Insulin Resistance and

Metabolic Syndrome
Thomas Repas D.O.
Diabetes, Endocrinology and Nutrition Center, Affinity Medical Group, Neenah, Wisconsin
Member, Inpatient Diabetes Management Committee, St. Elizabeths Hospital, Appleton, WI
Member, Diabetes Advisory Group, Wisconsin Diabetes Prevention and Control Program
Website: 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

Diabetes Mellitus in the US

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 societys

Obesity
Age
Growth of ethnic populations with high prevalence
Physical activity
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

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

Diabetes and Gestational Diabetes Trends Among

Adults in the U.S., BRFSS 1990

No Data
8%-10%

<4%
>10%

4%-6%

6%-8%

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

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 1993-94

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 1995-96

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 1995

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 1997-98

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 1999

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 2000

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 2001

No Data
8%-10%

<4%
>10%

4%-6%

6%-8%

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).

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

Fagot-Campagna A et al. J Pediatr. 2000;136:664

Rosenbloom A et al. Diabetes Care. 1999;22:345
3
Pinhas-Hamiel O et al. J Pediatr. 1996;128:608
4
Pihoker C et al. Clin Pediatr. 1998;37:97
5
Neufeld N et al. Diabetes Care. 1998;21:80
1
2

Projections of US Population with

Diagnosed Diabetes (millions)
44% Increase by 2020

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

Estimated prevalence (millions)

Estimates of Diabetes
Prevalence in World Regions
1995

Africa

2000

2025

Americas Eastern
Europe
Mediterranean

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

Southeast
Asia

Western
Pacific

Why is Type 2 Diabetes on the

rise?

Link Between Obesity and Type 2 Diabetes:

Nurses Health Study
Age-Adjusted Relative Risk

120
100
80
60
40
20
0
<22

22- 23- 24- 25- 27- 29- 31- 33- >35

22.9 23.8 24.9 26.9 28.9 30.9 32.9 34.9
BMI (kg/m2)

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

Obesity Trends* Among U.S. Adults

BRFSS, 1985

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

2001;286:10.

Obesity Trends* Among U.S. Adults

BRFSS, 1986

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

2001;286:10.

Obesity Trends* Among U.S. Adults

BRFSS, 1987

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

2001;286:10.

Obesity Trends* Among U.S. Adults

BRFSS, 1988

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

2001;286:10.

Obesity Trends* Among U.S. Adults

BRFSS, 1989

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

2001;286:10.

Obesity Trends* Among U.S. Adults

BRFSS, 1990

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

2001;286:10.

Obesity Trends* Among U.S. Adults

BRFSS, 1991

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

2001;286:10.

Obesity Trends* Among U.S. Adults

BRFSS, 1992

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

2001;286:10.

Obesity Trends* Among U.S. Adults

BRFSS, 1993

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

2001;286:10.

Obesity Trends* Among U.S. Adults

BRFSS, 1994

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

2001;286:10.

Obesity Trends* Among U.S. Adults

BRFSS, 1995

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

2001;286:10.

Obesity Trends* Among U.S. Adults

BRFSS, 1996

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

2001;286:10.

Obesity Trends* Among U.S. Adults

BRFSS, 1997

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

2001;286:10.

Obesity Trends* Among U.S. Adults

BRFSS, 1998

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

2001;286:10.

Obesity Trends* Among U.S. Adults

BRFSS, 1999

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

2001;286:10.

Obesity Trends* Among U.S. Adults

BRFSS, 2000

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

2001;286:10.

Obesity Trends* Among U.S. Adults

BRFSS, 2001

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

2001;286:10.

CV Risks of Type 2 Diabetes

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

National Institutes of Health;1995.

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eo li
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e
P
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in m
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en a
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ot
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be
te
s

h
ea I
rt sch
d e
is m
e a ic
se
O
th
er
di h
se ea
as rt
e

Percent of deaths

Causes of Death in
People With Diabetes

Hospitalization Costs for Chronic

Complications of Diabetes in the US
Ophthalmic Others
disease
Renal
disease

Neurologic
disease
Peripheral
vascular
disease

Total costs 12
billion US $

CVD accounts
for 64% of
total costs

Cardiovascular
disease

American Diabetes Association. Economic Consequences of Diabetes Mellitus

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

Hospitalization for MI Has Not Declined

Hospitalization for MI
(per 1,000)*

Men

Women

1987

1988

1989

Age-adjusted

Rosamond WD et al. N Engl J Med 1998;339:861-867.

1998 Massachusetts Medical Society. All rights reserved.

1990

1991 1992

1993

1994

CVD Death Rates Are Higher

in Patients With Diabetes
CVD Death Rate*
per 10,000 Person-Years

140

Nondiabetic
Diabetic

120
100
80
60
40
20
0

*Age adjusted.

