# Presentation: 031153

## 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**

## 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?**

## 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?

**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?**

**Outline**

## San Antonio Heart Study
NHANES
Insulin Resistance Atherosclerosis Study
Direct measure of IR
Three ethnic groups
Framingham Study (Factor Analyses)
Mexico City Diabetes Study

**NHANES**
**Insulin Resistance Atherosclerosis Study**
**Direct measure of IR**
**Three ethnic groups**
**Framingham Study (Factor Analyses)**
**Mexico City Diabetes Study**

**Data Sets**

## 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)

**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

**Early attempt at the metabolic syndome (IRS)**
**Glucose vs insulin as cause of elevated CVD risk**

## MI and Microvascular End Points: Incidenceby Mean Systolic BP and HbA1c Concentration 

**MI and Microvascular End Points: Incidence****by Mean Systolic BP and HbA****1c**** Concentration**

**MI**
**Microvascular end points**

**Updated mean systolic ****BP (mm Hg)**

**Adjusted incidence/****1000 person-y (%)**

**Updated mean HbA****1c**** ****concentration (%)**

**Adjusted incidence/****1000 person-y (%)**

**MI**
**Microvascular end points**

**50**

**40**

**30**

**20**

**10**

**0**

**110**

**120**

**130**

**140**

**150**

**160**

**5**

**6**

**7**

**8**

**9**

**10**

**11**

**170**

**Notes:**
Epidemiologic analyses from the United Kingdom Prospective Diabetes Study (UKPDS) demonstrated that BP and hyperglycemia are continuous risk factors for complications of diabetes. Data from 3642 patients enrolled in UKPDS, with an average duration of diabetes of 10 years, were included in risk analyses. 
The increase in risk with increased BP was monotonic, with no evidence of a threshold. At each level of BP, the incidence of myocardial infarction (MI) was about twice as high as the incidence of microvascular end points (retinopathy requiring photocoagulation, vitreous hemorrhage, and fatal or nonfatal renal failure). The risk for complications of diabetes was also strongly associated with hyperglycemia, measured as mean updated hemoglobin A1c (HbA1c). The association between microvascular complications and hyperglycemia was more pronounced than that between MIs and hyperglycemia; no threshold was observed in either case. 

## The prediabetic state as a model of the metabolic syndrome

## Elevated Risk of CVD Prior to Clinical Diagnosis of Type 2 Diabetes

**Nondiabetic**
**throughout the**
**study**

**Prior to diagnosis**
**of diabetes**

**After diagnosis**
**of diabetes**

**Diabetic at**
**baseline**

**Relative Risk**

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

## 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 Status at Follow-Up |  |  |
| --- | --- | --- | --- |
|  | Diabetes 
(n=18) | Normal
(n=490) | 
P-Value |
| Body Mass Index (kg/m2) | 28.2± 1.1 | 27.2± 0.02 | .472 |
| Centrality | 1.38± 0.09 | 1.16± 0.2 | .076 |
| Triglycerides (mmol/L) | 1.83± 0.12 | 1.28± 0.10 | .006 |
| High-density lipoprotein (mmol/L) | 1.14± 0.07 | 1.28± 0.02 | .045 |
| Systolic blood pressure (mm Hg) | 116.8± 3.0 | 108.8± 0.8 | .004 |
| Fasting glucose (mmol/L) | 5.28± 0.1 | 5.00± 0.02 | .032 |
| Fasting insulin (pmol/L) | 157± 27 | 81± 5 | .006 |
| Haffner SM et al. JAMA 1990; 263:2893-2898. |  |  |  |

## Conversion to Type 2 Diabetes (7-Year Incidence)

**Neither**
**Low**
**High**

**Low Insulin Secretion**
**Low**
**Low**

**Insulin-Resistant**
**High**
**High**

**Both**
**High**
**Low**

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

- Metabolic Status
- HOMA IR
- Δ I30-0min/Δ G30-0min

## Distribution by Metabolic Status Among Converters to Type 2 Diabetes

**Both (54%)**

**Insulin resistant; **
**good insulin secretion (28.7%)**

**Neither (1.5%)**

**Low insulin secretion; **
**insulin sensitive**

**(15.9%)**

**(n=195)**

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

## Mean Triglyceride Levels by Insulin Resistance/Secretion Category

**100**

**120**

**140**

**160**

**180**

**200**

**220**

- Triglyceride (mg/dL)

- 	                      Converters to type 2 diabetes

- Non-converters (all)

