ENDOCRINOLOGÍA Y NUTRICIÓN

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1 ENDOCRINOLOGÍA Y NUTRICIÓN Noviembre 2009, Volumen 56, Monográfico 4, Páginas 1-72 ENDOCRINOLOGÍA Y NUTRICIÓN Órgano de la Sociedad Española de Endocrinología y Nutrición Volumen 56, Monográfico 4, Noviembre º SIMPOSIO CIENTÍFICO DIABETES MELLITUS HOY Directores invitados: Manuel Serrano Ríos, Carlos Payá y José A. Gutiérrez-Fuentes Incluida en: EMBASE/Excerpta Medica y SCOPUS ISSN:

2 ENDOCRINOLOGÍA Y NUTRICIÓN Sumario 14. o SIMPOSIO CIENTÍFICO DIABETES MELLITUS HOY Directores invitados: Manuel Serrano Ríos, Carlos Payá y José A. Gutiérrez-Fuentes Introducción 3 J.A. Gutiérrez-Fuentes El arma de doble filo 5 R.N. Bergman Es importante la glucosa posprandial y por qué? 8 A. Ceriello Reactividad vascular en la diabetes mellitus 12 P. Dandona Guías clínicas en diabetes mellitus tipo 1 15 F. Escobar-Jiménez El riñón en la diabetes tipo 2: la estructura renal 18 M. Dalla Vestra, M. Arboit, como foco de atención M. Bruseghin y P. Fioretto Nuevos hallazgos genéticos aplicados a la clínica 21 J.C. Florez en la diabetes tipo 2 Formas monogénicas de la diabetes mellitus: 26 M. Vaxillaire y P. Froguel una actualización Causas principales de mortalidad precoz y exceso 30 A. Gómez de la Cámara, M.A. Rubio de mortalidad en la población diabética española. Herrera, J.A. Gutiérrez Fuentes, Estudio DRECE III J.A. Gómez Gerique, C. Jurado Valenzuela y P. Cancelas Navia, en representación del Grupo DRECE Una visión global de la genética en la diabetes tipo 2 34 L. Groop y V. Lyssenko Obesidad y diabetes 38 K. Lois y S. Kumar Trastornos lipídicos en la diabetes tipo 2 43 M. Laakso Recomendaciones actuales en el tratamiento 46 H.E. Lebovitz de la diabetes tipo 2 Historia natural e inmunopatogénesis de la diabetes 50 P. Pozzilli, R. Strollo e I. Barchetta tipo 1 Epidemiología de la diabetes tipo 1 infantil 53 G. Soltész en el ámbito mundial Interacción entre el gen y el entorno en la diabetes 56 M. Trucco mellitus tipo 1 Epidemiología de la diabetes tipo 2 60 N.J. Wareham Hipertensión en la diabetes mellitus 63 P.K. Whelton Síndrome metabólico. Declaración conjunta, 67 J.A. Gutiérrez Fuentes octubre 2009 Premio a una Carrera Distinguida en Endocrinología 70 y Nutrición 2008 Este suplemento ha sido patrocinado por la Fundación Lilly. Esta publicación refleja conclusiones, hallazgos y comentarios propios de los autores y se mencionan estudios clínicos que podrían contener indicaciones/posologías/formas de administración de productos no autorizadas actualmente en España. Se recuerda que cualquier fármaco mencionado deberá ser utilizado de acuerdo con la Ficha Técnica vigente en España.

