Insulin is a peptide hormone produced by beta cells of the pancreatic islets. It is the major hormone controlling critical energy functions such as glucose and lipid metabolism. Insulin signaling plays an important role in the physiological action of insulin. Insulin binds to its receptor, inducing intracellular signal transduction through a series of intracellular signaling molecules, activating signaling pathways, reaching the effector, and finally producing various physiological effects.
Insulin action is mediated through the insulin receptor, which is composed of two extracellular α subunits and two transmembrane β subunits linked together by disulphide bonds. Insulin activates the insulin receptor tyrosine kinase (IR) that phosphorylates and absorbs different substrate adaptors. Among them, PI3-kinase (Phosphoinositide 3-kinase) leads to crucial metabolic functions such as synthesis of lipids, proteins and glycogen mainly via the activation of the PKB(AKT) and the PKCζ cascades. AKT, a serine kinase, which can deactivate glycogen synthesis kinase 3 (GSK3), leads to the activation of glycogen synthase (GYS) and thus glycogen synthesis. it can influence the synthesis of protein via mTOR. Insulin activates several other protein kinases, such as p70 ribosomal S6 kinase (S6K), belonging to the same protein kinase subfamily as PKB, and also participates in the synthesis, growth and proliferation of protein. In addition, PKB can inhibit multiple pro-apoptotic factors (such as Bad, GSK-3, Caspase 9 and mTOR) to ensure cell survival. Insulin signaling also has growth and mitogenic effects, which are mostly mediated by activation of the Ras/MAPK pathway. This pathway involves the tyrosine phosphorylation of IRS proteins and/or Shc. With the adapter protein Grb2, recruiting the Son-of-sevenless (SOS) exchange protein to the plasma membrane for activation of Ras. Once activated, Ras operates as a molecular switch, stimulating a serine kinase cascade through the stepwise activation of Raf, MEK and ERK. Activated ERK can translocate into the nucleus, where it catalyses the phosphorylation of transcription factors that leads to cellular proliferation or differentiation. Insulin signal transduction promotes glucose uptake by activating intracellular signal transduction pathways that promote transports of GLUT4 glucose to the plasma membrane. In addition, binding of insulin to its receptor also causes it to phos-phorylate the protein Cbl in a complex with the adaptor protein CAP. At this location Cbl interacts with the adaptor protein Crk which is constitutively associated with the Rho-family guanine nucleotide exchange factor. C3G then activates members of the GTP-binding protein family, TC10, which activates unknown effector molecules to promote GLUT4 translocation. Insulin stimulates glucose uptake in muscle and adipocytes via translocation of GLUT4 vesicles to the plasma membrane. (Fig1)
Fig1. Insulin signaling pathway
Insulin signaling in diseases
(1) The Diabetes mellitus
The normal operation of the insulin signal pathways plays an important role in insulin physiological function. The disorder of insulin signal transduction will weak the physiological action of insulin, leading to insulin resistance and type 2 diabetes mellitus. Insulin resistance refers to the decrease in insulin utilization rate and insulin sensitivity caused by various reasons, which is the main pathological basis of type 2 diabetes. Current research suggests that the main cause of insulin resistance is the elevated levels of inflammatory cytokines, which interfere with the normal phosphorylation of IRS in the insulin signal transduction, blocking a series of cascade amplification reaction activated by the downstream signal, andthus affect the physiological function of insulin, such as generation, transportation, leading insulin resistance. The insulin signal enters cell and triggers a serial biochemical reaction through the insulin receptor (IR). Emerging knowledge of insulin pathway and pathogenic mechanisms has led to a host of new molecular drug targets mainly involved in improving the insulin sensitivity of target cells and promoting uptake and utilization of glucose. A key role of insulin is to stimulate glucose uptake into cells by inducing GLUT4, the translocation of the glucose transporter. When insulin is lacking, constitutively activated mutants of PI3-kinase and PKB overexpress and stimulate the recruitment of GLUT4 to the cell surface. Recently, some studies suggest that another PI3-kinase independent pathway may provide a second signal that plays an important role in allowing insulin to stimulate the recruitment of GLUT4 to the cell membrane. In this pathway, activated insulin receptor phosphorylates the proto-oncogene Cbl directly to activate the TC10 family of Rho GTP-binding proteins. Then these proteins interact with unknown effector proteins to allow translocation of insulin-stimulated GLUT4.
(2) Polycystic ovary syndrome
A majority of women with PCOS who have insulin resistance are obese. Their insulin level is often too high, resulting in the abnormalities of the hypothalamic-pituitary-ovarian. Hyperinsulinemia increases the frequency of GnRH pulse and LH, higher than FSH, increases the production of ovarian androgen, reduces follicular maturation and SHBG binding. In addition, excessive insulin can influence the synthetic of androgen precursors, via PI3-kinase, to upregulate the activity of 17 prun-hydroxylase. In conclusion, the combined effects of hyperinsulinemia contribute to an increased risk of PCOS.
(3) Alzheimer’s disease (AD)
Alzheimer’s disease (AD) has been considered as a metabolic dysfunction disease associated with impaired insulin signaling. It’s important to determine the mechanisms underlying insulin signaling dysfunction and resistance in AD. Impaired clearance of amyloid-b peptide (Aβ) significantly contributes to amyloid accumulation, which is typically observed in the brain of AD patients. Recent studies suggest that insulin through its transport into the brain or its signaling pathways within cerebral endothelial cells offers promising opportunities to increase Aβ clearance. Insulin promotes release of neprilysin (NEP) and increased insulin-degrading enzyme (IDE) expression at the cell membrane of astrocytes through activation of the ERK-mediated pathway and elevates degradation of soluble oligomeric and monomeric Aβ in the extracellular fluid in the brain. Additionally, inhibition of the insulin signaling pathway in the presence of insulin causes a marked delay in Aβ degradation by astrocytes. Peripheral vascular insulin combined with insulin receptor (INSR), either triggers cellular signaling pathways in the brain endothelial cells, or transports insulin capillary molecules to the brain parenchyma through a saturated trans-sensory dermal cell transport mechanism. A deeper understanding of the complicated mechanisms underlying insulin resistance and hyperinsulinemia in the brain may lead to better management strategies for controlling T2DM so as to reduce the subsequent risk for AD-related neuropathology.
The function of a signal transduction pathway is based on extra-cellular signaling that in turn creates a response which causes other subsequent responses, hence creating a chain reaction or cascade.
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