What is the Etiology(ies) of the Metabolic Syndrome?
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What is the Etiology(ies) of the Metabolic Syndrome? NIDDK Diabetes Mellitus Interagency Coordinating Committee (DMICC) The Metabolic Syndrome NIH Campus, Bethesda, MD February 25, 2003 Steven M. Haffner, MD Professor University of Texas Health Science Center at San Antonio San Antonio, Texas

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What is the Etiology(ies) of the Metabolic Syndrome?NIDDK Diabetes Mellitus Interagency Coordinating Committee (DMICC)The Metabolic SyndromeNIH Campus, Bethesda, MDFebruary 25, 2003

Steven M. Haffner, MD

Professor

University of Texas Health Science Center at San Antonio

San Antonio, Texas


Criteria for comparing different definitions for metabolic syndrome l.jpg
Criteria for Comparing Different Definitions for Metabolic Syndrome

  • Risk of

    • CHD

    • DM

  • Relation to insulin resistance

  • Prevalence in community could differ by race

    NCEP: 2 lipid criteria

    WHO: 1 lipid criteria

    African Americans have low triglycerides and high HDL and thus a lower prevalence of MS by NCEP than WHO

    4. How simple is the definition?


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Outline Syndrome

  • Methodological issues

  • Prediabetic State

  • Factor analyses (role of HBP)

  • Insulin as a predictor of MS, and CHD

  • Subclinical inflammation and MS

  • Do BP/lipid therapies work in MS?


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Data Sets Syndrome

  • San Antonio Heart Study

  • NHANES

  • Insulin Resistance Atherosclerosis Study

    • Direct measure of IR

    • Three ethnic groups

  • Framingham Study (Factor Analyses)

  • Mexico City Diabetes Study


Etiology of metabolic syndrome l.jpg
Etiology of Metabolic Syndrome Syndrome

  • Insulin Resistance (IRS)

    • Syndrome X: Reaven, Diabetes 1987

    • IRS: Ferrannini, Diabetologia 1991

    • IRS: Haffner, Diabetes 1992

      2. Obesity

    • Visceral fat: Despres (many papers)(“hypertriglyceridemic waist”)

    • Weight gain: Peter Wilson, Arch Int Med, 2000


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Etiology of Metabolic Syndrome (continued) Syndrome

  • Glycemia: non diabetic range

    • Gerstein: Dysglycaemic Syndrome

    • DECODE data: Post-prandial (“actually post glucose load”) glycemia and CVD

  • Cardiovascular risk factors (no additional effect of MS)

  • Subclinical Inflammation


The prediabetic state l.jpg
The Prediabetic State Syndrome

  • Early attempt at the metabolic syndome (IRS)

  • Glucose vs insulin as cause of elevated CVD risk


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80 Syndrome

60

40

20

0

MI and Microvascular End Points: Incidenceby Mean Systolic BP and HbA1c Concentration

50

MI

Microvascular end points

MI

Microvascular end points

40

30

Adjusted incidence/1000 person-y (%)

Adjusted incidence/1000 person-y (%)

20

10

0

110

120

130

140

150

160

170

5

6

7

8

9

10

11

Updated mean systolic BP (mm Hg)

Updated mean HbA1cconcentration (%)

Adler et al. BMJ. 2000;321:412. Stratton et al. BMJ. 2000;321:405.



Elevated risk of cvd prior to clinical diagnosis of type 2 diabetes l.jpg
Elevated Risk of CVD Prior to Clinical Diagnosis of Type 2 Diabetes

Relative Risk

Nondiabetic

throughout the

study

Prior to diagnosis

of diabetes

After diagnosis

of diabetes

Diabetic at

baseline

Hu FB, et al. Diabetes Care 2002;25(7):1129-1134.


