11/20/2023 0 Comments Negative feedback loop insulin![]() ĪKT plays a role in the regulation of gluconeogenic and adipogenic genes through the transcription factor FOXO1 (forkhead box-containing protein 1, subfamily O). GSK3 is inhibited when phosphorylated by AKT/PKB, which results in glycogen synthesis. ĪKT acts in the regulation of glycogen synthesis via glycogen synthase kinase 3 (GSK3), another serine/threonine kinase, which, amongst other roles, functions to inhibit glycogen synthase. mTOR stimulates protein synthesis through the phosphorylation of 4EBP1 (eukaryotic translation initiation factor 4E-binding protein 1) and p70S6K (p70 ribosomal protein S6-kinase). From here, AKT plays a role in four critical downstream processes.ĪKT is involved in the regulation of protein synthesis via the substrate protein mTOR, a serine/threonine kinase that functions as a nutrient sensor. ![]() PIP3 is an important second messenger that functions to recruit PDK1 (3-phosphoinositide dependent protein kinase-1) and AKT to the membrane, where phosphorylation of PDK1 then activates the serine/threonine residues of AKT. Once the p110 subunit is activated, PI3K then catalyzes the phosphorylation of phosphatidylinositol (PI) to generate PIP3 (phosphatidylinositol 3,4,5-triphosphate) at the cell membrane. This results in the activation of the PI3K catalytic subunit, p110. The PI3K pathway is activated by the binding of PI3K regulatory subunits p85 and p55 to IRS1 and IRS2. ![]() The MAPK pathway, on the other hand, stems from IRS, as well as Shc, and is involved in the regulation of gene expression and, in cooperation with the PI3K pathway, also regulates cell growth and differentiation. The PI3K (phosphoinositol 3-kinase) pathway is linked exclusively through IRS and is responsible for most of insulin's metabolic effects in the cell. Two principle pathways result from the insulin receptor-IRS interaction, the PI3K/AKT (also known as protein kinase B or PKB) pathway, and the Ras/MAPK (also known as extracellular signal regulated kinase or ERK). Binding of the insulin receptor to either IRS or Shc forms a platform that allows for the assembly of a signal transduction particle that gives rise to multiple intracellular signaling pathways. These form the binding sites for IRS proteins, which contain phosphotyrosine (PTB) binding domains, or for Shc adapter proteins, containing src-homology 2 (SH2) domains. When insulin binds to the extracellular α subunits of the insulin receptor, a conformational change is induced, which then results in the autophosphorylation of several tyrosine residues present in the β subunits. Insulin signaling pathways are highly conserved, with insulin-like signaling systems found in all metazoans, and they have been shown to regulate many evolutionarily conserved processes, including lifespan and reproduction. While insulin is widely viewed as a glucose homeostasis regulating hormone, an increasing body of research is illuminating broader roles for this peptide. Besides regulating blood glucose levels, insulin also plays critical roles in facilitating protein and lipid synthesis and preventing the conversion of protein and fat to glucose. Insulin also regulates blood sugar through inhibiting gluconeogenesis (de novo glucose production) and glycogenolysis (glycogen breakdown) in the liver. ![]() Once GLUT4 is incorporated into the plasma membrane, it functions to promote the uptake of extracellular glucose, which is then stored as glycogen in these cells, thereby regulating blood glucose. When insulin binds to its receptors on target cells, such as skeletal muscle cells and adipocytes, a signaling cascade is initiated, which culminates in the translocation of the glucose transporter GLUT4 from intracellular vesicles to the cell membrane. It is secreted from beta cells found in the islets of the pancreas in response to nutrient uptake and increased blood glucose levels. Insulin is a peptide hormone that predominantly functions to reduce blood glucose levels.
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