Number of Risk Factors

Copyright 1993 American Diabetes Association. From Diabetes Care. 1993;16:434-444.

Reprinted with permission from the American Diabetes Association.

Type 2 Diabetes is a Cardiovascular Risk

Factor
Diabetes and prior myocardial infarction (MI) carry the
same mortality risk
45.0%*

Fatal or Nonfatal MI

No Prior MI
Prior MI

18.8%*

20.2%

3.5%
Nondiabetic Subjects
(n=1373)
Seven-year incidence in a Finnish-based cohort.
*P<.001
Haffner SM, et al. N Engl J Med. 1998;339:229-234.

Type 2 Diabetic Subjects

(n=1059)

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

New Definition of Impaired

Fasting Glucose

In 11/03, The Expert Committee on the

Diagnosis and Classification of Diabetes Mellitus
redefined IFG as being 100-125 mg/dl

It is estimated that this will increase the numbers

of adults with prediabetes by approximately
20%

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

Pathophysiology of Type 2 Diabetes

Peripheral Tissues
(Muscle)

Receptor +
postreceptor defects

Glucose

Insulin
resistance

Liver
Increased glucose
production

Pancreas
Impaired insulin
secretion
Saltiel AR, Olefsky JM. Diabetes. 1996;45:1661-1669.

Natural History of Type 2 Diabetes

Severity of Glucose Intolerance
NGT

IGT

Frank
Diabetes

Insulin
Resistance
Insulin Secretion
Postprandial Glucose
Fasting Blood Glucose

Normal Blood
Glucose
Risk of Microvascular Complications
Risk of Macrovascular Complications

Years to
Decades

Typical Diagnosis of Diabetes

Worsens
with Time

Proportion without
Major CHD Event

Risk of Major CHD Event Associated with Insulin

Quintiles in Nondiabetic Subjects: Helsinki
Policemen Study

Q1
Q2

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

Q3
Q4
Q5

10

15
Years

Pyorala M et al. Circulation 1998;98:398-404.

1998 Lippincott Williams & Wilkins.

20

25

Honolulu Heart Study

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

12 year age-adjusted incidence of fatal/total CHD

By 1 hour post challenge serum glucose

Relation of Fasting Glucose to Risks

of MI
People without Diabetes or IGT

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

Risk for all Cause Mortality and Glycemic

Control: Think Continuum, Not Threshold
EPIC-Norfolk Study

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

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. 19881994. National Center for Health Statistics, Hyattsville, Md

Metabolic 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. J Clin Endocrinol Metab. 2001; 86 (2) : 713-718.

The Metabolic Syndrome

Dyslipidemia

Insulin Resistance

Prothrombotic State

Hypertension

Etiology of Metabolic Syndrome

The metabolic syndrome results from a complex

interplay of two important factors:

Genetics

Bogardus C, et al. Endocrinol Metab. 1985;11:E286-E291

Roberts K, et al. Nutr Rev. 2000 May;58(5):154-160.

Environment

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

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.

Risks of Metabolic Syndrome

Five year Progression of Carotid Atherosclerosis and Coronary Heart Disease

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

Diagnosis of Metabolic Syndrome

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

WHO
NCEP ATP III
AACE

The Metabolic Syndrome:

WHO criteria
IGT/IFG or
type 2 diabetes
Central Obesity
BMI > 30 kg/m

Insulin resistance
(glucose uptake below
lowest quartile)

METABOLIC SYNDROME
Microalbuminuria
UAE 20 g min

Blood pressure
160/90 mmHg
Triglycerides
> 150
mg/dl
& HDL-Ch
< 35 mg/dl

Alberti & Zimmet WHO 1998 Diabetic Medicine.

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 III

Risk Factor

Waist Circumference
Triglycerides
HDL Cholesterol
Blood Pressure
Fasting Blood Glucose

Level

>40 in (m) >35 in (f)

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

Dysmetabolic Syndrome = 3 out of 5

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

AACE Criteria for Dysmetabolic Syndrome X

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

Minor Features
Hypercoagulability
Polycystic ovary syndrome
Vascular endothelial dysfunction
Microalbuminuria
Coronary 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

Clinical Exam Findings Suggesting

Insulin Resistance

Acanthosis Nigricans

Skin Tags

Polycystic Ovarian Syndrome:

Menstrual irregularities
Hyperandrogenism
Insulin resistance

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

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

Typical polycystic ovaries. Multiple small follicular

cysts are apparent in the cut section.

