The Metabolic Syndrome The Metabolic Syndrome from Insulinfrom Insulin

Resistance to Obesity and Resistance to Obesity and DiabetesDiabetes

Endocrinol Metab Clin N AmEndocrinol Metab Clin N Am37 (2008) 559–57937 (2008) 559–579

growing prevalence of obesity growing prevalence of obesity worldwide is increasing concernworldwide is increasing concern surrounding the rising rates of surrounding the rising rates of diabetes, coronary, and diabetes, coronary, and cerebrovascular diseasecerebrovascular disease

Metabolic syndrome wMetabolic syndrome which affects an hich affects an estimated 20–estimated 20–3434% of the general% of the general populationpopulation

metabolic syndrome comprises an metabolic syndrome comprises an assembly of risk factorsassembly of risk factors for for developing diabetes and developing diabetes and cardiovascular diseasecardiovascular disease

metabolic syndrome and whether it metabolic syndrome and whether it should be definedshould be defined as a syndrome of as a syndrome of insulin resistance, the metabolic insulin resistance, the metabolic consequences ofconsequences of obesity, or risk obesity, or risk factors for cardiovascular diseasefactors for cardiovascular disease

Historic overviewHistoric overview clustering of metabolic risk factors clustering of metabolic risk factors

for coronary arteryfor coronary artery disease, diabetes, disease, diabetes, and hypertension was described as and hypertension was described as ‘‘Syndrome X’’ by‘‘Syndrome X’’ by

Reaven in 1988Reaven in 1988

Metabolic SyndromeMetabolic SyndromeWHO CriteriaWHO Criteria

Alberti & Zimmet WHO 1998 Diabetic Medicine.

METABOLIC SYNDROME

IGT/IFG or Type 2 DM

Insulin resistance

Triglycerides 1.7 mmol/l& HDL-Ch < 0.9 mmol/l

Blood pressure 160/90 mmHg

MicroalbuminuriaUAE 20 µg min

Central ObesityWHR > 0.9 men

> 0.8 womenor BMI > 30 kg/m²

NCEP-ATP III General Features of Metabolic SyndromeRisk Factor Defining Level

Abdominal Obesity(waist circumference)

Men > 102 cmWomen > 88 cm

Plasma Triglyceride > 150 mg/dLHDL-chol

Men < 40 mg/dLWomen < 50 mg/dL

Blood Pressure > 135 / > 85 mmHgFasting Blood glucose > 110 mg/dL

Metabolic Syndrome : > 3 risk factors

Genetic Genetic InfluencesInfluences

EnviromentaEnviromental Influencesl InfluencesInsulin ResistanceInsulin Resistance

HyperinsulinaemiaHyperinsulinaemia

Accelerated Accelerated AtherosclerosisAtherosclerosis

Glucose Glucose IntoleranceIntolerance

TriglyceridesTriglycerides

HDL HDL CholesterolCholesterol

Blood Blood PressurePressure

Free Free Fatty AcidsFatty Acids

Small Small Dense LDLDense LDL

Uric AcidUric Acid PAI-1PAI-1

Adapted from ReavenAdapted from Reaven GM. GM. Phys Rev 1995; Phys Rev 1995; 75(3): 6875(3): 68

Relationship Between Insulin Resistance Relationship Between Insulin Resistance and Accelerated Atherosclerosisand Accelerated Atherosclerosis

14

promoter Coding reg

transcription

mRNA

Modified from Howard L. Foyt et al. Thiazolidinediones. Diabetes Mellitus: a Fundamental and Clinical Text, 2nd Ed.

Synthesis GLUT 4

translocation

PPAR

PPRE

Insulinreceptor

Insulin

RXR

Glucose

NORMALPPAR-γ

PPAR

promoter Coding reg

+RXR

Modified from Howard L. Foyt et al. Thiazolidinediones. Diabetes Mellitus: a Fundamental and Clinical Text, 2nd Ed.

