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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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slide1

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
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?

slide3

Outline

  • 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?
slide4

Data Sets

  • 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
Etiology of Metabolic 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
etiology of metabolic syndrome continued
Etiology of Metabolic Syndrome (continued)
  • 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
The Prediabetic State
  • Early attempt at the metabolic syndome (IRS)
  • Glucose vs insulin as cause of elevated CVD risk
slide8

80

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
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.

slide11

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
Conversion to Type 2 Diabetes (7-Year Incidence)

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
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.

mean triglyceride levels by insulin resistance secretion category
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.

mean hdl cholesterol by insulin resistance secretion category
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.

mean systolic blood pressure by insulin resistance secretion category
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.

relationship of fasting insulin levels to relative risk for multiple metabolic disorders
Relationship of Fasting Insulin Levels to Relative 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.

risk of major chd event associated with high insulin levels in nondiabetic men
Risk of Major CHD Event Associated With High 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.

slide20

Markers of Inflammation and Cardiovascular DiseaseApplication 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

slide21

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.

slide22
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
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.

effect of insulin sensitizing interventions on reducing crp levels
Effect of Insulin Sensitizing Interventions on Reducing CRP Levels
  • Lifestyle

DPP – presented AHA, 2002

  • Pharmacological
    • Metformin – presented AHA, 2002
    • TZD-Rosiglitazone - Circulation 2002
the effect of rosiglitazone on crp
The Effect of Rosiglitazone on CRP

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

do elevated levels of c reactive protein predict the development of the ncep metabolic syndrome
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.

slide27

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)

slide28

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)

slide29

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

slide30

Factor Analyses

  • Framingham Study

Meigs, Diabetes 1997

  • IRAS

Hanley, Diabetes 2002

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

slide31

HTN

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
Factor Analysis of Metabolic Syndrome Using Directly-Measured Insulin Sensitivity: IRAS

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

summary
Summary
  • 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.