4. TIEMPO ( MIN ) 40 20 10 5 0 INSULINA PLASMA FASES DE LIBERACION DE LA INSULINA
5. H King et al, Diab Care 1998 PROYECCIÓN GLOBAL DEL AUMENTO DE INDIVIDUOS CON DM TIPO 2 McCarthy and Zimmet. 1997 H King et al. 1998 250 200 150 100 50 0 1997 2000 2010 Número (millones) AÑO 300 2025 “ Asia, población latina en los EE.UU. y América del Sur tendrán los mayores aumentos .. .” 120 280
15. SINDROME METABOLICO Y ECV EN PACIENTES DIABETICOS TIPO 2 Hiperglicemia: La punta del iceberg del Sindrome Metabolico Obesidad Abdominal Dislipidemia Aterogenesis Hipertension Resistencia a la Insulina Hiperinsulinemia fibrinolisis Inflamacion Hiperglicemia
16. Resistencia a la Insulina: Condiciones Asociadas Aterotrombosis Inflamación Vascular Disfunción Endotelial Hipertensión Síndrome de Ovario Poliquístico Obesidad Central Dislipidemia Intolerancia a la Glucosa Diabetes Tipo 2 Hiperinsulinismo Hiperuricemia Actividad Fibrinolítica Disminuida Pai-1 Aumento De Fibrinógeno Factor De Von Willebrand Adaptado de Consensus Development Conference of the American Diabetes Association, Diabetes Care , 1997 Microalbuminuria Esteatosis Hepática No Alcohólica Hiperferritininemia Sobrecarga de Hierro(*1) Mendler MH. Gastroenterology 117:1155, 1999 Resistencia a la Insulina
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23. OBESIDAD RESISTENCIA A LA INSULINA + HIPERINSULINEMIA HIPER/ ANDROGENISMO INSUFICIENCIA CEL BETA VLDL ATERO/ TROMBOSIS Higado Graso SÍNDROME METABÓLICO O SÍNDROME DE RESISTENCIA A LA INSULINA PCOS Diabetes Dislipidemia NASH IMA ACV Shulman GI. J Clin Invest. 2000;106:171-176
24. Insulino Resistencia y Marcadores de Daño Hiperinsulinemia Insulina Plasmática (pre –Diabetes y Diabetes temprana) Hiperglicemia AGEs, AGE derivados Coagulación Fibrinógeno, PAI-1, tPA Disfunción Endotelial PAI-1, celular adhesion moleculas, ej. e-selectina Stress oxidativo LDL oxidado y F2-isoprostanos Inflamación Proteína C reactiva (PCR), CD40L Matriz metaloproteinasa-9 (MMP-9) Dislipidemia FFA, TG, LDL pequeña-densa HDL, LDL grande-boyante Obesidad abdominal C/C , FFA, TNF , r esistina adiponectina, II- -hydroxi esteroide Ross R. N Engl J Med 1999; 340:115–126; Festa A, et al . Circulation 2000; 102:42–47; Leinonen E, et al . Atherosclerosis 2003; 166:387–394.
38. Factores de Riesgo para Aterotrombosis Aterosclerosis Manifestaciones Aterotrombóticas (IAM, ACV, Muerte Vascular) Homocisteinemia Estilo de vida (ej, fumar, dieta, falta de ejercicio) Sexo American Heart Association. Heart and Stroke Facts: 1997 Statistical Supplement; Wolf. Stroke 1990;21(suppl 2):II-4–II-6; Laurila et al. Arterioscler Thromb Vasc Biol 1997;17:2910-2913; Grau et al. Stroke 1997;28:1724-1729; Graham et al. JAMA 1997;277:1775-1781; Brigden. Postgrad Med 1997;101(5):249-262. Edad Obesidad Diabetes Hiperlipidemia Estados hipercoagulables Hipertensión Genética Infección?
39.