PPRE

receptor

Insulin

Insulin resistance

Glucose

mRNASynthesis GLUT 4

X

X

transcription

InsulinInsulin

METABOLISME LIPOPROTEIN PADA RESISTENSI INSULIN METABOLISME LIPOPROTEIN PADA RESISTENSI INSULIN

RIRI****

Sel LemakSel Lemak

ALB*HatiHati

TGTG ApoBApoB VLDLVLDL

VLDLVLDLbesar besar

(CETP)

(CETP)

LDLLDLkecil kecil padatpadat

(lipoprotein atau lipase hati)

ApoA1ApoA1

GinjalGinjal

TGTG

HDLHDL

LDLLDL

TGTG

Kwiterovich PO, Jr. The metabolic pathways of high-density lipoprotein, low-density lipoprotein, Kwiterovich PO, Jr. The metabolic pathways of high-density lipoprotein, low-density lipoprotein, and triglycerides: A current review. Am J Cardiol 2000;86:5L-10L and triglycerides: A current review. Am J Cardiol 2000;86:5L-10L

*Asam lemak bebas

** Resistensi insulin

β cells apoptosis

Glucose Uptake

Adapted from Ross RAdapted from Ross R. N Engl J Med. N Engl J Med 1999; 1999;362362:115–:115–126.126.

Tunica media:Tunica media:Smooth muscle cellSmooth muscle cellMatrix proteinsMatrix proteins

Internal elastic membraneInternal elastic membraneEndotheliumEndothelium

Tunica intima:Tunica intima:

External elastic membraneExternal elastic membrane

LumenLumen

Normal Arterial WallNormal Arterial Wall

CELLULAR CELLULAR ADHESION ADHESION MOLECULESMOLECULES

induces cell proliferation and a prothrombic state

‘‘activated’ activated’ endotheliumendothelium

attracts monocytes and T-lymphocytes

which adhere to endothelial cells

cytokines (eg. IL-1, TNF-)

chemokines (eg. MCP-1, IL-8)

growth factors (eg. PDGF, FGF)

Adapted from Koenig W. Eur Heart J 1999;1(Suppl T);T19–26.

The ‘Activated’ EndotheliumThe ‘Activated’ Endothelium

(IL-1, TNF a , MCP-1, IL-8)

Permeabel

INTIMA

SS S i iiiiPAI-1

SS

S = selectin i = imunoglobulin ( VCAM dll)

DiabetesShear stress (hypertensio

n),Smoking etc.

HSPG

HSPG

SEL OTOT POLOSMEDIASS

HSPG = heparan sulfate proteogycans

Endothelial Dysfunction in Atherosclerosis

Upregulation of Upregulation of endothelialendothelialadhesion moleculesadhesion molecules

Increased endothelial Increased endothelial permeabilitypermeability

Migration of Migration of leucocytes into the leucocytes into the artery wallartery wall

Leucocyte adhesionLeucocyte adhesion

Lipoprotein infiltrationLipoprotein infiltration

Adapted from Ross RAdapted from Ross R. N Engl J Med. N Engl J Med 1999; 1999;362362:115–:115–126.126.

Endothelial Dysfunction in AtherosclerosisEndothelial Dysfunction in Atherosclerosis

Monocyte

PAI-1

Free radical

s.AGEs

INTIMA

SMCMEDIASS

SS S i iiii

Small dense LDL

HSPGMacrophage

Foam cell

LDL

LDL ox

Cytokines+ PDGF,FGF

Lipid core

SRACD36

(IL-1, TNF a , MCP-1, IL-8)

Formation of Lipid Core

Clinical approachClinical approach Aggressive intervention to reduce Aggressive intervention to reduce

the risk of cardiovascular disease the risk of cardiovascular disease andand type 2 diabetes type 2 diabetes

DPDPP showed that lifestyle P showed that lifestyle intervention reduced the incidence ofintervention reduced the incidence of metabolic syndrome by 41% metabolic syndrome by 41% ccompared with placeboompared with placebo

