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Molecular Mechanisms of Brain Insulin Signaling 1
Published in André Kleinridders, Physiological Consequences of Brain Insulin Action, 2023
Simran Chopra, Robert Hauffe, André Kleinridders
To exert its effects in the CNS, insulin is transported across the blood-brain barrier by saturable insulin transporters (8–10) and is released into the cerebrospinal fluid (CSF) where it is distributed to insulin-sensitive brain regions. Upon insulin binding to the IR, the IR changes its conformation to bring kinase domains of the IR in proximity to tyrosine phosphorylation sites on the β-chain, allowing the autophosphorylation of at least eight tyrosine residues (11). This then leads to the activation of insulin receptor substrate (IRS) proteins and subsequently of two general downstream signaling arms through (i) the phosphoinositide 3-kinase (PI3K) and protein kinase B (PKB, also called AKT) axis, and (ii) the mitogen-activated protein kinase (MAPK), discussed in detail below (Figure 1.1)
Ameliorating Insulin Signalling Pathway by Phytotherapy
Published in Mahendra Rai, Shandesh Bhattarai, Chistiane M. Feitosa, Ethnopharmacology of Wild Plants, 2021
The insulin receptor is a transmembrane receptor that is activated by insulin molecules (White and Kahn 1994). Two alpha subunits and two beta subunits make up the insulin receptor. The alpha subunits are involved in ligand binding, while the two intracellular tyrosine kinase beta-subunits participate in transducing the signal into the cell. The alpha subunits are linked by disulfide bonds to the beta subunits (Gustafson et al. 1999). Activation of the insulin receptor (IR) after ligand binding is a multi-step process involving structural changes in both the ligand and the receptor. The binding of insulin to IR results in autophosphorylation of the receptor on a number of crucial tyrosine residues. This causes activation of the insulin receptor tyrosine kinase, followed by phosphorylation of various insulin receptor substrate (IRS) proteins to propagate the insulin-signalling event further downstream and mediate various biological effects. The phosphorylation on tyrosine residues in IR and IRS proteins develops docking sites for other enzymes and effector molecules containing SH2 or phosphotyrosine-binding (PTB) domains to propagate insulin signal (Taha and Klip 1999). A schematic view of the role of PTP1B in metabolic insulin signalling pathway is depicted in Figure 15.1.
Insulin Resistance and Glucose Regulation
Published in Awanish Kumar, Ashwini Kumar, Diabetes, 2020
Insulin receptor substrate (IRS-1 and IRS-2) proteins are the major proteins directly attached to the IR and convey the signalling cascade further. In a simple explanation of insulin action, insulin binds to the IR present on the cell membrane. The IR gets autophosphorylated at tyrosine residues and further activates IRS-1 and IRS-2. These proteins further activate PI-3 kinase and finally Akt/PKB. Akt finally activates and recruits GLUT-4 (the primary insulin responsive glucose transporter) on the cell membrane so that it can bring the circulating glucose inside the cell. Free fatty acids are seen to become stored in non-adipose cells, leading to increased intramyocellular lipid depots, and leading to insulin resistance. It has also been shown that FFA-induced insulin resistance is related to downregulation of the insulin receptor (IR) gene. FFA also inhibits the activation of PI-3 kinase in the skeletal muscle cells. It has also been found that saturated fats block the insulin activation of Akt/PKB signalling. These FFA inhibitory actions finally result in diminished GLUT-4 translocation to membranes, finally increasing the plasma glucose [16]. FFAs also serve as a great substrate for hepatic TG synthesis and hepatic gluconeogenesis which results in elevated plasma VLDL and hyperglycaemia.
Association between the Extent of Peripheral Blood DNA Methylation of HIF3A and Accumulation of Adiposity in community-dwelling Women: The Yakumo Study
Published in Endocrine Research, 2022
Genki Mizuno, Hiroya Yamada, Eiji Munetsuna, Mirai Yamazaki, Yoshitaka Ando, Ryosuke Fujii, Yoshiki Tsuboi, Atsushi Teshigawara, Itsuki Kageyama, Keisuke Osakabe, Keiko Sugimoto, Hiroaki Ishikawa, Naohiro Ichino, Yoshiji Ohta, Koji Ohashi, Shuji Hashimoto, Koji Suzuki
Obesity is a major public health concern worldwide. Non-esterified fatty acids, adipokines, and other factors are extensively released from adipose tissues in obese individuals, thereby leading to abnormalities in obesity-related cell functions.1 These substances cause alterations that dysregulate insulin signaling molecules such as insulin receptor substrate, resulting in insulin resistance in the liver and skeletal muscle. Consequently, obesity induces various diseases, such as insulin resistance, type 2 diabetes, and cardiovascular disease.2,3 Thus, obesity is a risk factor for various metabolic diseases, and preventing obesity helps to prevent metabolic diseases. Recent changes in lifestyles and food choice patterns (such as lack of exercise and nontraditional diets) have increased the number of obese individuals globally.4 Lifestyle, environmental, and genetic factors trigger obesity.5,6
The impact of the gut microbiota on the reproductive and metabolic endocrine system
Published in Gut Microbes, 2021
Xinyu Qi, Chuyu Yun, Yanli Pang, Jie Qiao
Insulin is an important hormone that increases membrane permeability to glucose and lowers the level of glucose by activating the insulin receptor. The binding of insulin to insulin receptors causes the activation of insulin receptor tyrosine kinase and the tyrosine phosphorylation of insulin receptor and insulin receptor substrate (IRS) proteins.80,81 Phosphorylation of IRS stimulates the binding of the lipid kinase phosphatidylinositol-3-kinase (PI3-K) at the plasma membrane, which phosphorylates the Thr308 residue of AKT by synthesizing Ptdlns(3,4,5)P3 (PIP3).82 AKT activation leads to glucose production, utilization and uptake, as well as the synthesis of glycogen, lipids, and proteins.82 Interestingly, mounting evidence suggests that the gut microbiome, as well as the metabolites of bacteria, are involved in the progression of insulin resistance.57,83,84
The Association between the Preservative Agents in Foods and the Risk of Breast Cancer
Published in Nutrition and Cancer, 2019
Fardin Javanmardi, Jamal Rahmani, Fatemeh Ghiasi, Hadi Hashemi Gahruie, Amin Mousavi Khaneghah
Insulin exerts mitogenic effects on epithelial cells via insulin and insulin-like growth factor-ι receptors (IGF-IRs) (98). A positive correlation was observed among premenopausal women between plasma IGF-I concentration and risk of BC (99). Monitoring of IGF-I concentration may be useful in the screening of women regarding the high risk of BC (100). Hyperinsulinemia with insulin resistance plays an important role in increasing the risk of BC (101). Protection from apoptosis requires the tyrosine kinase activity of IGF-IR in fibroblasts (102). Apoptosis protection by IGF is mediated by activation of post-receptor components such as PI3K and the Akt/protein kinase B pathway (103). In this context, IGF-like ligands bind to their receptors or IGF-IR/InsR hybrid receptor to mediate pleiotropic effects in BC (104). The adapter protein insulin receptor substrate (IRS) is phosphorylated by the activated receptor and serves as a coupling protein for other signaling molecules to protect fibroblasts against apoptosis. Insulin receptor substrate and Src homology and collagen protein (SHC) mediate adhesion and migration caused by IGF-like ligands (104).