Insulin: Difference between revisions
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[[Image:Insulin.gif|right|Insulin chain A and B. For interactive figures, scroll down and click on green links]] | [[Image:Insulin.gif|right|frame|Insulin chain A and B. For interactive figures, scroll down and click on green links]] | ||
'''Insulin''' is a peptide hormone that helps to maintain blood sugar within a healthy range by regulating [[Carbohydrate Metabolism|carbohydrate]] and lipid metabolism throughout the body | '''Insulin''' is a peptide [[hormone]] that helps to maintain blood sugar within a healthy range by regulating [[Carbohydrate Metabolism|carbohydrate]] and lipid metabolism throughout the body. It is secreted by specialized cells in the pancreas and acts by binding to [[insulin receptor|insulin receptors]] on other cells. Insulin in its mature form contains two peptide chains connected by [[Cystine|disulfide crosslinks]], and occurs either as monomer or as hexamer. Administering insulin in carefully determined doses at the appropriate times is used in managing [[diabetes]], a chronic condition where the body fails to maintain blood sugar levels by itself. | ||
*'''Proinsulin''' is the insulin precursor which is converted in the pancreas to insulin and C-peptide<ref>PMID:403392</ref>. | |||
*'''Leginsulin''' is an insulin-like peptide found in legumes <ref>PMID:30442953</ref>. | |||
*'''Insulin lispro''' is recombinant insulin which has more rapid absorption than regular insulin<ref>PMID:9339963</ref>. See also [[Insulin lispro]]. | |||
*'''Insulin glargine''' is a long-acting insulin <ref>PMID:10730548</ref>. See also [[Insulin glargine]]. | |||
*'''Insulin detemir''' is a long-acting analog used for patients with type 1 or 2 diabetes <ref>PMID:23110609</ref>. | |||
*'''Insulin desB30''' is an insulin with B chain lacking residue 30 (The) <ref>PMID:31039402</ref>. | |||
==Other Proteopedia pages about or relating to insulin== | ==Other Proteopedia pages about or relating to insulin== | ||
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[[Diabetes & Hypoglycemia]]<br> | [[Diabetes & Hypoglycemia]]<br> | ||
[[Insulin (Hebrew)]]<br> | [[Insulin (Hebrew)]]<br> | ||
[[Insulin | [[Insulin aspart]]<br> | ||
[[Insulin_mo-or-sl|Insulin and pro-insulin (Hebrew)]]<br> | [[Insulin_mo-or-sl|Insulin and pro-insulin (Hebrew)]]<br> | ||
[[Insulin-Degrading Enzyme]]<br> | [[Insulin-Degrading Enzyme]]<br> | ||
[[Molecular_Playground/Insulin]]<br> | [[Molecular_Playground/Insulin]]<br> | ||
[[Insulin Structure & Function]]<br> | [[Insulin Structure & Function]]<br> | ||
[[Insulin | [[Insulin signal transduction pathway]]<br> | ||
'''Proteins that interact with insulin''' | '''Proteins that interact with insulin''' | ||
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[[Insulin receptor]]<br> | [[Insulin receptor]]<br> | ||
[[Insulin-like growth factor receptor]]<br> | [[Insulin-like growth factor receptor]]<br> | ||
'''Tutorials we would love to see''' | '''Tutorials we would love to see''' | ||
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[[Image:Glucose insulin day.png|300px|left|thumb|Schematic of daily changes of blood sugar (red) and insulin (blue)]] | [[Image:Glucose insulin day.png|300px|left|thumb|Schematic of daily changes of blood sugar (red) and insulin (blue)]] | ||
Our blood sugar level (i.e. glucose concentration) varies over time with food intake and exercise, but has to remain in a narrow range so we stay healthy (not become hyperglycemic or hypoglycemic). Insulin, together with [[glucagon]], regulates blood sugar levels by changing fuel metabolism in all cells <ref>https://www.yourhormones.info/hormones/insulin/</ref> | Our blood sugar level (i.e. glucose concentration) varies over time with food intake and exercise, but has to remain in a narrow range so we stay healthy (not become hyperglycemic or hypoglycemic). Insulin, together with [[glucagon]], regulates blood sugar levels by changing fuel metabolism in all metabolic cells (e.g. liver, fat, kidney, muscle and nerve cells) on a timescale of minutes and hours<ref>https://www.yourhormones.info/hormones/insulin/</ref><ref>PMID:10927996</ref><ref>DOI:10.1111/dom.13402</ref>. In simplest terms, the presence of insulin in the blood signals the well-fed stage, while the presence of glucagon signals the fasting stage. | ||