Pathophysiology of Insulin Resistance

and
Metabolic Syndrome

The Metabolic Syndrome

Dyslipidemia
Dyslipidemia

Insulin Resistance

Prothrombotic State

Hypertension

Dyslipidemia

Diabetic Dyslipidemia

Triglycerides
HDL
Small, Dense LDL
LDL-C may be normal

Insulin Resistance
Postprandial Lipid Metabolism
Adipose Tissue
Accelerated FFA

Liver
Accelerated TG
CE

LDL
TG-Rich
LDL
Hepatic
Lipase
SD
LDL

CETP
TG

TG

VLDL

HDL
CETP
CE

Reduced
Lipoprotein Lipase

TG-Rich
HDL
Hepatic
Lipase

Remnants (to liver)

Decreased HDL2

Lipoprotein Classes and Inflammation

Chylomicrons,
VLDL, and
their catabolic
remnants

LDL

> 30 nm

2022 nm

Potentially proinflammatory

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.

HDL

915 nm
Potentially antiinflammatory

Hyperinsulinemia and Low

HDL
60

HDL-C (mg/dL)

50

p < 0.005

Hyperinsulinemic
Normoinsulinemic
p < 0.005

40
30
20
10
0

Non-obese

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

Obese

Cardiovascular Disease
and HDL-C Levels
180

Men
Women

Rate per 1000

150
120
90
60
30
0

< 34

35-54

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

> 55

Glycemia and Small Dense

LDL
Steady State Plasma
Glucose (mmol/L)

12
10
8
6
4
2
0

Pattern A

Intermediate Pattern
LDL Phenotype

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

Pattern B

LDL Subpopulations
Pattern A and Pattern B

Large Fluffy LDL

Small Dense LD

Glycemia and Small Dense

LDL
Steady State Plasma
Glucose (mmol/L)

12
10
8
6
4
2
0

Pattern A

Intermediate Pattern
LDL Phenotype

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

Pattern B

Small, Dense LDL

Permeates arterial wall

Binds proteoglycans
Susceptible to oxidation
Atherogenic lipid profile

Structure of LDL
Surface Monolayer
of Phospholipids
and Free
Cholesterol

apoB

Hydrophobic Core
of Triglyceride and
Cholesteryl Esters
Murphy HC et al. Biochemistry 2000;39:9763-970.