Weight loss of Weight loss of the order of 7% to 10% the order of 7% to 10% body weight over 6 to 12 months is body weight over 6 to 12 months is recommendedrecommended

FDP Study, weight lossFDP Study, weight loss contributed to a contributed to a 58% reduction in the development of 58% reduction in the development of diabetesdiabetes

Exercise enhances the expression and Exercise enhances the expression and translocation oftranslocation of GLUT4 and improves GLUT4 and improves insulin sensitivityinsulin sensitivity

Therapeutic Lifestyle ChangesTherapeutic Lifestyle ChangesNutrient Composition Nutrient Composition

NutrientNutrient Recommended IntakeRecommended Intake• Saturated fatSaturated fat Less than 7% of total caloriesLess than 7% of total calories• Polyunsaturated fatPolyunsaturated fat Up to 10% of total caloriesUp to 10% of total calories• Monounsaturated fat Monounsaturated fat Up to 20% of total caloriesUp to 20% of total calories• Total fatTotal fat 25–35% of total calories25–35% of total calories

• CarbohydrateCarbohydrate 50–60% of total calories50–60% of total calories• FiberFiber 20–30 grams per day20–30 grams per day• ProteinProtein Approximately 15% of total caloriesApproximately 15% of total calories• CholesterolCholesterol Less than 200 mg/dayLess than 200 mg/day• Total calories (energy)Total calories (energy) Balance energy intake and expenditure Balance energy intake and expenditure to to

maintain desirable body weight/maintain desirable body weight/ prevent weight gain prevent weight gain

For those in whom lifestyle change is For those in whom lifestyle change is not sufficient, pharmacotherapynot sufficient, pharmacotherapy

obesity : sibutramine, a serotonin obesity : sibutramine, a serotonin norepinephrine reuptake inhibitor; norepinephrine reuptake inhibitor; orlistat; rimonabant, which is an orlistat; rimonabant, which is an endocannabinoid receptor-1 endocannabinoid receptor-1 antagonistantagonist

Dislipidemia in Prediabetic and Insulin Resistance

Small Dense LDL Low HDL

High TriglyceridesSTATINS

HMG-CoA Reductase Inhibitor - Synthesis of cholesterol - Proinflammatory Cytokines - Inhibit platelet aggregation

Hypertension Hypertension JNHC 7JNHC 7 Treatment with lifestyle modification is Treatment with lifestyle modification is

first recommendedfirst recommended First-line medication would be a First-line medication would be a

thiazidethiazide diuretic in uncomplicated diuretic in uncomplicated cases; (ACEcases; (ACE-i-i)),, (ARBs) in those with (ARBs) in those with diabetes,diabetes, congestive cardiac failure, or congestive cardiac failure, or chronic kidney disease; anchronic kidney disease; and d betabeta

blockers in those with anginablockers in those with angina

PerioperativePerioperativeManagement of Management of

DiabetesDiabetes

Kasus Kasus Pria 48 thnPria 48 thn Pandanan Mata kabur sejak 2 bulanPandanan Mata kabur sejak 2 bulan Keluhan 3p+Keluhan 3p+ GDS 212GDS 212 Pasien dikonsul dari poli mata untuk Pasien dikonsul dari poli mata untuk

persiapan operasi katarakpersiapan operasi katarak Persiapan perioperatif??Persiapan perioperatif??

IntroductionIntroduction Diabetes : Diabetes :

• increased requirement for surgicalincreased requirement for surgical proceduresprocedures• increased postoperative morbidity and mortalityincreased postoperative morbidity and mortality

The actual treatment recommendationsThe actual treatment recommendations• prevention and treatment of metabolic derangementsprevention and treatment of metabolic derangements

careful attention be paid tocareful attention be paid to the metabolic statusthe metabolic status

• individualized, based on :individualized, based on : diabetes classificationdiabetes classification usual diabetesusual diabetes regimenregimen state of glycemic controlstate of glycemic control nature and extent of surgicalnature and extent of surgical procedureprocedure available expertiseavailable expertise

