Insulin Resistance and Metabolic Syndrome Thomas Repas D.O. Diabetes, Endocrinology and Nutrition...

Insulin Resistance and Insulin Resistance and Metabolic SyndromeMetabolic Syndrome

Thomas Repas D.O.Thomas Repas D.O.Diabetes, Endocrinology and Nutrition Center, Affinity Medical Group, Neenah, WisconsinDiabetes, Endocrinology and Nutrition Center, Affinity Medical Group, Neenah, Wisconsin

Member, Inpatient Diabetes Management Committee, St. Elizabeth’s Hospital, Appleton, WIMember, Inpatient Diabetes Management Committee, St. Elizabeth’s Hospital, Appleton, WIMember, Diabetes Advisory Group, Wisconsin Diabetes Prevention and Control Program Member, Diabetes Advisory Group, Wisconsin Diabetes Prevention and Control Program

Website: www.endocrinology-online.comWebsite: www.endocrinology-online.com

Overview

• Epidemic of Type 2 Diabetes

• Why is Type 2 DM on the Rise?

• CV Risks of Type 2 DM

• Metabolic Syndrome

• Diagnostic Criteria

• Pathophysiology

• Treatment Options

• Conclusion

Harris MI. In: Harris MI et al, eds. Diabetes in America. Bethesda, MD: USDHHS-NIH; 1995:DHHS Publication No. (NIH) 95-1468

Rubin RJ et al. J Clin Endocrinol Metab. 1994;78:809A

• Prevalence: 17 million Americans

– 1 in every 17 people (>90% type 2 diabetes)

– 1/3 undiagnosed

• Incidence: >1 million new cases diagnosed yearly

– >2000 cases diagnosed each day

Type 2 diabetes in children and adolescents

• Related to our society’s Obesity

Age

Growth of ethnic populations with high prevalence

Physical activity

Diabetes Mellitus in the US

Top Ten Causes of Death in U.S. 2000

1. Heart Disease

2. Cancer

3. Cerebrovascular Disease

4. COPD

5. Accidents

6. Diabetes

7. Pneumonia & Influenza

8. Alzheimer's Disease

9. Kidney Disease

10. Sepsis

No Data <4% 4%-6% 6%-8% 8%-10% >10%

Diabetes and Gestational Diabetes Trends Among Adults in the U.S., BRFSS 1990

Mokdad AH, Ford ES, Bowman BA, et al. Prevalence of obesity, diabetes, and other obesity-related health risk factors, 2001. JAMA 2003 Jan 1;289(1).

Diabetes and Gestational Diabetes Trends Among Adults in the U.S., BRFSS 1991-92


No Data <4% 4%-6% 6%-8% 8%-10% >10%



Emerging Epidemic of Type 2 Diabetes in Children and Adolescents

• Type 2 diabetes is a growing epidemic in US children and adolescents, especially among minorities1,2

– African-American youth accounted for 70%–75% of type 2 diabetes in Ohio and Arkansas studies3,4

– 31% of Mexican-Americans <17 yr in California study had type 2 diabetes5

1Fagot-Campagna A et al. J Pediatr. 2000;136:6642Rosenbloom A et al. Diabetes Care. 1999;22:3453Pinhas-Hamiel O et al. J Pediatr. 1996;128:6084Pihoker C et al. Clin Pediatr. 1998;37:975Neufeld N et al. Diabetes Care. 1998;21:80

12.1

14.5

17.4

10

11

12

13

14

15

16

17

18

19

20

2002 2010 2020

Diabetes Care 26(3):917-932, 2003

Projections of US Population with Projections of US Population with Diagnosed Diabetes (millions)Diagnosed Diabetes (millions)

44% Increase by 202044% Increase by 2020

0

10

20

30

40

50

60

70

80

Esti

mate

d p

r evale

nce (

million

s)

Estimates of Diabetes Estimates of Diabetes Prevalence in World RegionsPrevalence in World Regions

2025202519951995 20002000

Africa Americas EasternMediterranean

Europe SoutheastAsia

WesternPacific

WHO Report 1997. World Health Organization. Geneva;1997.

Why is Type 2 Diabetes on the Why is Type 2 Diabetes on the rise?rise?