LDL Subpopulations
LDL
VLDL

IDL

LDL LDL
LDL

LDL Subpopulations
VLDL
VLDL
VLDL

VLDL

IDL
IDL
IDL IDL

LDL

LDL Subpopulations
LDL
VLDL

IDL

LDL LDL
LDL

Small Dense LDL

VLDL

IDL

LDL

TG
VLDL

LDL

Cholesterol

Small Dense LDL

VLDL

IDL

LDL

TG
VLDL

LDL

Cholesterol

Small Dense LDL

VLDL

IDL

VLDL

LDL

LDL

Small Dense LDL

VLDL

IDL

VLDL

LDL

SD
LDL

LDL
LDL

LDL
LDL

IDL

De Novo
Synthesis
Assembly
Extrinsic
Sources

Cholesterol
Pool

Bile

Tissue
Tissue
Uptake
Uptake
VLDL

Lipoproteins

LDL
LDL

LDL

LDL
IDL

De Novo
Synthesis
Assembly
Extrinsic
Sources

Cholesterol
Pool

Bile

Tissue
Tissue
Uptake
Uptake
VLDL

Lipoproteins

LDL
LDL

LDL
LDL

IDL

De Novo
Synthesis
Assembly
Extrinsic
Sources

Cholesterol
Pool

Bile

Tissue
Tissue
Uptake
Uptake
VLDL

Lipoproteins

SD
LDL
SD
LDL

LDL

LDL
IDL

De Novo
Synthesis
Assembly
Extrinsic
Sources

Cholesterol
Pool

Bile

Tissue
Tissue
Uptake
Uptake
VLDL

Lipoproteins

SD
LDL

LDL
SD
LDL

LDL
IDL

De Novo
Synthesis
Assembly
Extrinsic
Sources

Cholesterol
Pool

Bile

Tissue
Tissue
Uptake
Uptake
VLDL

Lipoproteins

SD
LDL

LDL
SD
LDL

LDL
IDL

De Novo
Synthesis
Assembly
Extrinsic
Sources

Cholesterol
Pool

Bile

Tissue
Tissue
Uptake
Uptake
VLDL

Lipoproteins

SD
LDL

LDL

SD
LDL

LDL
IDL

De Novo
Synthesis
Assembly
Extrinsic
Sources

Cholesterol
Pool

Bile

Tissue
Tissue
Uptake
Uptake
VLDL

Lipoproteins

SD
LDL
SD
LDL

LDL

LDL
IDL

De Novo
Synthesis
Assembly
Extrinsic
Sources

Cholesterol
Pool

Bile

Tissue
Tissue
Uptake
Uptake
VLDL

Lipoproteins

SD
LDL

LDL

LDL
LDL

IDL

De Novo
Synthesis
Assembly
Extrinsic
Sources

Cholesterol
Pool

Bile

Tissue
Tissue
Uptake
Uptake
VLDL

Lipoproteins

SD
LDL

LDL

LDL

LDL
IDL

De Novo
Synthesis
Assembly
Extrinsic
Sources

Cholesterol
Pool

Bile

Tissue
Tissue
Uptake
Uptake
VLDL

Lipoproteins

Infiltration of LDL
IDL

LDL

VLDL

VLDL
LDL

Infiltration of LDL
VLDL

VLDL
IDL

LDL

LDL

LDL

LDL

Infiltration of LDL
VLDL

VLDL
IDL

LDL

SD
LDL

LDL

SD
LDL

The Problem With Treating Only Numbers

The Metabolic Syndrome

Dyslipidemia

Insulin Resistance

Prothrombotic
State
Prothrombotic State

Hypertension

Prothrombotic State

Factors Promoting Thromboembolic

Disease in Diabetes
Increased plasma fibrinogen
Increased plasminogen activator
inhibitor 1
Increased platelet aggregability

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

Plasma concentration of PAI-1 in

normal subjects, IGT, and type 2 diabetes
PAI-1 antigen (ng/mL)

35
30
25
20
15
10
5
0

NGT
(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;19:562568.

Vascular
endothelium
PAI-1

PAI-1 and inhibition of

fibrinolysis
Platelets

t-PA

Plasminogen
Bloodstream
t-PA

PAI-1

PAI-1

t-PA

Plasmin

t-PA

PAI-1 complexes and

inactivates t-PA

Free t-PA activates plasmin,

leading to fibrinolysis and
reducing the risk of
thrombosis

Kohler HP & Grant PJ. N Engl J Med 2000; 342:17921801.

The Metabolic Syndrome

Dyslipidemia

Insulin Resistance

Prothrombotic State

Hypertension
Hypertension

Hypertension

Hypertension,
Glucose Intolerance and CHD

150

200

No Glucose
Intolerance
Glucose
Intolerance

Age Adjusted CV Event Rate / 1000

Age Adjusted CV Event Rate / 1000

200

Men

100

50

150

135

165

Systolic BP (mm Hg)

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

195

No Glucose
Intolerance
Glucose
Intolerance

100

50

0
105

Women

105

135

165

Systolic BP (mm Hg)

195

Proteinuria and Hypertension

in Type 2 Diabetes
Standardized
mortality ratio

Status of Proteinuria (P) and

Hypertension (H) in Type 2 Diabetics

-P-H

-P+H

+P-H

+P+H

-P-H

-P+H

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

+P-H

Women

+P+H

Survival (all-cause mortality)

Proteinuria as a Risk Factor

for Mortality in Type 2 Diabetes
1.0
Normoalbuminuria
(n=191)

0.9

Microalbuminuria
(n=86)

0.8
0.7

Macroalbuminuria
(n=51)

0.6
0.5
0

P<0.01 normoalbuminuria vs microalbuminuria

P<0.001 normoalbuminuria vs macroalbuminuria
P<0.05 microalbuminuria vs macroalbuminuria
Gall MA, et al. Diabetes. 1995;44:1303-1309.
Copyright 1995, American Diabetes Association. Reprinted with permission.

6
Years

The Metabolic Syndrome

Dyslipidemia

Insulin
InsulinResistance
Resistance

Prothrombotic State

Hypertension

Insulin Resistance

Interrelation Between Atherosclerosis and

Insulin Resistance
Hypertension
Obesity
Hyperinsulinemia

Insulin
Insulin
Resistance
Resistance

Diabetes
Hypertriglyceridemia
Small, dense LDL
Low HDL
Hypercoagulability

Atherosclerosis
Atherosclerosis

Therapy for Insulin Resistance

Nonpharmacologic:

Exercise
Weight control
Diet
Smoking cessation

Pharmacologic:

Thiazolidinediones
Pioglitazone
Rosiglitazone

Metformin

Therapy for Metabolic Syndrome

The Metabolic Syndrome

Dyslipidemia

Insulin Resistance

Prothrombotic State

Hypertension

Treatment of Metabolic Syndrome

Risk Factor
Central Obesity

Treatment
Lifestyle Modification

Dyslipidemia

Statins and/or Fibrates

Hypertension (and/or

ACE I or ARBs

endothelial dysfunction)

Prothrombotic State
Insulin Resistance
And Hyperglycemia

ASA, Quit smoking

If T2DM: TZDs with or without
metformin