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Targeting Cardiovascular and Metabolic Risk in Patients with Intra-abdominal Adiposity and Related Comorbidities

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Targeting Cardiovascular and Metabolic Risk in Patients with Intra-abdominal Adiposity and Related Comorbidities Powered By Docstoc
					Targeting Cardiovascular and Metabolic Risk in Patients with Intra-abdominal Adiposity and Related Comorbidities

Obesity at the Core of Metabolic Risk
Obesity (esp. Abdominal Obesity)

Other Factors

Insulin Resistance

Metabolic Risk Factor Clustering

ASCVD

T2DM

Metabolic Risk Factors
 Dyslipidemia
— — — — Elevated TG Elevated apo B Small LDL Low HDL

 Elevated BP  Elevated Glucose  Prothrombotic state  Proinflammatory state

Abdominal Obesity

Metabolic Risk: Residual Risk Beyond Classical Risk Factors
Classical Risk Factors Metabolic Risk Factors
Abdominal Obesity

HDL-C

Smoking

BP
LDL-C

Thrombosis IR / T2DM

TG

Inflammation

CARDIOVASCULAR DISEASE

Clustering of the Metabolic Risk Factors: Nomenclature
 Metabolic syndrome  Syndrome X  Insulin resistance syndrome
 Dysmetabolic syndrome

 Deadly quartet  Cardiometabolic syndrome  Prediabetes and type 2 diabetes  CHAOS (Australia)

Identifying At-Risk Patients with 3+ Metabolic Risk Factors
Simple Clinical Measures

 

Increased waist circumference — > 102 cm in men or > 88 cm in women
Elevated serum triglycerides (> 150 mg/dL) Reduced HDL cholesterol — < 40 mg/dL in men and < 50 mg/dL in women




Elevated blood pressure — > 130 mmHg SBP or 85 mmHg DBP
Elevated plasma glucose (> 100 mg/dL)

NCEP ATPIII. JAMA. 2001;285:2486-2497. International Diabetes Federation. 2005. Grundy SM et al. Circulation. 2005;112:2735-2752.

Clustering of Metabolic Risk Factors: Clinical Associations
 Cardiovascular disease  Type 2 diabetes 


Fatty Liver
Cholesterol gallstones

 

Polycystic ovarian disease Sleep apnea

Grundy SM et al. Circulation. 2005;112:2735-2752. Hanley AJ et al. Diabetes. 2004; 53: 1773–1781. Browning JD et al. Hepatology. 2004; 40: 1387–1395. Tsai CJ et al. Am J Clin Nutr. 2004;80:38–44. Apridonidze T et al. J Clin Endocrinol Metab. 2004; 90: 1929–1935. Coughlin SR et al. Eur Heart J. 2004; 25: 735–741.

Relative Risk for CVD and T2DM Associated with Metabolic Risk Factor Clustering  Cardiovascular disease
— 2-fold increase in relative risk

 Type 2 diabetes
— 5-fold increase in relative risk

Alexander CM et al. Diabetes. 2003;52:1210-1214. Hunt KJ et al. Circulation. 2004; 110: 1251–1257.

Obesity

Connection Between Obesity and Metabolic Risk Factors

Adipose Tissue Products

Metabolic-Risk-Factor Clustering

The Evolving View of Adipose Tissue: an Endocrine Organ
Old View: inert storage depot
Fatty acids Glucose

Current View: secretory/endocrine organ

Fed
Tg
Multiple secretory products Muscle

Tg
Tg
Fasted

Fatty acids

Glycerol
Liver Pancreas

Vasculature

Lyon CJ et al. Endocrinology 2003;144:2195-200.

Adipokines: Adverse Cardiometabolic Effects
Hypertension

 Lipoprotein lipase ↑ IL-6

↑ Angiotensinogen
↑ Insulin ↑ FFA

Inflammation
↑ TNFα ↑ Adipsin (Complement D) ↓ Adiponectin

Atherogenic dyslipidemia

Adipose

tissue

↑ Resistin ↑ Leptin
↑ Lactate

Insulin Resistance Type 2 diabetes

Atherosclerosis

↑ Plasminogen activator inhibitor-1 (PAI-1)

Thrombosis
Lyon CJ et al. Endocrinology 2003;144:2195-200. Trayhurn P et al. Br J Nutr. 2004;92:347-55. Eckel RH et al. Lancet. 2005;365:1415-28.

Properties of Key Adipokines
Adiponectin
 in IAA

Anti-atherogenic/antidiabetic:
 foam cells  vascular remodelling  insulin sensitivity  hepatic glucose output

IL-6
 in IAA

Pro-atherogenic/pro-diabetic:
 vascular inflammation  insulin signalling

TNFa
 in IAA

Pro-atherogenic/pro-diabetic:
 insulin sensitivity in adipocytes (paracrine)

PAI-1
 in IAA

Pro-atherogenic:
 atherothrombotic risk

IAA: intra-abdominal adiposity Marette A. Curr Opin Clin Nutr Metab Care 2002;5:377-83.

Obesity, Insulin Resistance, and Metabolic Risk Factors
Obesity
NEFA & Adipokines

Insulin Resistance

Multiple Metabolic Risk Factors

Insulin Resistance: Inherited and Acquired Influences
Inherited Acquired
 Inactivity
 Overeating  Aging  Medications  Hyperglycemia  Elevated FFAS

Rare Mutations:
 Insulin Receptor  Glucose Transporter  Signaling Proteins

Common Forms:
 Largely unidentified

Insulin Resistance

Family History of Diabetes and Risk for Insulin Resistance in Mexican Americans
P<0.0001

HOMA-IR

9 8 7 6 5 4 3 2 1 0 Lean

P<0.001

Overweight

Obese

No family history

Family history

HOMA-IR = Homeostasis Model Assessment of Insulin Resistance = Fasting Plasma Insulin (μU/mL) X Fasting Plasma Glucose (mM)/22.5 Guerrero-Romero F et al. J Endocrinol Invest. 2001;24:580-586.

Association Between Insulin Sensitivity and Physical Exercise: The IRAS Study
Insulin Sensitivity
2

Fasting Insulin
20

min-1• μU-1• mL-1• 10-4

1

μU/mL
Rare or never 1-3 per month 1 per week 2-4 per week ≥ 5 per week

10

0

0
Rare or never 1-3 per month 1 per week 2-4 per week ≥ 5 per week

Exercise Frequency
Mayer-Davis EJ et al. JAMA. 1998;279:669-674.

Exercise Frequency

IRAS=Insulin Resistance Atherosclerosis Study


				
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