3 ENDOCRINOLOGÍA Y NUTRICIÓN Contents 14th SCIENTIFIC SYMPOSIUM DIABETES MELLITUS TODAY Invited directors: Manuel Serrano Ríos, Carlos Payá and José A. Gutiérrez-Fuentes Introduction 1 J.A. Gutiérrez-Fuentes The two-edged sword 5 R.N. Bergman Does postprandial blood glucose matter and why? 8 A. Ceriello Vascular reactivity in diabetes mellitus 12 P. Dandona Clinical guidelines in type 1 diabetes mellitus 15 F. Escobar-Jiménez The kidney in type 2 diabetes: focus 18 M. Dalla Vestra, M. Arboit, on renal structure M. Bruseghin and P. Fioretto Novel genetic findings applied to the clinic 21 J.C. Florez in type 2 diabetes Monogenic forms of diabetes mellitus: 26 M. Vaxillaire and P. Froguel an update Main cuases of early mortality and excess 30 A. Gómez de la Cámara, M.A. Rubio mortality in the Spanish diabetic population. Herrera, J.A. Gutiérrez Fuentes, The DRECE III study J.A. Gómez Gerique, C. Jurado Valenzuela and P. Cancelas Navia, on behalf of DRECE Group Genetics of type 2 diabetes. On overview 34 L. Groop and V. Lyssenko Obesity and diabetes 38 K. Lois and S. Kumar Lipid disorders in type 2 diabetes 43 M. Laakso Present recommendations in type 2 46 H.E. Lebovitz diabetes treatment Natural history and immunopathogenesis 50 P. Pozzilli, R. Strollo and I. Barchetta of type 1 diabetes Worldwide childhood type 1 diabetes 53 G. Soltész epidemiology Gene-environment interaction in type 1 56 M. Trucco diabetes mellitus Epidemiology of type 2 diabetes 60 N.J. Wareham Hypertension in diabetes mellitus 63 P.K. Whelton Metabolic syndrome. Joint Declaration, October J.A. Gutiérrez Fuentes Distinguished Career Award Endocrinology 70 & Nutrition 2008 This supplement has been sponsored by Fundación Lilly. This publication shows the conclusions, findings and comments of the authors and mentions clinical studies that could have indications/dosages/administration forms of currently unauthorized medicinal products in Spain. It is stressed that any drug mentioned should be used in accordance with the Data Sheet in force in Spain.

4 Introduction JOSÉ A. GUTIÉRREZ-FUENTES TYPE 1 DIABETES MELLITUS Type 1 diabetes results from cellular-mediated autoimmune destruction of pancreatic islet beta-cells causing the loss of insulin production. It ranks as the most common chronic childhood disease in developed nations, but occurs at all ages and the clinical presentation can vary with age. The predominant cause of hyperglycaemia in type 1 diabetes is the destruction of the beta cells, which leads to absolute dependence on insulin treatment and a high rate of complications typically occurring at relatively young ages. Type 1 diabetes, therefore, places a particularly heavy burden on the individual, the family and the health services. TYPE 2 DIABETES MELLITUS Type 2 diabetes is characterized by insulin resistance and relative insulin deficiency, either of which may be present at the time that diabetes becomes clinically manifest. The specific reasons for the development of these abnormalities are not yet known. The diagnosis of type 2 diabetes usually occurs after the age of 40 years although the age of onset is often a decade earlier in populations with high diabetes prevalence. People with type 2 diabetes may not show any symptoms for many years and the diagnosis is often made from associated complications or incidentally through an abnormal blood or urine glucose test. Type 2 diabetes is often, but not always, associated with obesity, which itself can cause insulin resistance and lead to elevated blood sugar levels. It is strongly familial, but major susceptibility genes have not yet been identified. In contrast to type 1 diabetes, patients with type 2 diabetes are not dependent on exogenous insulin and are not ketosis-prone, but may require insulin for control of hyperglycaemia if this is not achieved with diet alone or with oral hypoglycaemic agents. Type 2 diabetes constitutes about 85% to 95% of all diabetes in developed countries, and accounts for an even higher percentage in developing countries. It is now a common and serious global health problem, which, for most countries, has evolved in association with rapid cultural and social changes, ageing populations, increasing urbanization, dietary changes, reduced physical activity and other unhealthy lifestyle and behavioural patterns. RELATED DISORDERS AND COMPLICATIONS In virtually every developed society, diabetes is ranked among the leading causes of blindness, renal failure and lower limb amputation. It is also now one of the leading causes of death through its effects on cardiovascular disease (70%-80% of people with diabetes die of cardiovascular disease). The main relevance of diabetes complications in a public health perspective is the relationship to human suffering and disability, and the huge socio-economic costs through premature morbidity