Link Between Obesity and Type 2 Diabetes:Link Between Obesity and Type 2 Diabetes:Nurses’ Health StudyNurses’ Health Study

Colditz GA, et al. Ann Intern Med. 1995;122:481-486.

0

20

40

60

80

100

120

<22 22-22.9

23-23.8

24-24.9

25-26.9

27-28.9

29-30.9

31-32.9

33-34.9

>35

BMI (kg/m2)

Age

-Adj

uste

d Re

lativ

e Ri

sk

Obesity Trends* Among U.S. AdultsBRFSS, 1985

Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.

CV Risks of Type 2 DiabetesCV Risks of Type 2 Diabetes

40

15 13 1310

4 5

0

10

20

30

40

50

Perc

en

t of

death

s

Geiss LS, et al. In: Diabetes in America.

National Institutes of Health;1995.

Causes of Death in Causes of Death in People With DiabetesPeople With Diabetes

Isch

emic

hear

t di

seas

e

Oth

er h

eart

dise

ase

Dia

bete

s

Mal

igna

nt

neop

lasm

s

Cere

brov

ascu

lar

dise

ase

Pneu

mon

ia/

influe

nza

All ot

her

Hospitalization Costs for Chronic Hospitalization Costs for Chronic Complications of Diabetes in the USComplications of Diabetes in the US

American Diabetes Association. Economic Consequences of Diabetes Mellitusin the US in 1997. Alexandria, VA: American Diabetes Association, 1998:1-14.

Total costs 12 Total costs 12 billion US $billion US $

CVD accounts CVD accounts for 64% of for 64% of total coststotal costs

OthersOthersOphthalmic Ophthalmic diseasedisease

CardiovascularCardiovasculardiseasedisease

Renal Renal diseasedisease

NeurologicNeurologic disease disease

PeripheralPeripheral vascular vascular disease disease

0.0

1.0

2.0

3.0

4.0

5.0

6.0

Hospitalization for MI Has Not DeclinedHospitalization for MI Has Not Declined

Hospitalization for MI (per 1,000)*

* Age-adjusted

1987 1989 1990 19921988 1993 19941991

Rosamond WD et al. N Engl J Med 1998;339:861-867.©1998 Massachusetts Medical Society. All rights reserved.

Men

Women

Copyright © 1993 American Diabetes Association. From Diabetes Care. 1993;16:434-444. Reprinted with permission from the American Diabetes Association.

*Age adjusted.

140

120

100

80

60

40

20

00 1 2 3

Number of Risk Factors

NondiabeticDiabetic

CV

D D

ea

th R

ate

* p

er 1

0,0

00

Pe

rso

n-Y

ear

s

CVD Death Rates Are Higher CVD Death Rates Are Higher

in Patients With Diabetesin Patients With Diabetes

Seven-year incidence in a Finnish-based cohort.*P<.001Haffner SM, et al. N Engl J Med. 1998;339:229-234.

Type 2 Diabetes is a Cardiovascular Risk Type 2 Diabetes is a Cardiovascular Risk FactorFactor

Fat

al o

r N

onfa

tal M

I

0

10

20

30

40

50

Nondiabetic Subjects (n=1373)

Type 2 Diabetic Subjects (n=1059)

3.5%

20.2%18.8%*

45.0%*No Prior MI

Prior MI

Diabetes and prior myocardial infarction (MI) carry the same mortality risk

Matthaei, et al. Endocrine Reviews 21(6): 585-618.

New Definition of Impaired New Definition of Impaired Fasting GlucoseFasting Glucose

In 11/03, The Expert Committee on the In 11/03, The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus Diagnosis and Classification of Diabetes Mellitus redefined IFG as being 100-125 mg/dlredefined IFG as being 100-125 mg/dl

It is estimated that this will increase the numbers It is estimated that this will increase the numbers of adults with “prediabetes” by approximately of adults with “prediabetes” by approximately 20%20%

The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. . Diabetes Care VOLUME 26, NUMBER 11, 11/03.

Pathophysiology of Type 2 DiabetesPathophysiology of Type 2 Diabetes

Saltiel AR, Olefsky JM. Saltiel AR, Olefsky JM. DiabetesDiabetes. 1996;45:1661-1669.. 1996;45:1661-1669.