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Age- and Sex-Adjusted Anthopometric Variables and Cardiovascular Risk Factors at Baseline (Mean) in Subjects with Normal Glucose Tolerance at Baseline According to Conversation Status at 8-Year Follow-Up


Conversion to type 2 diabetes 7 year incidence l.jpg
Conversion to Type 2 Diabetes (7-Year Incidence) Cardiovascular Risk Factors at Baseline (Mean) in Subjects with Normal Glucose Tolerance at Baseline According to Conversation Status at 8-Year Follow-Up

Low Insulin Secretion

Low

Low

Neither

Low

High

Insulin-Resistant

High

High

Metabolic Status

HOMA IR

Δ I30-0min/Δ G30-0min

Both

High

Low

Haffner et al. Circulation 2000; 101: 975-980.


Distribution by metabolic status among converters to type 2 diabetes l.jpg
Distribution by Metabolic Status Among Converters to Type 2 Diabetes

Low insulin secretion;

insulin sensitive

(15.9%)

Neither (1.5%)

Both (54%)

Insulin resistant;

good insulin secretion (28.7%)

(n=195)

Haffner et al. Circulation 2000;101:975–980.


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Mean Triglyceride Levels by Insulin Resistance/Secretion Category

P<0.0001

P=0.033

P=0.47

220

200

180

160

Triglyceride (mg/dL)

140

120

100

Converters to type 2 diabetes

Non-converters (all)

Metabolic status HOMA IR

DI30–0 min/DG30–0min

Low insulin secretion

low

low

Insulin-resistant

high

high

Haffner et al. Circulation 2000;101:975–980.


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Mean HDL Cholesterol by Insulin Resistance/Secretion Category

P<0.0001

P=0.0001

P=0.90

50

40

HDL cholesterol (mg/dL)

30

20

Converters to type 2 diabetes

Non-converters (all)

Metabolic status HOMA IR

DI30–0 min/DG30–0min

Insulin-resistant

high

high

Low insulin secretion

low

low

Haffner et al. Circulation 2000;101:975–980.


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Mean Systolic Blood Pressure by Insulin Resistance/Secretion Category

P<0.0001

130

P=0.035

P=0.66

125

SBP (mm Hg)

120

115

110

Converters to type 2 diabetes

Non-converters (all)

Insulin-resistant

high

high

Metabolic status

HOMA IR

DI30–0 min/DG30–0min

Low insulin secretion

low

low

Haffner et al. Circulation 2000;101:975–980.



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Relationship of Fasting Insulin Levels to CategoryRelative Risk for Multiple Metabolic Disorders

Baseline insulin Low High Relative

Disorder (%) (%) risk P value

Hypertension 5.5 11.4 2.04 .020

Hypertriglyceridemia 2.6 8.9 3.46 <.001

Low HDL-C 16.2 26.3 1.63 .012

High LDL-C 16.4 20.1 1.23 .223

Type 2 diabetes 2.2 12.2 5.62 <.001

Haffner SM et al. Diabetes 1992;41:715–722.


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Risk of Major CHD Event Associated With CategoryHigh Insulin Levels in Nondiabetic Men

Kaplan-Meier Survival Curve

1.00

0.95

Q1

0.90

Proportion without major CHD event

0.85

Q2

Log rank:

Overall P=.001

Q5 vs Q1 P<.001

0.80

Q3

Q4

0.75

Q5

0

0

5

10

15

20

25

Years

Q1 to Q5=quintiles of area under the curve (AUC) insulin (Q1=lowest quintile; Q5=highest quintile).

Pyörälä M et al. Circulation 1998;98:398–404.


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Markers of Inflammation and Cardiovascular Disease CategoryApplication to Clinical and Public Health PracticeA Statement for Healthcare Professionals from the CDC and the AHA

Relative Risk Category and Average hs-CRP Level

Low: <1 mg/L

Average: 1.0 to 3.0 mg/L

High: >3.0 mg/L

(Class IIa, Level of Evidence B)

Pearson T, et al. Circulation 2003; 107:499-511


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Partial Spearman Correlation Analysis of Inflammation Markers With Variables of IRS Adjusted for Age, Sex, Clinic, Ethnicity, and Smoking Status: IRAS

*P<0.05, †P<0.005, ‡P<0.0001

CRP=C-reactive protein; IRS=insulin resistance system; WBC=white blood cell count.

