47 2 Macrophage Metabolic Reprogramming in Diabetes We now have clear evidence that macrophages can change metabolic pathways to respond to challenges they encounter. Macrophage polarization and function are highly dependent on fast changes in intracellular metabolism, which explains why macrophages can be extremely versatile in function. While this field is moving forward fast, our understanding of interactions between metabolic changes at the organism level such as found in DMTII/obesity and intracellular metabolic changes in macrophages still lags behind. Macrophages in adipose tissue from individuals with DMTII or obesity clearly show a different but pro-inflammatory phenotype from those of lean individuals or individuals without DMTII. However, those proinflammatory phenotypes appear to be unique to DMTII and obesity and are not found when macrophages are M1-polarized in acute inflammation (37), suggesting that metabolic changes at the organism level influence macrophage activation and metabolism. How they interact exactly remains an open question that could potentially be answered by improved analysis of macrophage cellular metabolism. To do this in complex conditions like DMTII and obesity, an approach from different angles is needed and integration of results from different analytical platforms is the way forward. This could help to better understand the mechanism underlying macrophages polarization in DMTII-related chronic inflammation and, even more importantly, how this affects disease progression. A better understanding of interaction between different metabolic pathways could also result in the development of new treatment options. Diabetes treatment now focuses on weight loss, rebalancing insulin resistance, and lowering blood glucose levels by using mostly gluconeogenesis inhibitors like metformin or hypoglycemic drugs that stimulate β-cells to release insulin (122). While weight loss should always remain the number one priority, redirecting adipose tissue macrophage metabolic programs, and thereby polarization, could be another interesting approach since pro-inflammatory macrophages contribute to onset of insulin resistance (123) and overall to DMTII-related meta-inflammation. Inhibiting chronic inflammation, would not only improve the comorbidities, like diabetic retinopathy, polyneuropathy, or nephropathy but also one of the main causes of diabetes onset. Another aspect that should be further investigated and could develop into a promising therapeutic approach is the link between metabolism and inflammation via epigenetic regulation of gene expression. Recent studies indicate that chronic inflammation is linked to changes in energy metabolism via lysine acetylation of both histones and non-histone proteins (77). Therefore, deacetylase inhibitors or activators may be additional approaches to inhibit macrophage-induced metainflammation by rebalancing the expression of pro- and anti-inflammatory mediators.
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