40. Trombo Injuria de la Pared Vascular Adhesión de Plaquetas Activación Plaquetaria Reclutamiento Plaquetario Formación del Trombo
41. Adhesión y Activación Plaquetaria Agregación de plaquetas en un trombo Plaquetas Células endoteliales Espacio subendotelial Adhesión de plaquetas al espacio subendotelial Trombo plaquetario Plaquetas Normales en sangre circulante Plaquetas adhiriendo al endotelio dañado y activándose
42. Aterogénesis y Aterotrombosis: Un Proceso Progresivo Normal Estría Lipídica Placa Fibrosa Placa Ateros- clerótica Ruptura de Placa/ Fisura & Trombosis Infarto de Miocardio ACV Isquemia Crítica de Miembro inferior Clínicamente silencioso Muerte Cardiovascular Aumento de edad Angina Isquemia cerebral transitoria Claudicación/AP
45. Incidencia de Primer Infarto de Miocardio y ACV Isquémico 170 130 120 180 350 150 150 250 0 100 200 300 400 USA 1 Francia 2,3 Italia 2 Gran Bretaña 4 Tasa Anual por 100000 hab. 1 American Heart Association. Heart and Stroke Facts, 1995 Statistical Supplement. 2 WHO MONICA Project. Circulation 1994;90:583-612. 3 Giroud et al. Int J Epidemiol 1991;20:892-899; Giroud. Ann Cardiol Angeiol 1994;43:214-218. 4 Stevens and Raftery. Heath Care Needs Assessment, National Health Service, 1994. Infarto de Miocardio ACV Isquémico
46. M ortalidad a 5 años en pacientes diabéticos y no diabéticos durante el seguimiento posterior a un infarto de miocardio
47. P REVALENCIA DEL ICTUS PREVIO AJUSTADA POR EDADES EN PAC. CON DIABETES TIPO 2 Y EN SUJETOS CONTROL (grupo de edades de 45 a 64 años)
48. P REVALENCIA DE LA CLAUDICACION INTERMITENTE AJUSTADA POR EDADES EN PAC. CON DIABETES TIPO 2 Y EN SUJETOS CONTROL (grupo de edades de 45 a 64 años).
But we cannot be naive; it’s an ‘uphill’ battle! It’s important to note, it’s not just job-related physical activity that’s declined. The reductions in physical activity associated with everyday living may be even more substantial. We have remote controls for the TV, automatic garage door openers… Talking Points … and look, people standing in line to get on the escalator!
Además de la diabetes tipo 2, la resistencia a la insulina es un factor patogénico en el desarrollo de un amplio espectro de condiciones clínicas. Estas incluyen hipertensión, aterosclerosis, dislipidemia, actividad fibrinolítica disminuida, intolerancia a la glucosa, acantosis nigricans, hiperuricemia, enfermedad de ovario poliquístico y obesidad.
Interrelationship Between Insulin Resistance and Atherosclerosis Insulin resistance is associated with a cluster of metabolic and biochemical abnormalities, including hypertension, endothelial dysfunction, hyperinsulinemia, hyperglycemia, inflammation, dyslipidemia (elevated triglycerides, low HDL-C, and increased small, dense LDL particles), impaired fibrinolysis, and hypercoagulability (increased prothrombotic and antifibrinolytic factors). Each of these abnormalities favors atherosclerosis, thus predisposing the individual with insulin resistance to atherosclerosis.
Originalmente descrito por GM Reaven en 1988 como Síndrome X, este síndrome ha recibido diversas denominaciones. Actualmente se le conoce más comunmente como Síndrome Metabólico por las diferentes alteraciones metabólicas que lo constituyen.
The World Health Organisation (WHO) 1 recognises that insulin resistance may be the common factor for the individual components of the Metabolic Syndrome (also known as the Insulin Resistance Syndrome). WHO recommends that the management of patients with hyperglycaemia and other features of the Metabolic Syndrome should include not only blood-glucose control but also strategies for the management of other cardiovascular risk factors. There is currently no internationally agreed definition for the Metabolic Syndrome. The definition provided by WHO, which does not imply causal relationships, is therefore suggested as a working definition to be improved upon in due course. Several other components of the Metabolic Syndrome have been described (eg hyperuricaemia, coagulation disorders, raised PAI-1 etc) but they are not necessary for the recognition of the condition. Reference 1. Definition, Diagnosis, and Classification of Diabetes Mellitus and its Complications. World Health Organization, 1999.
Una de las definiciones de síndrome metabólico más recientes es la del NCEP III. En ésta se requiere que al menos existan 3 de los componentes que se describen. Todos estos elementos tienen en comun la presencia de resistencia a la insulina y representan factores de riesgo de enfermedad arterial ateroesclerosa.