and mortality. Chronic elevation of blood glucose, even when no symptoms are present to alert the individual to the presence of diabetes, will eventually lead to tissue damage, with consequent, and often serious, disease. Whilst evidence of tissue damage can be found in many organ systems, it is the kidneys, eyes, peripheral nerves and vascular tree, which manifest the most significant, and sometimes fatal, diabetic complications. The mechanism by which diabetes leads to these complications is complex, and not yet fully understood, but involves the direct toxic effects of high glucose levels, along with the impact of elevated blood pressure, abnormal lipid levels and both functional and structural abnormalities of small blood vessels. About half of all the money spent on diabetes care goes towards the costs of managing diabetic complications. Cardiovascular complications frequently account for the bulk of the costs. The trend of escalating diabetes prevalence will no doubt lead to an immense financial burden in many countries unless action is taken to prevent both diabetes and its complications. DIABETES TREATMENT The major goal in treating diabetes is controlling elevated blood sugar without causing abnormally low levels of blood sugar. Treatment for type 1 diabetes is Endocrinol Nutr. 2009;56(Supl 4):1-2 1

5 Gutiérrez-Fuentes JA. Introduction with insulin, exercise, and a diabetic diet. Treatment for type 2 diabetes is first treated with weight reduction, a diabetic diet, and exercise. When these measures fail to control the elevated blood sugar, oral medications are used. If oral medications are still insufficient, insulin medications are considered. The 14th Lilly Foundation Scientific Symposium Diabetes mellitus today mixes scientists with different views and cultures in their approach to diabetes mellitus research and clinical practice. Aim of this symposium is to provide the participants with first-hand cutting-edge information on a crucial morbidity as diabetes, from molecular to genetic epidemiology, its pathophisiology, and the newer components such as nitric oxide, inflammation molecules, prothrombotic state, endothelial dysfunction, or related disorders and complications such as dyslipidemias, obesity or arterial hypertension. It is the purpose of Fundación Lilly ( in accordance to its statutory objectives, to help spread these concepts, and we are quite confident we have accomplished our aims thanks to the highly qualified personalities who accepted our invitation to contribute their knowledge and ideas in each of the programmed interventions. Conflic of interest The author declares he has no conflict of interest. 2 Endocrinol Nutr. 2009;56(Supl 4):1-2

6 Introducción JOSÉ A. GUTIÉRREZ-FUENTES DIABETES MELLITUS TIPO 1 La diabetes mellitus tipo 1 es el resultado del déficit de insulina originado por la destrucción autoinmunitaria de los islotes pancreáticos de células beta. Se trata de la enfermedad crónica más frecuente en la infancia en los países desarrollados, aunque puede iniciarse a cualquier edad y su presentación clínica ser variable. La causa predominante de hiperglucemia en la diabetes tipo 1 es la destrucción de las células beta que conduce a una dependencia absoluta del tratamiento con insulina y a una alta tasa de complicaciones en edades tempranas. Es por ello, que la diabetes tipo 1 supone una pesada carga para el paciente, su familia y los servicios de salud. DIABETES MELLITUS TIPO 2 La diabetes tipo 2 se caracteriza por la resistencia a la insulina y un déficit relativo de la hormona. Cualquiera de estas circunstancias puede estar presente en el momento que la enfermedad se inicia en la clínica. Sus causas aún no se conocen. Se suele diagnosticar pasados los 40 años, aunque suele ser más precoz en las poblaciones con mayor prevalencia de la enfermedad. Puede cursar asintomáticamente durante años, y con frecuencia el diagnóstico se hace a través de la aparición de sus complicaciones, o incidentalmente al practicar un análisis rutinario de sangre u orina. Con frecuencia, aunque no siempre, se asocia a obesidad, que a su vez puede ser causa de resistencia insulínica y motivar valores elevados de glucosa en sangre. Aunque se observa asociación familiar, no se han podido identificar los genes de susceptibilidad. En contraste con la diabetes tipo 1, estos pacientes no son dependientes de la insulina ni propensos a la cetosis, pero pueden llegar a precisar insulina para el control de la hiperglucemia cuando éste no se logra con dieta y antidiabéticos orales. La diabetes tipo 2 supone entre el 85 y el 95% de los diabéticos en los países desarrollados, y un porcentaje aún mayor en las regiones en desarrollo. Se trata de un serio problema global de salud que en la mayoría de los países se ha puesto de manifiesto asociado a los cambios culturales y sociales, el