1、 Willa Hsueh, M.D.Professor of MedicineChief, Division of Endocrinology, Diabetes, and Hypertension UCLA David Geffen School of Medicine Los Angeles, CaliforniaCardiovascular Risk Continuum: Implications of Insulin Resistance and DiabetesDiabetes is a vascular disease: Angiotensin II has been implic
2、ated in both the development of diabetes and its complicationsDiabetes Insulin-mediated glucose uptake Skeletal muscle Adipose FFA Inflammatory AdipokinesLiver Glucose productionPancreas Insulin production Atherosclerosis CAD, Stroke, Peripheral vascular diseaseDiabetic Nephropathy Albumin excretion
3、Diabetic Retinopathy VEGF neovascularizationDiastolic dysfunction, interstitial fibrosis heart failureCardiomyopathy IL6PAI-1TNF adiponectinleptinInsulin sensitivity insulin resistanceVascular inflammation endothelial dysfunctionangiotensinogenFFAAdipokines Mediate Insulin Resistance and Inflammatio
4、nProgression of Atherosclerosis in Insulin ResistanceEndothelial 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 I
5、mpaired Glucose Tolerane Type 2 Diabetes Hsueh WA, Law R. AJC, 2003 Insulin ResistanceFor individuals born in 2000: Males 32.8% Females 38.5% Estimated loss of life expectancy if diagnosed at age 40: Males 11.6 years Females 14.3 years Narayan JAMA 2003 Lifetime Risk for Diabetes in the US 13NH313NH
6、313NH3Dipyridamole (0.56 mg/kg)135RestQuinones et al Ann Intern Med., 2004; 140:700-8 Noninvasive Measurements of Myocardial Blood Flow: Positron Emission Tomography0 25 45 70 90 115CPT DIPApproaches that Improve Coronary Vasomotor Function in Insulin Resistance: Insulin sensitizers: TZDs, PPAR liga
7、nds AT1 receptor blockers: ARBs Glucose control in type 2 diabetes: Metformin 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 d
8、iabetes 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 hypertrophyCHARM (Candesartan in Heart
9、 Failure: Assessment of Reduction in Mortality and Morbidity): 40% less new onset diabetes with candesartan in patients with heart failureInhibition of the Renin-angiotensin System Prevents Diabetes:Mechanisms by Which ACEIs and ARBs Prevent Diabetes: Improve endothelial function: Up to 40% of insul
10、in-mediated glucose uptake may be endothelial dependent Allow fat cell differentiation Protect islet cells ?Alter adipokine production ?Alter liver glucose production Angiotensin IIinflammation oxidation thrombosis vascular growth and remodelinghypertensionPPAR Ligands AT1 Receptor Blockers reverse cholesterol transportAngiotensin II Activates Multiple Mechanisms Promoting Tissue Injury that are Antagonized by PPAR Ligands