Components of the Metabolic Syndrome and Incidence of CHD Events In a study of baseline characteristics of 6,447 men, risk factors of the metabolic syndrome (MS) predicted coronary heart disease (CHD) events, with the risk of CHD events increasing with the number of MS components. Sattar and colleagues examined baseline characteristics of men in the West of Scotland Coronary Prevention Study for components of the metabolic syndrome, as defined by the National Cholesterol Education Program (NCEP) Adult Treatment Panel III. The hazard ratio (HR) rose from 1 for 0 MS components, to 1.79 for 1 component (95% CI, 1.11-2.89, P <0.05), 2.25 for 2 (95% CI, 1.40-3.60, P <0.001), 3.19 for 3 (95% CI, 1.98-5.12, P <0.001), and 3.65 for 4 or more (95% CI, 2.11-6.33, P <0.001). NCEP MS criteria includes triglyceride levels 150 mg/dL, HDL-C <40 mg/dL, fasting glucose 100 mg/dL, and systolic blood pressure (BP) 130 mm Hg or diastolic BP 85 mm Hg. For the purposes of the study, the authors changed the fifth component, waist circumference, to body mass index (BMI) >28.8 kg/m 2 . The study also examined MS components as predictors of newly diagnosed diabetes (not shown on slide) and concluded that MS strongly predicts type 2 diabetes, with a 24.4 HR for individuals with 4 or more MS components. Sattar N et al. Circulation . 2003;108:414-419.
Relationship Between Type 2 Diabetes and the Metabolic Syndrome The metabolic syndrome is very common in the US population over age 50: ~43.5% meet the criteria established by ATP III. However, type 2 diabetes without the metabolic syndrome is uncommon in the over-50 population. As illustrated here, only an estimated 13% of patients with diabetes do not meet the criteria for the metabolic syndrome. Alexander CM et al. Diabetes . 2003;52:1210-1214.
Not only is insulin resistance associated with type 2 diabetes, it is also linked to a cluster of metabolic abnormalities collectively known as the Insulin Resistance Syndrome that are associated with an increased risk of cardiovascular disease (CVD) . This cluster can be further sub-divided into “traditional” and “non-traditional” or “emerging” risk factors: traditional: hyperglycemia, hyperinsulinemia, hypertriglyceridemia, hypertension and dyslipidemia. Also microalbuminuria which is a marker for the presence of atherosclerosis is associated non-traditional/emerging: plasminogen activator inhibitor-1 (PAI-1), matrix metalloprotease-9 (MMP-9) and markers of inflammation such as C-reactive protein (CRP). WHR: waist:hip ratio FFA: free fatty acids TNF tumor necrosis factor TG: triglycerides LDL: low density lipoprotein HDL: high density lipoprotein PAI-1: plasminogen activator inhibitor-1 tPA: t issue plasminogen activator AGEs: advanced glycation endproducts Ross R. N Engl J Med 1999; 340 :115–126. Festa A, et al . Circulation 2000; 102 :42–47.
Slide 3 The formation of a thrombotic plug at a site of vascular injury serves an important hemostatic function. This response is controlled via several receptor-mediated interactions that result in platelet adhesion, activation, and aggregation. Platelets bear specific receptors that can bind with constituents of plaque or the vascular subendothelium, promoting adhesion. Receptors such as those for ADP and thrombin mediate platelet activation, while others, such as the glycoprotein (Gp) IIb/IIIa fibrinogen receptor, mediate platelet aggregation. Pseudopods develop in contact with subendothelial constituents, causing platelet adherence and activation. Activated platelets flatten and degranulate, releasing preformed mediators that recruit and activate additional platelets.
Slide 6 Under normal conditions, platelets neither adhere to, nor are activated by the vascular endothelium. However, damage to the endothelium or disruption of plaque exposes the flowing blood to a variety of thrombogenic elements. Circulating platelets bear receptors that bind to components of the subendothelial matrix and plaque, including collagen, fibronectin, and von Willebrand factor, on contact. During platelet activation, cell surface receptors for fibrinogen are activated. Fibrinogen may form multiple bonds with these receptors, causing platelets to aggregate into a thrombus via fibrinogen bridges.
Slide 2 The early stages of atherogenesis—fatty streaks and small fibrous plaques—are usually clinically silent, and even plaques of moderate size may not cause significant stenosis of the vessel. With time, however, the cellular and lipid constituents of plaque accumulate, producing stenosis severe enough to cause stable/unstable angina, transient ischemic attack, or intermittent claudication. Some enlarging plaques may become increasingly vulnerable to disruption, in which the fibrous cap is ruptured or fissured. Plaque rupture exposes the thrombogenic constituents of the plaque and subendothelial tissues to the flowing blood. Resultant thrombotic subocclusion may cause unstable angina, transient ischemic attack, or intermittent claudication. Complete occlusion may cause myocardial infarction, ischemic stroke, blockage of the peripheral arteries, or even death. Thrombosis superimposed on atherosclerotic plaque is known as atherothrombosis . Some of the processes underlying atherosclerosis and thrombosis are closely allied; thus, the development of thrombi is often enhanced by the presence of plaque, while the development of plaque may in turn be enhanced by thrombosis.