25 2 Macrophage Metabolic Reprogramming in Diabetes INTRODUCTION Diabetes mellitus type II (DMTII) is one of the main causes of death in modern society according to the World Health Organization (1). It correlates with long-term complications that include nephropathy, peripheral neuropathy, and cardiovascular disease. The International Diabetes Federation has estimated that globally the diagnosis of DMTII has been made in 415 million people and anticipates growth to up to 642 million by the year 2040 (2). Several factors can contribute to a higher risk of developing DMTII, but it has been proven that overweight or obesity are the most important ones (3). DMTII is often linked to obesity and both are associated with metabolic syndrome, which encompasses conditions such as high blood pressure, excess body fat around the waist, high blood sugar, high serum cholesterol or triglyceride levels, and low highdensity lipoprotein (HDL) cholesterol. Metabolic syndrome is characterized by low-grade chronic inflammation (meta-inflammation) (4) in all tissues involved in energy homeostasis, including adipose tissue, pancreatic islets, and liver (5). Studies have shown that the metabolic consequences of adipose tissue dysfunction increase mortality in patients with DMTII, emphasizing the importance of metainflammation in the context of DMTII (6) Macrophages are part of the innate immune system and are present in all tissues of our body, including adipose tissues (7). They play a crucial role in the first line of defense against microorganisms and other external or internal threats to homeostasis by initiating essential inflammatory responses (8). These inflammatory responses are facilitated by changes in macrophage cellular metabolism, with a focus on glycolysis that is induced in cells producing inflammatory mediators. The inflammatory response is counter-balanced by stimulation of tissue repair and antiinflammatory mechanisms once the threat has been overcome. At the same time, the cellular metabolism changes from glycolysis to oxidative phosphorylation to aid in tissue repair. Continuous exposure to pro-inflammatory stimuli, however, can shift the balance of inflammation and repair in favor of chronic inflammation and tissue damage. Excessive activation of macrophage inflammatory responses is seen in many diseases characterized by the continuous presence of pro-inflammatory stimuli, including DMTII, and explains in part the meta-inflammation found in this condition. Many studies have described how macrophages become activated by inflammatory stimuli (9,10) and there is increasing consensus that a particular macrophage activation state is associated with DMTII. Characterization of the different macrophage activation states is complicated, but in recent years has been aided by the development and use of novel techniques like multiparametric flow cytometry,
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