aumento de la expectativa de vida, la urbanización, los cambios dietéticos, la reducción de la actividad física y otros patrones y estilos de vida no saludables. ENFERMEDADES RELACIONADAS Y COMPLICACIONES En la mayoría de las sociedades desarrolladas, la diabetes se encuentra entre las principales causas de ceguera, fracaso renal y amputación de extremidades inferiores. Además, es una de las primeras causas de muerte a través de su efecto predisponente a las enfermedades cardiovasculares (del 70 al 80% de los diabéticos fallece de enfermedades cardiovasculares). Sin embargo, desde una perspectiva de salud pública, alcanzan especial relevancia el sufrimiento y las discapacidades en los pacientes y los grandes costes socioeconómicos, así como la morbimortalidad prematura ocasionada por las complicaciones de la diabetes. La elevación crónica de la glucemia, aun en ausencia de síntomas, puede conducir a la aparición de daño tisular y originar complicaciones importantes. Aunque los daños causados pueden afectar a diferentes tejidos, las complicaciones diabéticas más notables afectan a riñones, ojos, nervios periféricos y árbol vascular. El mecanismo por el que estas complicaciones se originan es complejo e insuficientemente entendido aún, pero incluye los efectos tóxicos directos de la glucosa elevada, junto a la elevación de la presión arterial, el aumento de los lípidos en sangre, y alteraciones funcionales y estructurales de los vasos sanguíneos menores. Alrededor de la mitad del gasto empleado en el tratamiento de la diabetes lo absorbe el de sus complicaciones, siendo las cardiovasculares responsables de la mayor parte. El crecimiento de la prevalencia de la diabetes supondrá en muchos países una muy elevada carga financiera a menos que se pongan en marcha acciones tendentes a prevenir la enfermedad y sus complicaciones. TRATAMIENTO DE LA DIABETES MELLITUS El objetivo principal del tratamiento de la diabetes es el control de las concentraciones de glucosa en sangre sin Endocrinol Nutr. 2009;56(Supl 4):3-4 3

7 Gutiérrez-Fuentes JA. Introducción caer en situaciones de hipoglucemia. El tratamiento de la diabetes tipo 1 es con insulina, ejercicio y dieta. En la diabetes tipo 2, el tratamiento procurará, en primer lugar, controlar el peso corporal, una dieta diabética adecuada y el ejercicio físico. Cuando con estas recomendaciones no se consigan los objetivos terapéuticos se utilizarán antidiabéticos orales, y sólo cuando éstos resulten insuficientes se considerará administrar insulina. El 14.º Simposio Científico de la Fundación Lilly Diabetes mellitus hoy incluye una mezcla de científicos con diferentes culturas y puntos de vista en su aproximación a la investigación y la práctica clínica de la diabetes. Es objetivo del simposio acercar a los participantes una información novedosa y de primera mano acerca de una enfermedad prevalente, como es la diabetes, referida a su epidemiología genética y molecular, su fisiopatología, los nuevos componentes como el óxido nítrico, las moléculas inflamatorias, el estado protrombótico, la disfunción endotelial, o alteraciones relacionadas como las dislipemias, la obesidad o la hipertensión arterial. Es propósito de la Fundación Lilly ( en consonancia con sus objetivos estatutarios, colaborar al mejor conocimiento de estos conceptos, y confiamos en lograrlo gracias al notable plantel de personalidades que han aceptado nuestra invitación para compartir sus conocimientos e ideas en cada una de las intervenciones programadas. Conflicto de intereses El autor declara no tener ningún conflicto de intereses. 4 Endocrinol Nutr. 2009;56(Supl 4):3-4

8 Diabetes mellitus hoy The two-edged sword RICHARD N. BERGMAN Keck Professor of Medicine. University of Southern California. Los Angeles CA. USA. Unlike most chronic illnesses which have been declining or stabilizing in prevalence, incidence of type 2 diabetes has been increasing in the Western Hemisphere, and is now increasing at alarming rates in Asia 1. While all causes of these increases cannot be identified, without question the increase in adiposity is an important contributor. The latter is due to increased caloric intake and reduced energy expenditure, although other factors may contribute 2. Adiposity leads to insulin resistance, which in normal individuals elicits an hyperinsulinemic response, which compensates for the insulin resistance. Unresolved questions relate to whether fat storage in specific depots is particularly egregious, what mechanisms are responsible for the pancreatic islet-cell compensation, and why said compensation can fail, leading to diabetes in some, but not all individuals. Epidemiological studies suggest that visceral fat is particularly detrimental to metabolic health. Direct evidence favoring the importance of visceral fat is the result of surgical extirpation of the superior