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Professor of Medicine Chief, Division of Endocrinology, Diabetes, and Hypertension
UCLA David Geffen School of Medicine
Los Angeles, California
Cardiovascular Risk Continuum: Implications of Insulin Resistance and Diabetes
Diabetes is a vascular disease: Angiotensin II has been implicated in both the development of diabetes and its complications
Diabetes
Insulin-mediated glucose uptake
Skeletal muscle
Adipose
FFA
Inflammatory Adipokines
Liver
Glucose production
Pancreas
Insulin production
Atherosclerosis
CAD, Stroke, Peripheral vascular disease
Diabetic Nephropathy
Albumin excretion
Diabetic Retinopathy
VEGF neovascularization
Diastolic dysfunction, interstitial fibrosis heart failure
Cardiomyopathy
IL6
PAI-1
TNF
adiponectin
leptin
Insulin sensitivity
insulin resistance
Vascular inflammation
endothelial dysfunction
angiotensinogen
FFA
Adipocyte
Adipokines Mediate Insulin Resistance and Inflammation
Progression of Atherosclerosis in Insulin Resistance
Endothelial
Dysfunction
TG, HDL-C
sd LDL-C
Hypertension
Uric Acid
PAI-1
Inflammation
Thrombosis
Oxidation
Atherosclerosis
Atherosclerosis
Unstable plaque
Inflammation, Fibrosis Cap
Thrombosis and Rupture
Event
Hyperinsulinemia
Metabolic Syndrome
Impaired Glucose Tolerane
Type 2 Diabetes
Hsueh
WA, Law R. AJC, 2003
Insulin Resistance
For individuals born in 2000:
Males – %
Females – %
Estimated loss of life expectancy if diagnosed at age 40:
Males – years
Females – years
Narayan JAMA 2003
Lifetime Risk for Diabetes in the US
13NH3
13NH3
13NH3
Dipyridamole
( mg/kg)
135’
Rest
Noninvasive Measurements of Myocardial Blood Flow: Positron Emission Tomography
0’
25’
45’
70’
90’
115’
CPT
DIP
Insulin sensitizers: TZDs, PPAR ligands
AT1 receptor blockers: ARBs
Glucose control in type 2 diabetes: Metformin
Approaches that Improve Coronary Vasomotor Function in Insulin Resistance:
VALUE (Valsartan Antihypertensive Long-Term Use Evaluation): 23% less new onset diabetes with valsartan compared to amlodipine in patients with hypertension
HOPE (Heart Outcomes Prevention Evaluation): 32% less new onset diabetes with ramipril compared to placebo in high cardiovascular risk patients
LIFE (Losartan Intervention for Endpoint Reduction in Hypertension): 25% less new onset diabetes with losartan compared to atenolol in patients with hypertension and left ventricular hypertrophy
CHARM (Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity): 40% less new onset diabetes with candesartan in patients with heart failure
Inhibition of the Renin-angiotensin System Prevents Diabetes:
Mechanisms by Which ACEIs and ARBs Prevent Diabetes:
Improve endothelial function: Up to 40% of insulin-mediated glucose uptake may be endothelial dependent
Allow fat cell differentiation
Protect islet cells
?Alter adipokine production
?Alter liver glucose production
Angiotensin II
inflammation
oxidation
thrombosis
vascular growth
and remodeling
hypertension
PPAR Ligands
AT1 Receptor Blockers
reverse cholesterol transport
Angiotensin II Activates Multiple Mechanisms Promoting Tissue Injury that are Antagonized by PPAR Ligands
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