User:Karsten Theis/Insulin

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<StructureSection load='' size='350' side='right' scene='User:Whitney_Stoppel/sandbox1/Human_insulin2/1' caption='Human insulin chain A (grey) and chain B (green), [[3i40]]'>
<StructureSection load='' size='350' side='right' scene='User:Whitney_Stoppel/sandbox1/Human_insulin2/1' caption='Human insulin chain A (grey) and chain B (green), [[3i40]]'>
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===Structure of mature insulin===
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===Structure of mature insulin monomer===
Mature insulin contains two chains, A and B, held together by disulfide bonds and non-covalent interactions. The <scene name='82/821037/Spacefilling/2'>surface of insulin</scene> contains quite a few hydrophobic side chains, which form protein:protein contacts when insulin forms hexamers or binds to its receptor. Select coloring of the side chains below to explore the surface properties.
Mature insulin contains two chains, A and B, held together by disulfide bonds and non-covalent interactions. The <scene name='82/821037/Spacefilling/2'>surface of insulin</scene> contains quite a few hydrophobic side chains, which form protein:protein contacts when insulin forms hexamers or binds to its receptor. Select coloring of the side chains below to explore the surface properties.
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These two chains are joined by disulfide bonds, which are shown in yellow. This single piece made up of the A- and B-chains is the active form of the insulin hormone. This is the form that binds the insulin receptor on fat or muscle cells in the body, singling them to take up glucose, or sugar, from the blood and save it for later. Insulin occurs in two states, <scene name='82/821037/Rvst/1'>T or R</scene>. (A) <scene name='82/821037/T6/1'>T6 hexamer</scene>, (B) T3Rf3 hexamer and (C) R6 hexamer. Coordinates were obtained from PDB entries 4INS, 1TRZ and 1ZNJ
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These two chains are joined by disulfide bonds, which are shown in yellow.
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===Targeting, processing, and storage===
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===Targeting and processing===
[[Image:Proinsulin.jpg|400 px]]
[[Image:Proinsulin.jpg|400 px]]
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<script>anim mode loop; anim on</script>
<script>anim mode loop; anim on</script>
<text>disordered</text></jmolLink></jmol> in the proinsulin structure, is an independent peptide whose biological role after processing is unclear.
<text>disordered</text></jmolLink></jmol> in the proinsulin structure, is an independent peptide whose biological role after processing is unclear.
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===Storage===
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Before insulin is secreted, it is able to pair-up with itself and form a dimer by forming hydrogen bonds between the ends of two B-chains, which then combine in threes to form a hexamer (a trimer of dimers to be exact). In crystal structures, insulin occurs in two states, <scene name='82/821037/Rvst/1'>T or R</scene>. In an animation (takes long to load), the <scene name='82/821037/Rvst/2'>dimer organisation is conserved in the R and the T state</scene>.
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Before insulin is secreted, it is able to pair-up with itself and form a dimer by forming hydrogen bonds between the ends of two B-chains. These <scene name='User:Whitney_Stoppel/sandbox1/Insulin_dimer/2'>hydrogen bonds</scene> are shown above in white. Then, 3 dimers can come together in the presence of zinc ions and form a hexamer. Insulin is stored in the <scene name='User:Whitney_Stoppel/sandbox1/Insulin_hexamer/4'>hexameric form</scene> in the body. This <scene name='User:Whitney_Stoppel/sandbox1/Insulin_ph7/2'>scene highlights</scene> the hydrophobic (gray) and polar (purple) parts of an insulin monomer at a pH of 7.
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(A) <scene name='82/821037/T6/1'>T6 hexamer</scene>, (B) T3Rf3 hexamer and (C) R6 hexamer. Coordinates were obtained from PDB entries 4INS, 1TRZ and 1ZNJ
</StructureSection>
</StructureSection>

Revision as of 01:57, 13 July 2019

Insulin is a peptide hormone that controls carbohydrate metabolism and storage in the human body[1][2]. It is secreted by specialized cells in the pancreas, enters the bloodstream and reaches other cells. There, it binds to the extracellular side of the insulin receptor, triggering tyrosine kinase activity within the target cell, which in turn regulates glucose uptake, metabolism and storage.