Peripheral TissuesPeripheral Tissues(Muscle)(Muscle)

GlucoseGlucose

LiverLiver

Impaired insulin Impaired insulin secretionsecretion

Increased glucose Increased glucose productionproduction

Receptor +Receptor +postreceptor defectspostreceptor defects

InsulinInsulinresistanceresistance

PancreasPancreas

Typical Diagnosis of Diabetes

Severity of Glucose Intolerance

Years to Decades

Normal Blood Normal Blood GlucoseGlucose

Natural History of Type 2 DiabetesNatural History of Type 2 Diabetes

Risk of Macrovascular ComplicationsRisk of Macrovascular Complications

Insulin Insulin ResistanceResistance

IGTIGT

Insulin SecretionInsulin Secretion

Postprandial GlucosePostprandial Glucose

Risk of Microvascular ComplicationsRisk of Microvascular Complications

Fasting Blood GlucoseFasting Blood Glucose

Frank Frank DiabetesDiabetes

NGTNGT

Worsens with Time

Risk of Major CHD Event Associated with Insulin Risk of Major CHD Event Associated with Insulin Quintiles in Nondiabetic Subjects: Quintiles in Nondiabetic Subjects: Helsinki Helsinki

Policemen StudyPolicemen Study

0.70

0.75

0.80

0.85

0.90

0.95

1.00

Years5 10 200 15 25

Pyorala M et al. Circulation 1998;98:398-404.©1998 Lippincott Williams & Wilkins.

Log rank:Overall P = .001Q5 vs. Q1 P < .001

Q1

Q2

Q3

Q4Q5P

roport

ion w

ithout

Majo

r C

HD

Event

0

Honolulu Heart StudyHonolulu Heart Study

0

10

20

30

40

50

60

CH

D R

isk

pe

r 1

00

0

Fatal CHD Total CHD

CHD Risk40-114 mg/dl

115-133 mg/dl

134-156 mg/dl

157-189 mgdl

190-532 mg/dl

Donahue RP, et al. 1987;36:689-692.

12 year age-adjusted incidence of fatal/total CHDBy 1 hour post challenge serum glucose

Relation of Fasting Glucose to Risks Relation of Fasting Glucose to Risks of MIof MI

People without Diabetes or IGTPeople without Diabetes or IGT

0.9

2.8

4.2

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

Od

ds

Ra

tio

fo

r M

I

<81 82-93 94-114 >114

Fasting Glucose

Gerstien HC, et al. J AM Coll Cardiology. 1999;33:612-619.

Risk for all Cause Mortality and Glycemic Risk for all Cause Mortality and Glycemic

Control:Control: Think Continuum, Not ThresholdThink Continuum, Not Threshold

0

1

2

3

4

5

6

All

Ca

us

e M

ort

alit

y*

%

<5 5-5.4 5.4-6.9 >7 Known DM

HgbA1C*Age-Adjusted. Adapted from: Khaw, et al. BMJ. 2001; 222:1.

EPIC-Norfolk StudyEPIC-Norfolk Study

Type 2 Diabetes: Elevated Postprandial Glucose Occurs at All Levels of Glycemic Control

HgbAIC (%) Mean FBG Mean 2-hr PPG

<6 116 208

6-6.9 132 233

7-7.9 172 315

8-8.9 205 371

>9 278 432

NHANES III: Third National Health and Nutrition Examination Survey. 1988-1994. National Center for Health Statistics, Hyattsville, Md

Metabolic SyndromeMetabolic Syndrome

Metabolic and Cardiovascular Risk Factors That Cluster Together

• Hyperinsulinemia/ insulin resistance

• High triglycerides• Low HDL• Increased apolipoprotein B• Small, dense LDL cholesterol• Increased fibrinogen• Increased plasminogen

activator inhibitor-1 • Increased blood viscosity

• Endothelial dysfunction• Elevated c-reactive protein• Microalbuminuria• Increased uric acid• Elevated systolic & diastolic

blood pressure• Absent nocturnal decreases in

BP & HR• Increased LVH• Premature atherosclerosis• CVA

McFarlane SI, et al. Insulin Resistance and Cardiovascular Disease. McFarlane SI, et al. Insulin Resistance and Cardiovascular Disease. J Clin Endocrinol Metab. J Clin Endocrinol Metab. 2001; 86 (2) : 713-718. 2001; 86 (2) : 713-718.