Adapted from Festa et al. Circulation 2000;102:42–47.


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Mean values of CRP by number of metabolic disorders (dyslipidemia, upper body adiposity, insulin resistance, hypertension): IRAS

Festa et al. Circulation 102:42-7, 2000.


Five year incidence of type 2 diabetes stratified by quartiles of inflammatory proteins iras l.jpg
Five Year Incidence of Type 2 Diabetes Stratified by Quartiles of Inflammatory Proteins: IRAS

%

P=0.001

P=0.001

P=0.06

Festa A et al. Diabetes, in press.


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Effect of Insulin Sensitizing Interventions on Reducing CRP Levels

  • Lifestyle

    DPP – presented AHA, 2002

  • Pharmacological

    • Metformin – presented AHA, 2002

    • TZD-Rosiglitazone - Circulation 2002


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The Effect of Rosiglitazone on CRP Levels

n=124

n=95

n=134

Placebo

Rosiglitazone 4 mg/day

Rosiglitazone 8 mg/day

Difference = -26.8%(95% CI: -39.7, -21.8 )

Difference = -21.8 (95% CI: -34.7, -5.6)

Haffner SM et al. Circulation, 2002; 106:679-684


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Do Elevated Levels of C-Reactive Protein Predict the Development of the NCEP Metabolic Syndrome?

Han TS, Sattar N, Williams K, Gonzalez-Villalpando C, Lean MEJ, Haffner SM. Prospective study of c-reactive protein in relation to the development of diabetes and metabolic syndrome in the Mexico City Diabetes Study. Diabetes Care, 25:2016-2021, 2002.


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CRP Predicts a Development of the Metabolic Syndrome (NCEP) in Women but not in Men: Mexico City (Han et al, Diabetes Care, 25:2016-2021, 2002)


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Both CRP and BMI Predict a Development of the Metabolic Syndrome (NCEP) in Women: Mexico City Diabetes Study (Han et al, Diabetes Care, 25:2016-2021, 2002)


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CRP Predicts Development of the Metabolic Syndrome (NCEP) in Women Independently of BMI and HOMA IR : Mexico City Diabetes Study (Han et al, Diabetes Care, 25:2016-2021, 2002)

Additionally adjusting for:

-

BMI

HOMA-IR

BMI & HOMA IR

1/2 1 2 4 8 16

Odds ratio (95% CI) for 3rd vs. 1st CRP tertile


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Factor Analyses Women Independently of BMI and HOMA IR : Mexico City Diabetes Study (Han et al,

  • Framingham Study

    Meigs, Diabetes 1997

  • IRAS

    Hanley, Diabetes 2002

    Conclusion: Hypertension not associated (separate factor) with Insulin Resistance


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HTN Women Independently of BMI and HOMA IR : Mexico City Diabetes Study (Han et al,

IGT

BP

Systolic

Fasting

Glucose

TG

Fasting

Insulin

Body

Mass

Index

BP

Diastolic

2-hour

Glucose

HDL-C

Waist-

Hip

Ratio

Central Syndrome

5-6 Traits May Represent 2-4 Physiologic PhenotypesInsulin Resistance Syndrome Factor Pattern Interpretation

Meigs et al. Diabetes 1997;46:1594-1600


Factor analysis of metabolic syndrome using directly measured insulin sensitivity iras l.jpg
Factor Analysis of Metabolic Syndrome Using Directly-Measured Insulin Sensitivity: IRAS

Loadings > 0.40 in Red; Hanley et al. Diabetes, 2002; 51: 2642-2647.


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Summary Directly-Measured Insulin Sensitivity: IRAS

  • Most subjects with the Metabolic Syndrome do not have type 2 diabetes.

  • The Metabolic Syndrome is associated with increased risk of heart disease although the increased risk may not be entirely due to increased insulin resistance.


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