Goals Management PerioperatifGoals Management Perioperatif

Avoid hyperglycemia: fluid losses Avoid hyperglycemia: fluid losses and electrolyte abnormalityand electrolyte abnormality

Avoid hypoglycemiaAvoid hypoglycemia

Perioperative Response to Surgery and Perioperative Response to Surgery and AnesthesiaAnesthesia

Surgery and anesthesia invoke :Surgery and anesthesia invoke :• a neuroendocrine stress response a neuroendocrine stress response • release of counter-regulatory hormones, which results release of counter-regulatory hormones, which results

peripheral insulin resistanceperipheral insulin resistance increased hepatic glucose productionincreased hepatic glucose production impaired insulin secretionimpaired insulin secretion fat and protein breakdownfat and protein breakdown potential hyperglycemia and ketosispotential hyperglycemia and ketosis

• The degree of this response depends on The degree of this response depends on the complexity of the surgerythe complexity of the surgery postsurgical complicationspostsurgical complications

Also contribute to metabolic decompensationAlso contribute to metabolic decompensation• FastingFasting• volume depletionvolume depletion

Perioperative Response to Surgery and Perioperative Response to Surgery and AnesthesiaAnesthesia

The stress of surgery The stress of surgery • alter glucose homeostasisalter glucose homeostasis• persistentpersistent hyperglycemiahyperglycemia

endothelial dysfunctionendothelial dysfunction postoperative sepsispostoperative sepsis impaired wound healingimpaired wound healing cerebralcerebral ischemiaischemia

Hyperglycemia Hyperglycemia • inhibits host defenses against infectioninhibits host defenses against infection

including many leukocyte functionsincluding many leukocyte functions

• impairs wound healingimpairs wound healing detrimental effects on collagen formation detrimental effects on collagen formation diminished wound tensile strengthdiminished wound tensile strength

stress

Increased sympathetic activityIncreased counter-regulatory hormones:catecholamines cortisol

Insulin secretioninhibited

Insulin resistance

Intravenousfluids

Increased catabolismPerioperative

starvation

diabetes

surgery

Glycogenolysis Gluconeogenesis Proteolysis Lipolysis

Ketogenesis

TraumaHaemorrhageInfection

Pre-excistingInsulin deficiencyPre-excisting Insulin resistance

STRESS RESPONSE- SURGERY

Preoperative EvaluationPreoperative Evaluation In elective surgical proceduresIn elective surgical procedures

• potential problems should be identified, corrected, potential problems should be identified, corrected, and stabilized before surgeryand stabilized before surgery

Preoperative evaluation includes assessment ofPreoperative evaluation includes assessment of• metabolic controlmetabolic control

• any diabetes-associated complicationsany diabetes-associated complications cardiovascular diseasecardiovascular disease autonomic neuropathyautonomic neuropathy nephropathynephropathy

Glycemic Glycemic ControlControl

Patient taking insulin Patient taking insulin • frequent glucose monitoringfrequent glucose monitoring• insulin dosages adjustedinsulin dosages adjusted

Long-acting insulin Long-acting insulin • discontinued 1-2 days before surgerydiscontinued 1-2 days before surgery• can be continued throughout the daycan be continued throughout the day

if the patient's control is goodif the patient's control is good if the patient is using glargineif the patient is using glargine

• maintains a stable level throughout the daymaintains a stable level throughout the day

Preoperative EvaluationPreoperative Evaluation

Oral agents are generally discontinued Oral agents are generally discontinued • Long-acting sulfonylureasLong-acting sulfonylureas

stopped 48 to 72 hours before surgerystopped 48 to 72 hours before surgery

• Short-acting sulfonylureas, other insulin secretagogues, Short-acting sulfonylureas, other insulin secretagogues,

and metformin and metformin withheld the night before or the day of surgerywithheld the night before or the day of surgery

• Thiazolidinediones Thiazolidinediones No recommendations exist for discontinuation of before surgery; No recommendations exist for discontinuation of before surgery;

