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Insulin and glucose uptake in muscle and adipose tissue
Aleksi Huuha & Iiro Repo
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Introduction Insulin Glucagon Glucose transporters (GLUT)
Peptide hormone Anabolic, increases the storage of glucose, amino acids and fatty acids Glucagon Antagonist of insulin Catabolic, releases glucose, amino acids and fatty acids from the storages Glucose transporters (GLUT) Membrane proteins Multiple different types
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Insulin Insulin is a polypeptide containing two chains of amino acids linked by disulfide bridges It is synthesized as a part of larger preprohormone in the rough ER of the β-cells of Langerhans islets in pancreas Preproinsulin is processed and proinsulin is formed Then proinsulin is cleaved internally at two sides to yield insulin and C peptide (connecting peptide) Insulin is transported to the Golgi apparatus and packaged into vesicles, which are stored inside the β-cells
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Glucose transporters Glucose mostly enters cells by facilitated diffusion, which is mediated by glucose transporters (GLUTs) GLUTs are transmembrane proteins that span the cell membrane 12 times and have their N- and C-terminals inside the cell Insulin stimulates glucose uptake in muscle, adipose and some other tissues by increasing the number of GLUTs in the cell membrane GLUT2 is the glucose transporter for example in β-cells of Langerhans islets in pancreas GLUT4 is the glucose transporter in muscle and adipose tissue that is stimulated by insulin
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Insulin secretion Glucose concentration increases in blood activates secretion of insulin from β-cells of Langerhans islets in pancreas When the glucose concentration in blood increases, glucose is transported into the β-cells through GLUT2-transporters by facilitated diffusion Glucose is phosphorylated by glucokinase into glucose-6- phosphate, which is then used for ATP production ATP induces the closing of K+- channels, which leads to depolarisation of the cell and opening of Ca2+-channels Ca2+ induces exocytosis of insulin to the bloodstream
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Insulin receptor Insulin receptor is a tetramer, which consists of two α- and two β-subunits It has a molecular weight of approximately 340 kDa Binding of insulin triggers autophosphorylation of the β-subunits on tyrosine residues, which in turn triggers phosphorylations and dephosphorylations of some cytoplasmic proteins Insulin receptor substrate 1 (IRS-1) is one of the mediators of the insulin effects in humans α α β β
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Glucose uptake When the concentration of glucose is high and the insulin receptors are activated by insulin, GLUT4-transporters stored in vesicles are transferred to the cell membrane which leads to uptake of glucose Glucose is stored in muscles as glycogen and in adipose tissue as fat ~ 90 % of insulin-stimulated glucose uptake occurs in skeletal muscle ~ 10% in adipose tissue
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Effects of insulin Increases the rates of glucose uptake and glycolysis in muscle and adipose tissue Stimulates glycogen synthesis Stimulates fatty acid and triacylglycerol synthesis Stimulates cholesterol synthesis Increases rate of transport of some amino acids into tissues Stimulates protein synthesis Inhibits glycogenolysis and gluconeogenesis Decreases lipolysis Decreases the rate of protein degradation in muscle tissue
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Insulin resistance In insulin resistance the insulin signal transduction is dysfunctional Alterations in receptor expression, binding, phosphorylation state or kinase activity Overall, it is usually caused by some genetic defects combined with environmental stresses Ability to remove and process glucose from bloodstream is defected Constantly high blood glucose Increased chance of type 2 diabetes
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References Barrett K.E., Barman S.M., Boitano S. & Brooks H.L. (2016) Ganong’s Review of Medical Physiology. McGraw-Hill Education. Chakraborty C. (2006) Biochemical and Molecular Basis of Insulin Resistance. Current Protein and Peptide Science. Figure 1: Dorland's Medical Dictionary for Health Consumers. © 2007 by Saunders, an imprint of Elsevier, Inc. Figure 2: Bryant N.J., Govers R. & James D.E. (2002) Regulated transport of the glucose transporter GLUT4. Figure 3: Figure 4: Barrett K.E., Barman S.M., Boitano S. & Brooks H.L. (2016) Ganong’s Review of Medical Physiology. McGraw-Hill Education. Figure 5: Figure 6:
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