The Metabolic SyndromeThe Metabolic Syndrome

Prothrombotic StateProthrombotic State HypertensionHypertension

DyslipidemiaDyslipidemia

Insulin ResistanceInsulin Resistance

EnvironmentEnvironmentGeneticsGenetics

Bogardus C, et al. Endocrinol Metab. 1985;11:E286-E291 Roberts K, et al. Nutr Rev. 2000 May;58(5):154-160.

Etiology of Metabolic SyndromeEtiology of Metabolic SyndromeEtiology of Metabolic SyndromeEtiology of Metabolic Syndrome

• The metabolic syndrome results from a complex The metabolic syndrome results from a complex interplay of two important factors:interplay of two important factors:

• The metabolic syndrome results from a complex The metabolic syndrome results from a complex interplay of two important factors:interplay of two important factors:

Kalff KG, et al. Aviat Space Environ Med. 1999 Dec;70(12):1223-1226.Hansen BC. Ann N Y Acad Sci. 1999 Nov 18;892:1-24.

Prevalence of Metabolic Syndrome

– Approximately 20% to 30% of the middle-aged population in highly industrialized countries has the metabolic syndrome

– By the year 2010, the number of people with the metabolic syndrome in the US could rise to between 50 and 75 million

Risks of Metabolic SyndromeRisks of Metabolic Syndrome

19

40

34

51

0

10

20

30

40

50

60

No Metabolic Syndrome Metabolic Syndrome

Carotid Stenosis

Carotid Atherosclerosis

Five year Progression of Carotid Atherosclerosis and Coronary Heart DiseaseFive year Progression of Carotid Atherosclerosis and Coronary Heart Disease

3

8

0

1

2

3

4

5

6

7

8

9

No Metabolic Syndrome Metabolic Syndrome

No Metabolic Syndrome

Metabolic Syndrome

Bonora, et al. Diabetes Care, 26,4 4/03. 1251-

Bruneck StudyBruneck Study

Diagnosis of Metabolic SyndromeDiagnosis of Metabolic Syndrome

Diagnostic Criteria

Three expert groups have devised criteria for diagnosis of metabolic syndrome:

–WHO

–NCEP ATP III

–AACE

Alberti & Zimmet WHO 1998 Diabetic Medicine.

IGT/IFG or IGT/IFG or type 2 diabetestype 2 diabetes

Central ObesityCentral ObesityBMIBMI > 30 kg/m²> 30 kg/m²

MicroalbuminuriaMicroalbuminuriaUAE UAE 20 µg min 20 µg min

Insulin resistanceInsulin resistance(glucose uptake below(glucose uptake belowlowest quartile)lowest quartile)

Triglycerides > 150 Triglycerides > 150 mg/dlmg/dl& & HDL-Ch HDL-Ch << 35 mg/dl 35 mg/dl

Blood pressureBlood pressure 160/90 mmHg160/90 mmHg

METABOLIC SYNDROMEMETABOLIC SYNDROME

The Metabolic Syndrome: The Metabolic Syndrome: WHO criteriaWHO criteria

Metabolic Syndrome Factors That Cluster with Microalbuminuria

• Central Obesity• Insulin Resistance• Decreased HDL• Elevated Triglycerides• Small, Dense LDL• Systolic Hypertension• Absent normal nocturnal

decrease in BP or HR• Salt Sensitivity• Male sex; postmenopausal or

diabetic status in women

• Increased cardiovascular oxidative stress

• Endothelial dysfunction• Abnormal

Coagulation/fibrinolytic profiles

• LVH• Hyperuricemia• Elevated levels of c-reactive

protein and other inflammatory markers

McFarlane SI, et al. Insulin Resistance and Cardiovascular Disease. J Clin Endocrinol Metab. 2001; 86 (2) : 713-718.

