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Insulin Signaling Pathway

Figure 1. Insulin signaling pathway

Insulin signaling pathway overview

The insulin signaling pathway is the sum of all proteins involved in the action of insulin in the body and the factors that regulate this pathway. Since the discovery of insulin in 1921, people's perspective has focused on insulin in the liver, skeletal muscle and blood sugar control, which stimulates skeletal muscle and adipose tissue to take up glucose, inhibits gluconeogenesis of liver tissue, and exerts hypoglycemic effects. More and more studies have shown that the biological effects of insulin, such as insulin acting on the kidneys, can increase the kidneys blood flow and glomerular filtration rate, increase glomerular filtration rate and may be associated with polymorphism in the human IRS(insulin receptor substrate) gene. Decreased insulin sensitivity in the brain is closely related to the occurrence of neurodegenerative diseases such as Alzheimer's disease, suggesting that insulin also plays an important role in learning and memory. In diabetes, the development of insulin resistance keeps the body's blood in a persistently high insulin state, which can reduce the NO content of the vascular protective agent, cause endothelial dysfunction, and promote the formation of atherosclerosis. Therefore, insulin secreted by islet B cells (Figure 2) is a pleiotropic hormone that stimulates nutrient transport, regulates gene expression, enzyme activity, and regulates energy homeostasis. Among them, insulin regulates blood glucose homeostasis. Fat and protein metabolism is especially prominent, but its physiological function depends on a variety of target tissues and signal transduction pathways within cells.

Pancreatic islets and beta cells

Figure 2. Pancreatic islets and beta cells

Insulin family

The insulin protein family combines several evolutionarily related active peptides: these include insulin, relaxin, insect prothoracicotropic hormone (bombyxin), insulin-like growth factors (IGF1 and IGF2), mammalian Leydig cell-specific insulin-like peptide (gene INSL3), early placenta insulin-like peptide (ELIP), locust insulin-related peptide (LIRP), molluscan insulin-related peptides (MIP), and Caenorhabditis elegans insulin-like peptides. The 3D structure (Figure 3) of a number of family members has been determined. The fold comprises two polypeptide chains (A and B) linked by two disulphide bonds: all share a conserved arrangement of four cysteines in their A chain, the first of which is linked by a disulfide bond to the third, while the second and fourth are linked by interchain disulfide bonds to cysteines in the B chain.

3D structure of human insulin

Figure 3. 3D structure of human insulin

Insulin signaling pathway

Insulin mediates the role of its signal transduction pathway through the insulin receptor(IR) on the cell membrane. IR-mediated signal transduction can be divided into IRS-mediated signal transduction pathways and non-IRS-mediated signal transduction pathways depending on whether IRS(insulin receptor substrate) is mediated.

  1. IRS-mediated insulin signaling pathway

    IR is a heterotetrametric transmembrane glycoprotein composed of α2β2 and is a casein kinase receptor. The α-subunit located outside the membrane binds to insulin, causing the conformational change of the receptor to cause autophosphorylation of a specific tyrosine residue on the β subunit, and the tyrosine phosphorylated β subunit further increases its kinase activity. A series of IRS1~4 proteins were recruited and phosphorylated, with IRS1 and IRS2 being the most widely expressed. The tyrosine phosphorylated IRS protein recruits and binds to a SH2 domain-containing signaling molecule that activates two signal transduction pathways in the cell: 1) phosphatidylinositol-3-kinase(PI3K)-protein kinase B(Akt or PKB) pathway: phosphorylated IRS protein then binds to the P85 subunit of PI3K and recruits its catalytic subunit P110 to activate PI3K; PI3K activates phosphorylation of phosphatidylinositol to produce 3,4,5-phosphatidylinositol-3,4,5-triphosphate (PIP3), which in turn activates the serine/threonine protein kinase Akt that activates a variety of substrates and mediates multiple organisms of insulin effect. For example, by monophosphorylation of AS160, glucose transporter 4(GLUT4) is translocated to the cell membrane to uptake glucose; phosphorylation of glycogen synthase kinase 3(GSK3) inhibits GSK3 activity, increases the activity of glycogen synthase, promotes cellular uptake of glucose and synthesis of glycogen, and lowers blood glucose; Phosphorylation of the transcription factor, fork head box protein O1(FOXO1), inactivates and degrades FOXO1, and inhibits phosphoenolpyruvate carboxykinase(PEPCK) and its key enzyme of gluconeogenesis. Then the transcriptional regulation of glucose-6-phosphatase(G6Pase) inhibits hepatic gluconeogenesis and lowers blood glucose, activates mammalian target ofrapamycin(mTOR), promotes protein synthesis and cell growth, etc. The metabolic function of insulin is to be carried out through this branch. 2) Ras-mitogen-activated protein kinase(MAPK) pathway: the growth signaling pathway. Mammalian MAPK families include p38, extracellular-signal-regulated kinase(ERK) and c-Jun N-terminal kinase(JNK). IRS1/2 activates MAPK by binding to growth factor receptor-bound protein 2(Grb2), regulates gene transcription and regulates cell proliferation and differentiation by interacting with PI3K-AKT pathway. IRS acts as the intersection of the two signal pathways, and the signaling pathways mediated by different subtypes are also different. In the liver, insulin receptor substrate(IRS1) and insulin receptor substrate 2(IRS2) mediate lipid production and glycogen synthesis, respectively, and IRS2-mediated signaling pathways are impaired during insulin resistance, while the IRS1-mediated signaling pathway is relatively intact. Insulin resistance in skeletal muscle appears to primarily attenuate IRS1-mediated signaling pathways for GLUT4 transport and glucose uptake, although some studies have also shown that IRS2-mediated signaling pathways are also involved in glucose metabolism.

