13 - Chronic Inflammatory Hypothesis in the Metabolic Syndrome

Abstract

Globalization of the occidental way of life is leading to increasing prevalence of obesity and type 2 diabetes, the greatest pandemy of the xxi century. Type 2 diabetes is the result of concomitant peripheral insulin resistance and decreased β cell insulin secretion. In the last years, type 2 diabetes is increasingly recognized as an inflammatory state. Decreased insulin action was initially proposed as the triggering factor of the different components of the Metabolic Syndrome, which are direcly linked to cardiovascular disease. In fact, insulin resistance and cardiovascular disease share common pathophysiological mechanisms, as the chronic activation of the innate immune system. This system constitutes the first line of body's defence and it is constituted by different barriers (epithelia, adipose tissue), and different blood and tissue components as macrophages, and neutrophils. This system generates the acute phase response in which different acute phase proteins and cytokines are produced in response to different aggresions as infections and traumatisms. The aim of this response is to eradicate these agents, to repair the harmed tissues, and, through increased insulin resistance, to optimize the energetic substrates, which will be drained to vital tissues and organs (i.e. brain and the immune system). Evolution pressures have led to survival of the fittest individuals, those with genetics which allows the best defence against infection and periods of famine. The evolutive advantages of increased inflammatory responses, hypersecretion of proinflammatory cytokines (TNF-α, interleukin (IL)-1β, IL-6, IL-18, etc.), or decreased antiinflammatory molecules (adiponectin, certain TNF-αreceptor isoforms, sCD14, etc.), would lead to chronic inflammation conditions, such as obesity and type 2 diabetes, leading to cardiovascular disease. Increasing evidence is reported according to which chronic inflammation precedes these conditions. The knowledge of how these metabolic pathways interact with the inflammatory cascade will facilitate new therapeutic approaches. Anti-inflammatory drugs are only the first step of this new approach.