omentum in the canine model. While eliminating only 7% of total visceral fat in the dog, insulin sensitivity increased over 50%. This study compliments human data from Klein et al that evisceration of subcutaneous fat did not alter insulin resistance 3. Why is visceral fat detrimental? Induction of visceral adiposity by feeding of an hypercaloric high fat diet leads to insulin resistance for several reasons: a) increase of stored visceral fat in adipocytes which are themselves insulin resistant resulting in flux of free fatty acids (FFA) from viscera to liver and extrasplanchnic tissues; b) action of the sympathetic nervous system (SNS) which favors lipolysis and causes pulsatile release of FFA from visceral fat into the portal circulation; c) effects of pulsatile release of FFA which results in hepatic insulin resistance, associated with upregulation of liver gluconeogenic enzymes (fig. 1). Interestingly, the resultant insulin resistance of liver can be successfully reversed by antagonism of the cannabanoid system with rimonabant. The role of FFA in pathogenesis of insulin resistance has been questioned, as evidence was lacking for increased fasting FFA in obese individuals. Recently we reported a powerful circadian rhythm in FFA levels, with a peak in levels between 2 and 4 AM 4. We propose that it is the nocturnal surge in plasma FFA which is responsible for onset of insulin resistance in the overweight subject (fig. 2). This surge is due at least in part to a night-time outpouring of FFA from the visceral fat depot. We propose that omentectomy reduces this outpouring and increases insulin sensitivity. Not all insulin obese, insulin resistant individuals develop Type 2 diabetes, and induction of insulin resistance per se does not cause Correspondence: Dr. R.N. Bergman. Keck Professor of Medicine. University of Southern California Los Angeles CA. USA. hfreed@usc.edu Endocrinol Nutr. 2009;56(Supl 4):5-7 5

9 Bergman RN. The two-edged sword Night-time pathogenesis of the metabolic syndrome Mesenteric fat depot Hyperinsulinemia CNS Nocturnal, pulsatile FFA Other hormone? Muscle Fig. 1. Pathogenesis of insulin resistance syndrome. Sympathetic nervous system drives FFA release from visceral fat depot; insulin resistance results as does hyperinsulinemia. FFA: free fatty acids; CNS: central nervous system. diabetes 5. Type 2 diabetes occurs when the ability of the beta-cells of the pancreatic islets fail to compensate for diet-induced insulin resistance. It is only recently that it has been widely accepted that type 2 diabetes is usually due to a combination of insulin resistance and failed pancreatic compensation. This failure of compensation can be most well understood in terms of the hyperbolic relationship between insulin resistance and islet compensation (fig. 3). Normally resistance results in upregulation of beta-cell function which is described by a rectangular hyperbola 6 : insulin sensitivity x insulin secretion = constant (disposition index, DI ). A higher value of DI is protective, a reduced DI portends conversion to type 2 diabetes mellitus. In fact, at this juncture, the value of DI is the most powerful predictor of conversion from prediabetes to frank diabetes mellitus, and this predictive power of DI far outweighs predictability of genes for type 2 diabetes so far identified. Interestingly, all genes for type 2 diabetes so far identified are related to beta-cell failure, rather than insulin resistance. What is responsible for the hyperbolic relationship between insulin action and insulin secretion? It is widely believed that insulin resistance results in increased glycemia, which in turn increases secretory potential of the pancreatic islets. But, recent evidence from our laboratory shows that hyperinsulinemic compensation for insulin resistance can occur even in the absence of increased fasting glucose levels. Thus, it is unknown what the signal or signals are which account for hyperinsulinemic compensation. Because it is such compensation which fails as an initial step in progress to diabetes, it is important to understand beta-cell compensation. We hypothesize that nocturnal FFA, not only responsible for insulin resistance, may also mediate islet cell compensation. Thus, we are reminded of the importance of battle by sword here in El Escorial; by analogy, nocturnal FFA secondary to visceral lipolysis may not only cause insulin resistance, but may function as a two-edged sword, also mediating the islet cell response to compensate for insulin resistance. It is only in the modern world with a plethora of foodstuffs that such a 1,0 0,8 Week 0 Week 6 After fat FFA (mm) 0,6 0,4 Before fat 0,2 0,0 6 am 12 pm 6 pm 12 pm 6 am Following a high fat diet, overnight FFFA are elevated FFA (mm) 1,0 0,8 0,6 0,4 0,2 0,0 p = 24 1,0 0,8 0,6 0,4 0,2 0,0 * 1,0 0,8 0,6 0,4 0,2 0,0 * Week 0 Week 6 Fasting Week 0 Week 6 Fasting Week 0 Week 6 Fasting Fig. 2. Nocturnal increase in plasma fatty free acids. FFFA: flux of free fatty acids. 6 Endocrinol Nutr. 2009;56(Supl 4):5-7

