kuliah insulin resisten.ppt [Read-Only]ocw.usu.ac.id/course/download/1110000095...2)Dyslipidemia...
Transcript of kuliah insulin resisten.ppt [Read-Only]ocw.usu.ac.id/course/download/1110000095...2)Dyslipidemia...
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)
G������ ������������ ��� �������
������
Shepherd PR et al. Glucose transporters and insulin action. NEJM, July 22, 1999
I������ R��������� I������ R��������� ����������������
* 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