Contents

Function

Insulin, together with glucagon, regulates blood sugar levels by changing fuel metabolism in all cells [3] within minutes and hours. The presence of insulin in the blood signals the well-fed stage, while the presence of glucagon signals the fasting stage. [1]

  1. Biosynthesis

"The pancreas of a normal adult contains approximately 200 units of insulin, and the average daily secretion of insulin into the circulation in healthy individuals ranges from 30 to 50 units. https://www.britannica.com/science/insulin" 1 IU = 0.0347 mg

foo1[4]


  1. Secretion and transport

[5]

  1. Receptor interaction

foo3[6]

  1. Degradation

foo4[7]

Receptor recycling [8]

The body is able to sense the concentration of glucose in the blood and respond by secreting insulin, which is produced by beta cells in the pancreas. Insulin then binds to the insulin receptor, changing its conformation [9]. Depending on cell type and the presence of other signals (glucogon, epinephrine), the cell will modify its metabolism.

Disease and Treatment

In patients with diabetes, insulin signalling is compromised[10].

Type I: Insulin is not produced


Type II: Insulin is produced, but receptor does not trigger signal: [11]

[12]

Synthesis of human insulin in E. coli is important to producing insulin for the treatment of type 1 diabetes. It is believed that the hydrophobic sections on the B-chain cause insulin aggregation which initially caused problems in the manufacture and storage of insulin for pharmaceutical use.

In patients with diabetes, insulin signalling is compromised[13]. Synthesis of human insulin in E. coli is important to producing insulin for the treatment of type 1 diabetes. It is believed that the hydrophobic sections on the B-chain cause insulin aggregation which initially caused problems in the manufacture and storage of insulin for pharmaceutical use.

Structure

Human insulin chain A (grey) and chain B (green), 3i40

Drag the structure with the mouse to rotate

References

  1. ↑ Sonksen P, Sonksen J. Insulin: understanding its action in health and disease. Br J Anaesth. 2000 Jul;85(1):69-79. PMID:10927996
  2. ↑ Weiss MA, Lawrence MC. A thing of beauty: Structure and function of insulin's "aromatic triplet". Diabetes Obes Metab. 2018 Sep;20 Suppl 2:51-63. doi: 10.1111/dom.13402. PMID:30230175 doi:http://dx.doi.org/10.1111/dom.13402
  3. ↑ https://www.yourhormones.info/hormones/insulin/
  4. ↑ https://www.who.int/biologicals/expert_committee/BS_2143_Human_Recombinant_Insulin_final.pdf
  5. ↑ "https://www.diabetesselfmanagement.com/diabetes-resources/definitions/portal-vein/"
  6. ↑ https://pdb101.rcsb.org/motm/182
  7. ↑ Duckworth WC, Bennett RG, Hamel FG. Insulin degradation: progress and potential. Endocr Rev. 1998 Oct;19(5):608-24. doi: 10.1210/edrv.19.5.0349. PMID:9793760 doi:http://dx.doi.org/10.1210/edrv.19.5.0349
  8. ↑ Haeusler RA, McGraw TE, Accili D. Biochemical and cellular properties of insulin receptor signalling. Nat Rev Mol Cell Biol. 2018 Jan;19(1):31-44. doi: 10.1038/nrm.2017.89. Epub 2017 , Oct 4. PMID:28974775 doi:http://dx.doi.org/10.1038/nrm.2017.89
  9. ↑ Gutmann T, Kim KH, Grzybek M, Walz T, Coskun U. Visualization of ligand-induced transmembrane signaling in the full-length human insulin receptor. J Cell Biol. 2018 May 7;217(5):1643-1649. doi: 10.1083/jcb.201711047. Epub 2018, Feb 16. PMID:29453311 doi:http://dx.doi.org/10.1083/jcb.201711047
  10. ↑ https://www.endotext.org/section/diabetes/
  11. ↑ Samuel VT, Shulman GI. The pathogenesis of insulin resistance: integrating signaling pathways and substrate flux. J Clin Invest. 2016 Jan;126(1):12-22. doi: 10.1172/JCI77812. Epub 2016 Jan 4. PMID:26727229 doi:http://dx.doi.org/10.1172/JCI77812
  12. ↑ doi: https://dx.doi.org/10.1530/endoabs.56.PL5
  13. ↑ https://www.endotext.org/section/diabetes/
  14. ↑ Davidson HW. (Pro)Insulin processing: a historical perspective. Cell Biochem Biophys. 2004;40(3 Suppl):143-58. PMID:15289650

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Karsten Theis

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