10 Bergman RN. The two-edged sword Secretion by pancreas Patient at risk Fig. 3. DI: disposition index. DI-perbola Secretion x sensitivity = constant (DI) Insulin sensitivity of tissues two-edged sword has turned towards the owner to result in an international epidemic of type 2 diabetes. Conflict of interest The author declares he has no conflict of interest. REFERENCES 1. Yoon KH, Lee JH, Kim JW, Cho JH, Choi YH, Ko SH, et al. Epidemic obesity and type 2 diabetes in Asia. Lancet. 2006;368: Ludvigsson, J. Why diabetes incidence increases a unifying theory. Ann NY Acad Sci. 2006;1079; Klein S, Fontana L, Young VL, Coggan AR, Kilo C, Patterson BW, et al. Absence of an effect of liposuction on insulin action and risk factors for coronary heart disease. N Engl J Med. 2004;350: Kim SP, Catalano IR, Hsu JD, Chiu JM, Richey J, Bergman RN. Nocturnal free fatty acids are uniquely elevated in the longitudinal development of diet-induced insulin resistance and hyperinsulinemia. Am J Physiol. 2007;292:E Yechoor VK, Patti ME, Ueki K, Laustsen PG, Saccone R, Rauniyar R, et al. Distinct pathways of insulin-regulated versus diabetes-regulated gene expression: an in vivo analysis in MIRKO mice. Proc Natl Acad Sci USA. 2004;101: Bergman RN, Ader M, Huecking K, Van Citters G. Accurate assessment of beta-cell function: the hyperbolic correction. Diabetes. 2002;51 Suppl 1:S Endocrinol Nutr. 2009;56(Supl 4):5-7 7

11 Diabetes mellitus hoy Does postprandial blood glucose matter and why? ANTONIO CERIELLO Warwick Medical School. Clinical Science Research Institute. University of Warwick. UK. Type 2 diabetes is characterized by a gradual decline in insulin secretion in response to nutrient loads; hence, it is primarily a disorder of postprandial glucose (PPG) regulation. However, physicians continue to rely on fasting plasma glucose (FPG) and glycosylated hemoglobin (HbA1c) to guide management. There is a linear relationship between the risk of cardiovascular (CV) death and the 2-hour oral glucose tolerance test (OGTT), while a recent study confirms postprandial hyperglycemia as independent risk factor for CVD in type 2 diabetes. At the same time, several intervention studies show that treating postprandial hyperglycemia may reduces the incidence of new CV events. Evidence supports the hypothesis postprandial hyperglycemia may favour the appearance of the CV disease trough the generation of an oxidative stress. Furthermore, clinical data suggest that postprandial hyperglycemia is a common phenomenon even in patients who may be considered in good metabolic control. Therefore, physicians should consider monitoring and targeting PPG, as well as HbA1c and FPG, in patients with type 2 diabetes. Over the last several years, diabetes organisations around the world have begun to recognise that prandial glucose regulation (PGR) leads to improved outcomes in patients with diabetes. As a result, they have strengthened their recommendations for monitoring and treating postprandial glucose (PPG) 1 (reviewed in reference 1). These recommendations are supported by an increasing body of evidence. Many epidemiological data support this concept, showing that the value of glucose after 2h during an oral glucose tolerance test (OGTT) is an independent risk factor for cardiovascular disease, while fasting glucose is not 2-7.Clearly, the OGTT is highly nonphysiological and can not be considered as a meal. However two studies have confirmed that PPG is an independent risk factor for CVD in type 2 diabetes in the clinical setting: The Diabetes Intervention Study, which showed that in type 2 diabetics 1h PPG predicts myocardial infarction 8, and, more recently, a prospective study, with a mean follow-up of 5 years, able to show that PPG is an independent CVD risk factor, particularly in women, in patients with type 2 diabetes 9. Intervention studies are also coming and support the relevance of PPG in the development of CVD. Correspondence: Dr. A. Criello. Warwick Medical School. Clinical Science Research Institute. University of Warwick, UK. antonio.ceriello@warwick.ac.uk 8 Endocrinol Nutr. 2009;56(Supl 4):8-11

