormality

IGT = impaired glucose tolerance

Joslin ; Diabetes Mellitus 14th Edit