1. Insulin and glucose uptake in muscle and adipose tissue
Aleksi Huuha & Iiro Repo

2. 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

3. 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

4. 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

5. 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

6. 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

7. 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

8. 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

9. 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

10. 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.
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