Adult Treatment Panel IIIAdult Treatment Panel III

Risk FactorRisk Factor Waist CircumferenceWaist Circumference

TriglyceridesTriglycerides HDL CholesterolHDL Cholesterol Blood PressureBlood Pressure Fasting Blood GlucoseFasting Blood Glucose

LevelLevel >40 in (m) >35 in (f)>40 in (m) >35 in (f) >150 mg/dl>150 mg/dl <40 (m) <50 (f)<40 (m) <50 (f) >130/85>130/85 >110>110

Dysmetabolic Syndrome = 3 out of 5Dysmetabolic Syndrome = 3 out of 5

ATP III, Nat. Chol. Ed. Program, NIH

Major criteria•Insulin resistance (denoted by hyperinsulinemia relative to glucose levels) Insulin resistance (denoted by hyperinsulinemia relative to glucose levels) or or •Acanthosis Nigricans Acanthosis Nigricans •Central Obesity (waist circumference > 102 cm for men and >88 cm for Central Obesity (waist circumference > 102 cm for men and >88 cm for women) women) •Dyslipidemia (HDL cholesterol <45 mg/dl for women, HDL cholesterol Dyslipidemia (HDL cholesterol <45 mg/dl for women, HDL cholesterol <35mg/dl for men, or triglycerides >150 mg/dl) <35mg/dl for men, or triglycerides >150 mg/dl) •Hypertension Hypertension •Impaired fasting glucose or Type 2 diabetes Impaired fasting glucose or Type 2 diabetes •HyperuricemiaHyperuricemia

Minor Features•Hypercoagulability Hypercoagulability •Polycystic ovary syndrome Polycystic ovary syndrome •Vascular endothelial dysfunction Vascular endothelial dysfunction •Microalbuminuria Microalbuminuria •Coronary heart diseaseCoronary heart disease

The CDC does not require that a given number of components of Dysmetabolic Syndrome X be present when using ICD-9-CM diagnosis code 277.7. The code may be used if in the professional opinion of the physician Dysmetabolic Syndrome X is present

AACE Criteria for Dysmetabolic Syndrome X

Clinical Exam Findings Suggesting Clinical Exam Findings Suggesting Insulin ResistanceInsulin Resistance

Acanthosis NigricansAcanthosis Nigricans

Skin TagsSkin TagsSkin TagsSkin Tags

Polycystic Ovarian Syndrome:Polycystic Ovarian Syndrome:•Menstrual irregularitiesMenstrual irregularities•HyperandrogenismHyperandrogenism•Insulin resistanceInsulin resistance

Please note the central obesity, hirsutism, acne, and acanthosis nigricans in this patient.Please note the central obesity, hirsutism, acne, and acanthosis nigricans in this patient.

Polycystic Ovarian Syndrome:Polycystic Ovarian Syndrome:•Menstrual irregularitiesMenstrual irregularities•HyperandrogenismHyperandrogenism•Insulin resistanceInsulin resistance

Please note the central obesity, hirsutism, acne, and acanthosis nigricans in this patient.Please note the central obesity, hirsutism, acne, and acanthosis nigricans in this patient.

Close up of facial hirsutism in 17 year old female with PCOSClose up of facial hirsutism in 17 year old female with PCOSClose up of facial hirsutism in 17 year old female with PCOSClose up of facial hirsutism in 17 year old female with PCOS

Typical polycystic ovaries. Multiple small follicular Typical polycystic ovaries. Multiple small follicular cysts are apparent in the cut section. cysts are apparent in the cut section. Typical polycystic ovaries. Multiple small follicular Typical polycystic ovaries. Multiple small follicular cysts are apparent in the cut section. cysts are apparent in the cut section.

Pathophysiology of Insulin Resistance Pathophysiology of Insulin Resistance andand

Metabolic SyndromeMetabolic Syndrome

Diabetic DyslipidemiaDiabetic Dyslipidemia TriglyceridesTriglycerides HDLHDL Small, Dense LDLSmall, Dense LDL LDL-C may be “normal”LDL-C may be “normal”

Adipose Tissue

LiverLiver

Remnants (to liver)

VLDLVLDLHDL

Reduced Lipoprotein LipaseReduced Lipoprotein Lipase

TGTG

TGTG

Accelerated FFAAccelerated FFA

Accelerated TGAccelerated TG

Decreased HDL2

HepaticLipaseHepaticLipase

CECE

CETPCETPCETPCETP

CECE

LDL

TG-Rich LDL

Hepatic LipaseHepatic Lipase

SDLDL

Insulin ResistanceInsulin ResistancePostprandial Lipid MetabolismPostprandial Lipid Metabolism

TG-RichHDL

Lipoprotein Classes and InflammationLipoprotein Classes and Inflammation

Doi H et al. Circulation 2000;102:670-676; Colome C et al. Atherosclerosis 2000;149:295-302; Cockerill GW et al. Arterioscler Thromb Vasc Biol 1995;15:1987-1994.