  2. Non-IRS-mediated insulin signaling pathway

    Studies have shown that in addition to IRS1 to 4, several other substrates can also mediate the biological effects of insulin. 1) Src homologous region 2 contains protein. The activated insulin receptor phosphorylates the Shc tyrosine residue, which in turn binds to Grb2 to trigger the Ras-MAPK signaling pathway, regulating cell growth and proliferation. 2) Heterotrimeric G protein Gаq /11: Gaq /11 phosphorylated by the insulin receptor activates PI3K and stimulates GLUT4 to mediate glucose uptake. 3) Cbl associated protein(CAP): proto-oncogene product Cbl adaptor protein is recruited to the insulin receptor near CAP, causing Cbl adaptor protein phosphorylation, and then CAP/Cbl complex directly causes GLUT4 to be transported to the cell membrane and uptake of glucose.

  3. Pathway regulation

    Since the insulin signaling pathway is a complex pathway, many factors can regulate this pathway. The study found that protein tyrosine phosphatase 1B(PTP1B) plays a role in regulating insulin signaling pathway sensitivity and energy metabolism. Importantly, PTP1B knockout mice are significantly more sensitive to insulin signaling pathways and are resistant to obesity. Specific inhibitors of PTP1B can significantly increase the body's sensitivity to insulin; α-G(α-glucose): inhibition of α-glucoside activity can slow down the production and absorption of glucose α-glucoside can increase the postprandial blood glucose peak by increasing the insulin signaling pathway, and adjust blood sugar levels, thereby reducing the stimulation of pancreas by hyperglycemia, improving the sensitivity of the pancreas, protecting the function of the pancreas, effectively preventing diabetes and improving complications. The occurrence of aldose reductase(AR) is the rate-limiting enzyme of glucose metabolism, catalyzing the conversion of glucose to sorbitol, attenuating the occurrence of insulin signaling pathway, and ultimately triggering diabetes; dipeptide kininase IV(DPPIV) can lyse and inactivate the incretin, attenuating the sensitivity of the insulin signaling pathway. In addition, the signaling pathway of NF-κB is closely related to the development of insulin resistance. Abnormal expression of NF-κB and its related genes may indirectly or directly affect the conduction of insulin signaling pathway through different pathways in different parts of the body.

  4. Relationship with diseases

    The related disease is type II diabetes. Type II diabetes refers to the problem of glucose uptake, which is not caused by insulin deficiency, but due to the problem of insulin signaling pathway, since insulin cannot function properly.

    Alzheimer's disease(AD)

    Alzheimer's disease(AD) is a slowly developing neurodegenerative disease. In recent decades, AD patients have been associated with brain insulin signaling pathway disorders and cerebral glucose metabolism disorders. Therefore, some researchers believe that the insulin signaling pathway and cerebral glucose metabolism homeostasis play an important role in AD, and even put forward the hypothesis that AD is "type 3 diabetes".

    Atherosclerosis

    Atherosclerosis(AS) vasculopathy is one of the leading causes of disability and death in patients with type 2 diabetes. Ultimately, most diabetic patients die from AS-related complications. Insulin secretion and insulin resistance are the main pathophysiological features of type 2 diabetes. Insulin receptors are widely distributed in various organs and tissues of the body, and activation of the insulin receptor signaling pathway plays an important role in maintaining the normal physiological functions of cells.

    Cancer

    Insulin and insulin analogs bind to insulin receptors, insulin-like growth factor receptors and hybrid receptors, activate intracellular mitogen-activated protein kinase signaling pathways, phosphatidylinositol 3-kinase signaling pathways, and other possible signals pathway, promote cell mitosis, proliferation and anti-apoptosis, and increase the risk of tumor formation and carcinogenesis metastasis.

    Nonalcoholic fatty liver

    The exact pathogenesis of nonalcoholic fatty liver disease is still unclear, but the second-strike theory is more prevalent. This theory suggests that insulin resistance causes liver fat deposition to become a hit in the pathogenesis of nonalcoholic fatty liver disease. The occurrence of oxidative stress and lipid peroxidation on the second stroke will eventually lead to the occurrence of nonalcoholic fatty liver disease! The researchers found that insulin resistance and glucose metabolism disorder are nonalcoholic in rats by establishing a high-fat rat model. The onset and important factors in the development of fatty liver disease and also related to the prognosis of nonalcoholic fatty liver disease suggest that insulin resistance is not only the first blow but also the second blow!

References:

  1. Ho, C. K., Rahib, L., Liao, J. C., Sriram, G., & Dipple, K. M. (2015). Mathematical modeling of the insulin signal transduction pathway for prediction of insulin sensitivity from expression data. Molecular Genetics & Metabolism, 114(1), 66-72.
  2. Chakraborty, C., Doss, C. G., Bandyopadhyay, S., & Agoramoorthy, G. (2014). Influence of mirna in insulin signaling pathway and insulin resistance: micro-molecules with a major role in type-2 diabetes. Wiley Interdisciplinary Reviews Ran, 5(5), 697.
  3. Ho, C. K., Sriram, G., & Dipple, K. M. (2016). Insulin sensitivity predictions in individuals with obesity and type ii diabetes mellitus using mathematical model of the insulin signal transduction pathway. Molecular Genetics & Metabolism, 119(3), 288-292.
  4. Pérezhedo, M., Rivera Perez, C., & Noriega, F. G. (2013). The insulin/tor signal transduction pathway is involved in the nutritional regulation of juvenile hormone synthesis in Aedes aegypti. Insect Biochemistry & Molecular Biology, 43(6), 495.
  5. Zeng, Y., Zhang, L., & Hu, Z. (2016). Cerebral insulin, insulin signaling pathway, and brain angiogenesis. Neurological Sciences, 37(1), 9-16.

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