27 2 Macrophage Metabolic Reprogramming in Diabetes Figure 1: Regulation of glucose entrance through insulin signaling. Insulin receptors are tyrosine kinases consisting of two extracellular α-subunits and two transcellular β-subunits. In healthy individuals, insulin will bind the α subunit of the insulin receptor, causing a conformational change that leads to phosphorylation of tyrosine residues in its β subunit. The proteins insulin receptor substrates 1 or 2 (Irs-1/-2) will then bind to the tyrosinephosphorylated region of insulin receptors and be themselves phosphorylated. Phosphoinositide-3-kinase (PI3K) will bind to the phosphorylated IRS-1 or -2 and be activated, producing 3-phosphorylated polyphosphoinositides (PiP3) from phosphatidylinositol 4,5-bisphosphate (PiP2). PiP3 will recruit the serine/threonine kinase Akt (also known as protein kinase B) from the cytosol to the plasma membrane, where it will be phosphorylated and activated, leading to glycogen synthase kinase-3β (GSK3B) inhibition and therefore to higher glycogen synthesis. AKT is also responsible for the translocation of the glucose transporter (GLUT) to the plasma membrane, allowing glucose entry. DMTII is caused by the development of insulin resistance, meaning the inability of cells to respond to insulin due to a transmission blockage of the insulin receptor, mainly in muscle and liver cells. Pancreatic β-cells will at first try to compensate for the higher levels of glucose by increasing insulin production. This will eventually lead to lower glucose availability in combination with lower tissue insulin sensitivity resulting in loss of β-cell function. This will result in lower insulin secretion, which will consequently lead to a higher concentration of glucose in blood (14). Insulin resistance can be caused by many different factors, with obesity being the most important one (14). Elevated levels of circulating free fatty acids are one of the reasons for the development of insulin resistance in obese patients. These
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