HDLHDLLDLLDLChylomicrons,Chylomicrons,VLDL, and VLDL, and

their catabolic their catabolic remnantsremnants

> 30 nm> 30 nm 20–22 nm20–22 nm

Potentially proinflammatoryPotentially proinflammatory

9–15 nm9–15 nm

Potentially anti- Potentially anti- inflammatoryinflammatory

0

10

20

30

40

50

60

HD

L-C

(m

g/d

L)

Non-obese Obese

Hyperinsulinemic

Normoinsulinemic

0

10

20

30

40

50

60

HD

L-C

(m

g/d

L)

Non-obese Obese

Hyperinsulinemic

Normoinsulinemic

Hyperinsulinemia and Low HDL

Hyperinsulinemia and Low HDL

p < 0.005p < 0.005

Zavaroni I, et al. J Intern Med. 1994;235:51-56

0

30

60

90

120

150

180

Ra

te p

er

100

0

< 34 35-54 > 55

HDL Cholesterol

Men

Women

0

30

60

90

120

150

180

Ra

te p

er

100

0

< 34 35-54 > 55

HDL Cholesterol

Men

Women

Cardiovascular Disease and HDL-C Levels

Cardiovascular Disease and HDL-C Levels

Kannel WB, Am J Cardiol. 1983;52:9b-12b.

0

2

4

6

8

10

12

Ste

ady

Sta

te P

lasm

a G

luco

se (

mm

ol/

L)

Pattern A Intermediate Pattern Pattern B

LDL Phenotype

0

2

4

6

8

10

12

Ste

ady

Sta

te P

lasm

a G

luco

se (

mm

ol/

L)


LDL Phenotype

Glycemia and Small Dense LDL


Reaven GM, et al. J Clin Invest. 1993;92:141-146

LDL SubpopulationsLDL Subpopulations

Large Fluffy LDLLarge Fluffy LDL

Small Dense LDLSmall Dense LDL

Pattern A and Pattern BPattern A and Pattern B

0

2

4

6

8

10

12

Ste

ady

Sta

te P

lasm

a G

luco

se (

mm

ol/

L)


LDL Phenotype

0

2

4

6

8

10

12

Ste

ady

Sta

te P

lasm

a G

luco

se (

mm

ol/

L)


LDL Phenotype



Reaven GM, et al. J Clin Invest. 1993;92:141-146

Small, Dense LDL

• Permeates arterial wall• Binds proteoglycans• Susceptible to oxidation• Atherogenic lipid profile

Structure of LDLStructure of LDL

Murphy HC et al. Biochemistry 2000;39:9763-970.

Hydrophobic CoreHydrophobic Core of Triglyceride and of Triglyceride and Cholesteryl EstersCholesteryl Esters

apoBapoB

Surface Monolayer Surface Monolayer of Phospholipids of Phospholipids and Free and Free CholesterolCholesterol