• their extremely long duration of action probably indicates no their extremely long duration of action probably indicates no

rationale for stopping them at allrationale for stopping them at all

Preoperative EvaluationPreoperative Evaluation

Glycemic ControlGlycemic Control

American Diabetes Association Recommendations American Diabetes Association Recommendations for Target Inpatient Blood Glucose Concentrations for Target Inpatient Blood Glucose Concentrations

Glucose, Fluid and Electrolyte Glucose, Fluid and Electrolyte ManagementManagement

Glucose 5g/h for basal energy requirements Glucose 5g/h for basal energy requirements • prevent hypoglycemia, ketosis, and protein breakdown prevent hypoglycemia, ketosis, and protein breakdown

during surgeryduring surgery• More glucose may be needed if conditions are very More glucose may be needed if conditions are very

stressfulstressful

If additional fluids are needed (e.g., maintain hemodynamic If additional fluids are needed (e.g., maintain hemodynamic stability) stability) non dextrose-containing solutionsnon dextrose-containing solutions

Intraoperative ManagementIntraoperative Management

Kasus Kasus Pria 48 thnPria 48 thn Pandanan Mata kabur sejak 2 bulanPandanan Mata kabur sejak 2 bulan Keluhan 3p+Keluhan 3p+ GDS 212GDS 212 Pasien dikonsul dari poli mata untuk Pasien dikonsul dari poli mata untuk

persiapan operasi katarakpersiapan operasi katarak Persiapan perioperatif??Persiapan perioperatif??

EdukasiEdukasi Diet DM 1700 kalDiet DM 1700 kal Olahraga 3x/mggOlahraga 3x/mgg Metformin 2x500mgMetformin 2x500mg Captopril 2x12,5Captopril 2x12,5

Pasien kontrol 2 minggu kemudianPasien kontrol 2 minggu kemudian

S: Mata kanan buram S: Mata kanan buram O:O: TD : 1TD : 1440/0/880 mmHg, FN : 82x/m, regular, RR:20x/mnt, 0 mmHg, FN : 82x/m, regular, RR:20x/mnt,

S:afebrisS:afebris Mata Mata : konj.anemis-/-, SI-/-: konj.anemis-/-, SI-/- JantungJantung : BJ I/II N, M(-), G(-): BJ I/II N, M(-), G(-) Paru Paru : vesikuler rh-/-, wh -/-: vesikuler rh-/-, wh -/- Abdomen Abdomen : : datar lemas NT-, h/l ttbdatar lemas NT-, h/l ttb Ekstremitas Ekstremitas : edema -/- akral hangat, : edema -/- akral hangat, Pulsasi A.dorsalis pedis +/+N, A.tibialis post +/+N, refleks Pulsasi A.dorsalis pedis +/+N, A.tibialis post +/+N, refleks

DBNDBN

Laboratorium Laboratorium Hb 13,2Hb 13,2 Leukosit 8700Leukosit 8700 Trombosit 266.000Trombosit 266.000 Ur /crUr /cr 14/0,914/0,9 GDP/2JPP 109/121GDP/2JPP 109/121

EKG: SR, NA, QRS rate 82x/mnt, EKG: SR, NA, QRS rate 82x/mnt, R/LBBB-, R/LVH-, ST/T change-R/LBBB-, R/LVH-, ST/T change-

Daftar masalah Daftar masalah DM tipe 2 NW terkendali sedangDM tipe 2 NW terkendali sedang Katarak OD pro operasiKatarak OD pro operasi Hipertensi Gr 1Hipertensi Gr 1

Tatalaksana perioperatifTatalaksana perioperatif 1 hari sebelum operasi obat pasien di 1 hari sebelum operasi obat pasien di

minum spt biasaminum spt biasa Pasien puasa 6 jam, infus D5 4jam Pasien puasa 6 jam, infus D5 4jam

sebelum waktu makansebelum waktu makan Post op bila pasien sudah biasa Post op bila pasien sudah biasa

makan obat diteruskan seperti biasamakan obat diteruskan seperti biasa