*P*<0.0001

*P*=0.033

*P*=0.47

**Mean Triglyceride Levels by Insulin Resistance/Secretion Category**

- Insulin-resistant
- high
- high

- Low insulin secretion
- low
- low

- Metabolic status HOMA IR
- I30–0 min/G30–0min

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

## Mean HDL Cholesterol by Insulin Resistance/Secretion Category

**20**

**30**

**40**

**50**

- HDL cholesterol (mg/dL)

- Non-converters (all)

- 		    Converters to type 2 diabetes

*P*<0.0001

*P*=0.0001

*P*=0.90

**Mean HDL Cholesterol by Insulin Resistance/Secretion Category**

- Insulin-resistant
- high
- high

- Low insulin secretion
- low
- low

- Metabolic status HOMA IR
- I30–0 min/G30–0min

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

## Mean Systolic Blood Pressure by Insulin Resistance/Secretion Category

**110**

**115**

**120**

**125**

**130**

- SBP (mm Hg)

- Non-converters (all)

- 	               Converters to type 2 diabetes

*P*<0.0001

*P*=0.035

*P*=0.66

**Mean Systolic Blood Pressure by Insulin Resistance/Secretion Category**

- Low insulin secretion
- 	low
- 	low

- Insulin-resistant
- high
- high

- Metabolic status
- HOMA IR
- I30–0 min/G30–0min

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

## Insulin as a predictor of the metabolic syndrome and CHD

## Relationship of Fasting Insulin Levels to Relative Risk for Multiple Metabolic Disorders

**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**

- 	                 **Baseline insulin****	****Low****	****High****	****Relative**
**Disorder****	****(%)****	****(%)****	****risk****	*****P***** value**

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

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

- 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.

- Years

**Proportion without major CHD event**

- 0

- 0

- 5

- 0.75

- 0.80

- 0.85

- 0.90

- 0.95

- 1.00

- 10

- 15

- 20

- 25

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

- Q1

- Q2

- Q3

- Q4

- Q5

**Kaplan-Meier Survival Curve**

## Markers of Inflammation and Cardiovascular DiseaseApplication to Clinical and Public Health PracticeA 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**
** **

## 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

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

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

|  | CRP | WBC | Fibrinogen |
| --- | --- | --- | --- |
| BMI | 0.40‡  | 0.17‡  | 0.22‡  |
| Waist | 0.43‡  | 0.18‡  | 0.27‡  |
| Systolic BP | 0.20‡  | 0.08* | 0.11†  |
| Fasting Glucose | 0.18‡  | 0.13‡  | 0.07* |
| Fasting Insulin | 0.33‡  | 0.24‡  | 0.18‡  |
| SI | -0.37‡  | -0.24‡  | -0.18‡  |

## 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

**%**

**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

**Lifestyle**
**DPP – presented AHA, 2002**
**Pharmacological**
**Metformin – presented AHA, 2002**
**TZD-Rosiglitazone - Circulation 2002**

## The Effect of Rosiglitazone on CRP

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

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

- 	**Placebo**
**	****Rosiglitazone 4 mg/day**
**	****Rosiglitazone 8 mg/day**

- n=95

- n=124

- n=134

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

## 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.**

## 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)

## 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)

## 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

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

**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)**

## Framingham Study
Meigs, Diabetes 1997
IRAS
Hanley, Diabetes 2002

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

**Meigs, Diabetes 1997**
**IRAS**
**Hanley, Diabetes 2002**
**Conclusion:  Hypertension not associated (separate factor) with Insulin Resistance**

**Factor Analyses**

## 5-6 Traits May Represent 2-4 Physiologic PhenotypesInsulin Resistance Syndrome Factor Pattern Interpretation

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

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

| Variable | Factor |  |
| --- | --- | --- |
|  | Metabolic | Blood Pressure |
| BMI | 0.71 | 0.24 |
| Waist | 0.81 | 0.22 |
| Fasting Glucose | 0.44 | 0.24 |
| 2-Hour Glucose | 0.51 | 0.18 |
| Log (SI +1) | -0.67 | -0.19 |
| Log Triglyceride | 0.44 | -0.09 |
| HDL-C | -0.46 | 0.15 |
| Systolic BP | 0.12 | 0.71 |
| Diastolic BP | 0.09 | 0.61 |
| Log Albumin/Creatinine Ratio | 0.01 | 0.25 |
| % Total Variance | 28.1 | 8.8 |
| % Cumulative Variance | 28.1 | 36.9 |

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

## 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.**
**  **