VLDLVLDL IDLIDL LDLLDL

LDLLDL

LDLLDLLDLLDL


VLDLVLDL IDLIDL LDLLDLVLDLVLDL

VLDLVLDLVLDLVLDL

IDLIDL

IDLIDLIDLIDL



LDLLDL

LDLLDLLDLLDL



TGTG

CholesterolCholesterol


VLDLVLDL LDLLDL



VLDLVLDL LDLLDL



VLDLVLDLSDLDLSDLDL

Tissue Uptake

Tissue Uptake

IDLIDLLDLLDL

AssemblyAssembly

ExtrinsicSourcesExtrinsicSources

LipoproteinsLipoproteins

VLDLVLDL

LDLLDL

Cholesterol Pool

Cholesterol Pool

BileBile

De NovoSynthesisDe Novo

Synthesis

LDLLDL

LDLLDL

LDLLDL

Tissue Uptake

Tissue Uptake

IDLIDL



Synthesis

LDLLDL

AssemblyAssembly

BileBile


VLDLVLDL

LDLLDL

Cholesterol Pool

Cholesterol Pool

LDLLDL

Tissue Uptake

Tissue Uptake

IDLIDL



Synthesis

LDLLDL

AssemblyAssembly

BileBile


VLDLVLDL

LDLLDL

Cholesterol Pool

Cholesterol Pool

LDLLDL

LDLLDL

Tissue Uptake

Tissue Uptake

IDLIDL



Synthesis

LDLLDL

AssemblyAssembly

BileBile


VLDLVLDL

LDLLDL

Cholesterol Pool

Cholesterol Pool

SDLDLSDLDL

SDLDLSDLDL

SDLDLSDLDL

Tissue Uptake

Tissue Uptake

IDLIDL



Synthesis

LDLLDL

AssemblyAssembly

BileBile


VLDLVLDL

LDLLDL

Cholesterol Pool

Cholesterol Pool

SDLDLSDLDL

Tissue Uptake

Tissue Uptake

IDLIDL



Synthesis

LDLLDL

AssemblyAssembly

BileBile


VLDLVLDL

LDLLDL

Cholesterol Pool

Cholesterol Pool

SDLDLSDLDL

SDLDLSDLDL

Tissue Uptake

Tissue Uptake

IDLIDL



Synthesis

LDLLDL

AssemblyAssembly

BileBile


VLDLVLDL

LDLLDL

Cholesterol Pool

Cholesterol Pool

SDLDLSDLDL

LDLLDL

LDLLDL

Tissue Uptake

Tissue Uptake

IDLIDL



Synthesis

LDLLDL

AssemblyAssembly

BileBile


VLDLVLDL

LDLLDL

Cholesterol Pool

Cholesterol Pool

SDLDLSDLDL

Infiltration of LDL Infiltration of LDL

LDLLDLLDLLDL

VLDLVLDL VLDLVLDL

IDLIDL

LDLLDL


LDLLDL

VLDLVLDL VLDLVLDL

IDLIDL

LDLLDL LDLLDL

LDLLDL


VLDLVLDL VLDLVLDL

IDLIDL

LDLLDL

SDLDLSDLDL

SDLDLSDLDL

The Problem With Treating Only NumbersThe Problem With Treating Only Numbers





Prothrombotic StateProthrombotic State

Increased plasma fibrinogenIncreased plasma fibrinogen

Increased plasminogen activator Increased plasminogen activator inhibitor 1inhibitor 1

Increased platelet aggregabilityIncreased platelet aggregability

Factors Promoting Thromboembolic Disease in Diabetes

Thompson SG et al. N Engl J Med 1995;332:635-641.

PA

I-1

ant

igen

(ng

/mL

)

35

30

25

20

15

10

5

0NGT

(n=693)IGT

(n=348)Type 2 diabetes

(n=510)

P<0.001, adjusted for age, gender. Mean SE.

GT=glucose tolerance; IGT=impaired glucose tolerance; PAI-1=plasminogen activator inhibitor-Festa et al. Arterioscler Thromb Vasc Biol 1999;19:562–568.

Plasma concentration of PAI-1 in Plasma concentration of PAI-1 in normal subjects, IGT, and type 2 diabetesnormal subjects, IGT, and type 2 diabetes

Vascular endothelium

Free t-PA activates plasmin, Free t-PA activates plasmin, leading to fibrinolysis and leading to fibrinolysis and

reducing the risk of reducing the risk of thrombosisthrombosis

PAI-1 t-PAt-PA

PAI-1 t-PAt-PA

PAI-1 complexes and PAI-1 complexes and inactivates t-PAinactivates t-PA

Plasmin

t-PAt-PA

PlateletsPlatelets

t-PAt-PAPlasminogen

Kohler HP & Grant PJ. N Engl J Med 2000; 342:1792–1801.