12 Ceriello A. Does postprandial blood glucose matter and why? NT (µmol/l) t 0 1 h 2 h 4 h 6 h Time Fig. 1. Nitrotyrosine (a marker of oxidative stress) before and after a mixed meal: regular insulin, insulin aspart and control. From: Ceriello et al 18. The STOP-NIDDM Trial has shown that treatment of subjects with IGT with the -glucosidase inhibitor acarbose, a compound which specifically reduces postprandial hyperglycemia, is associated not only with a 36% reduction in the risk of progression to diabetes 10, but also a 34% risk reduction in the development of new cases of hypertension and a 49% risk reduction in cardiovascular events 11, particularly of silent myocardial infarction 12. In addition, in a subgroup of patients from this study, carotid intima media thickness was measured before randomisation and at the end of the study 13. Acarbose treatment was associated with a significant decrease in the progression of intima media thickness, an accepted surrogate for atherosclerosis 13. Furthermore, in a recent metaanalysis in type 2 diabetic patients, acarbose treatment was associated with a significant reduction in cardiovascular events relative to placebo treatment, even after adjusting for other risk factors 14. Finally, the effects of two insulin secretagogues, repaglinide and glyburide, known to have different efficacy on postprandial hyperglycemia, on carotid intima-media thickness (CIMT) and markers of systemic vascular inflammation in type 2 diabetic patients has been evaluated 15. Although a similar reduction in A1c was observed in both groups ( 0.9%), CIMT, interleukin-6 and C-reactive protein decreased more in the repaglinide group than in the glyburide group. The reduction in CIMT was associated with changes in postprandial but not fasting hyperglycemia 15. The mechanisms through which PPG exerts its effects may be identified in the production of free radicals, which, in turn, can induce an endothelial dysfunction and the production of an inflammation 16 (revised in reference 16). Studies confirm that after a meal an oxidative stress is generated 17,18 (fig. 1) and that it is related to the level of hyperglycemia reached 19, and, particularly, as very recently demonstrated, to the level of glucose fluctuations 20. In parallel, the production of this oxidative stress induces an endothelial dysfunction and the release of cytokines 21,22, convincingly related to the activation of the transcription factor NF-kB, which plays a key role on endothelial function and inflammation 23. Therefore, it is not surprising that controlling PPG with various different compounds specifically working on PPG, such as, fast acting insulin analogues, hypoglycaemic agents improving the first phase of insulin secretion, an amylin analogue and acarbose, is accompanied by a significant improvement not only of the oxidative stress 18,24-26, but also of endothelial dysfunction 26-29, myocardial blood flow 30, inflammation 15 and NF-kB activation 31. However, also dyslipidaemia is a recognized risk factor for cardiovascular disease in diabetes 32 and today the contribution of postprandial hyperlipidaemia to this risk is well-recognized 33. In non-obese type 2 diabetic patients with moderate fasting hypertriglyceridaemia, atherogenic lipoprotein profile is amplified in the postprandial state 34. These evidences have frequently raised the question that being postprandial hyperglycemia accompanied by a concomitant increase of postprandial hyperlipidaemia, the latter was the true risk factor 35. It is today well recognized that endothelial dysfunction is an early factor involved in the development of cardiovascular disease 36. Evidence suggests that both postprandial hypertriglyceridemia and hyperglycemia induce an endothelial dysfunction, through an oxidative stress 21,37. Finding shows an independent and cumulative effect of postprandial hypertriglyceridemia and hyperglycemia on endothelial function, suggesting oxidative stress as common mediator of such effect 21,22. Therefore, evidence exists to support a specific and direct role of posprandial hyperglycemia, independent from lipids, in favouring cardiovascular disease. The production of an oxidative stress in postprandial state, due to postprandial hyperglycemia, is of particular relevance because recent studies demonstrate that a single hyperglycemia-induced process of overproduction of superoxide by the mitochondrial electron-transport chain seems to be the first and key event in the activation of all other pathways involved in the pathogenesis of diabetic complications 38 (fig. 2). Interestingly enough, it has very recently been shown that hyperlipidemia works in generating an oxidative stress in the mitochondria through the same pathway of hyperglycemia 39. The evidence described up to now proves that hyperglycemia can acutely induce alterations of normal human homeostasis. It should be noted that acute increases of glucose levels cause alterations even in healthy normoglycemic subjects 16. Diabetic subjects also have basal hyperglycemia and it can be hypothesized that the acute effects of mealtime hyperglycemia can exacerbate those produced by chronic hyperglycemia, thus contributing to the final picture of complicated diabetes. The precise relevance of PPG in the daily life of diabetic patients has recently been quantified 40. Endocrinol Nutr. 2009;56(Supl 4)::8-11 9