PAI-1 BloodstreamBloodstream

PAI-1 and inhibition of fibrinolysis

PAI-1 and inhibition of fibrinolysis





HypertensionHypertension

Hypertension, Glucose Intolerance and CHD

Hypertension, Glucose Intolerance and CHD

0

50

100

150

200

Ag

e A

dju

ste

d C

V E

ve

nt

Ra

te /

10

00

105 135 165 195Systolic BP (mm Hg)

No GlucoseIntolerance

GlucoseIntolerance

0

50

100

150

200

Ag

e A

dju

ste

d C

V E

ve

nt

Ra

te /

10

00



GlucoseIntolerance

Kannel WB, et al. Am Heart J. 1991;121:1268-1273.

MenMen

0

50

100

150

200

Ag

e A

dju

ste

d C

V E

ve

nt

Ra

te /

10

00



GlucoseIntolerance

0

50

100

150

200

Ag

e A

dju

ste

d C

V E

ve

nt

Ra

te /

10

00



GlucoseIntolerance

WomenWomen

-P-H-P+H

+P-H+P+H

0

500

1,000

Sta

nd

ar d

ized

m

ort

ality

rati

oProteinuria and Hypertension Proteinuria and Hypertension

in Type 2 Diabetesin Type 2 Diabetes

Status of Proteinuria (P) and Status of Proteinuria (P) and Hypertension (H) in Type 2 DiabeticsHypertension (H) in Type 2 Diabetics

-P-H

Men

-P+H +P-H +P+H

Women

Wang SL, et al. Diabetes Care. 1996;19:305-312. Copyright ©1996, American Diabetes Association. Reprinted with permission.

1.0

0.9

0.8

0.7

0.6

0.5

0 1 2 3 4 5 6

Years

Su

rviv

al (a

ll-c

au

se m

ort

ality

)

NormoalbuminuriaNormoalbuminuria(n=191)(n=191)

MicroalbuminuriaMicroalbuminuria(n=86)(n=86)

MacroalbuminuriaMacroalbuminuria(n=51)(n=51)

P<0.01 normoalbuminuria vs microalbuminuriaP<0.001 normoalbuminuria vs macroalbuminuriaP<0.05 microalbuminuria vs macroalbuminuria

Proteinuria as a Risk Factor Proteinuria as a Risk Factor for Mortality in Type 2 Diabetesfor Mortality in Type 2 Diabetes

Gall MA, et al. Diabetes. 1995;44:1303-1309.Copyright ©1995, American Diabetes Association. Reprinted with permission.




Insulin ResistanceInsulin ResistanceInsulin ResistanceInsulin Resistance

Interrelation Between Atherosclerosis and Interrelation Between Atherosclerosis and Insulin ResistanceInsulin Resistance


ObesityObesity

HyperinsulinemiaHyperinsulinemia

DiabetesDiabetes

HypertriglyceridemiaHypertriglyceridemia

Small, dense LDLSmall, dense LDL

Low HDLLow HDL

HypercoagulabilityHypercoagulability

InsulinInsulinResistanceResistance

InsulinInsulinResistanceResistance AtherosclerosisAtherosclerosisAtherosclerosisAtherosclerosis

Therapy for Insulin ResistanceTherapy for Insulin Resistance

• Exercise

• Weight control

• Diet

• Smoking cessation

• Thiazolidinediones– Pioglitazone – Rosiglitazone

• Metformin

Pharmacologic:Pharmacologic:Nonpharmacologic::Nonpharmacologic::

Therapy for Metabolic SyndromeTherapy for Metabolic Syndrome

Treatment of Metabolic SyndromeTreatment of Metabolic Syndrome

If T2DM: TZDs with or without If T2DM: TZDs with or without metforminmetformin


And HyperglycemiaAnd Hyperglycemia

ASA, Quit smokingASA, Quit smokingProthrombotic StateProthrombotic State

ACE I or ARBsACE I or ARBsHypertension Hypertension (and/or (and/or endothelial dysfunction)endothelial dysfunction)

Statins and/or FibratesStatins and/or FibratesDyslipidemiaDyslipidemia

Lifestyle ModificationLifestyle ModificationCentral ObesityCentral Obesity

TreatmentTreatmentRisk FactorRisk Factor

Insulin Resistance and Metabolic Syndrome Thomas Repas D.O. Diabetes, Endocrinology and Nutrition...

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Transcript of Insulin Resistance and Metabolic Syndrome Thomas Repas D.O. Diabetes, Endocrinology and Nutrition...