Biosynthesis and processing of insulin occurs in the [https://en.wikipedia.org/wiki/Beta_cell beta cells] of the pancreas. The beta cells are found in the islets of Langerhans, which also contain the alpha cells that synthesize glucagon. Insulin is made as a 110 amino acid pre-proinsulin, which is processed to the mature 51 amino acid insulin and targeted to secretory vesicles. In a healthy adult, about 200 units of insulin are available in the pancreas, of which 30-50 units are secreted daily<ref>https://www.britannica.com/science/insulin</ref>. With a unit of insulin corresponding to 0.0347 mg mature insulin <ref>https://www.who.int/biologicals/expert_committee/BS_2143_Human_Recombinant_Insulin_final.pdf</ref>, the body contains only about 7 mg of insulin. In its stored form, insulin is a hexamer complexed to zinc ions. | Biosynthesis and processing of insulin occurs in the [https://en.wikipedia.org/wiki/Beta_cell beta cells] of the pancreas. The beta cells are found in the islets of Langerhans, which also contain the alpha cells that synthesize glucagon. Insulin is made as a 110 amino acid pre-proinsulin, which is processed to the mature 51 amino acid insulin and targeted to secretory vesicles. In a healthy adult, about 200 units of insulin are available in the pancreas, of which 30-50 units are secreted daily<ref>https://www.britannica.com/science/insulin</ref>. With a unit of insulin corresponding to 0.0347 mg mature insulin <ref>https://www.who.int/biologicals/expert_committee/BS_2143_Human_Recombinant_Insulin_final.pdf</ref>, the body contains only about 7 mg of insulin. In its stored form, insulin is a hexamer complexed to zinc ions. | ||
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<StructureSection load='' size='350' side='right' scene='82/821037/Ribbon/1' caption=''> | <StructureSection load='' size='350' side='right' scene='82/821037/Ribbon/1' caption=''> | ||
===Structure of mature insulin monomer=== | ===Structure of mature insulin monomer=== | ||
<scene name='82/821037/Ribbon/1'> | Mature insulin (<scene name='82/821037/Ribbon/1'>reload initial figure</scene>) contains two chains, A <jmol> | ||
<jmolLink> | <jmolLink> | ||
<script>select :A; selectionHalos ON; delay 0.5;selectionHalos OFF; </script> | <script> select backbone and *:A; selectionHalos ON; delay 0.5;selectionHalos OFF; </script> | ||
<text>(☼)</text> | <text>(☼)</text> | ||
</jmolLink> | </jmolLink> | ||
</jmol> and B <jmol> | </jmol> and B <jmol> | ||
<jmolLink> | <jmolLink> | ||
<script>select :B; selectionHalos ON; delay 0.5;selectionHalos OFF; </script> | <script> select backbone and *:B; selectionHalos ON; delay 0.5;selectionHalos OFF; </script> | ||
<text>(☼)</text> | <text>(☼)</text> | ||
</jmolLink> | </jmolLink> | ||
</jmol>, held together by disulfide bonds <jmol> | </jmol>, held together by disulfide bonds <jmol> | ||
<jmolLink> | <jmolLink> | ||
<script>select (:A or :B) and cys; selectionHalos ON; delay 0.5;selectionHalos OFF; </script> | <script> select (*:A or *:B) and cys and (*.CA or *.SG); selectionHalos ON; delay 0.5;selectionHalos OFF; </script> | ||
<text>(☼)</text> | <text>(☼)</text> | ||
</jmolLink> | </jmolLink> | ||
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[[Image:Proinsulin.jpg|400 px]] | [[Image:Proinsulin.jpg|400 px]] | ||
Insulin | Insulin is synthesized as so-called preproinsulin and gets targeted into the ER and Golgi via a signal sequence, which then is removed to yield proinsulin. <scene name='82/821037/Proinsulin/1'>Proinsulin</scene> is processed by several proteases in the Golgi apparatus to form 3 separate chains, named B, C and A (see figure above)<ref>PMID:15289650</ref>. Chains B and A are linked through disulfide bonds, and are the components of mature insulin. | ||
<jmol> | <jmol> | ||
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<jmolLink> | <jmolLink> | ||
<script>anim mode loop; anim on</script> | <script>anim mode loop; anim on</script> | ||
<text>disordered</text></jmolLink></jmol> in the proinsulin structure, is no longer connected to insulin after processing | <text>disordered</text></jmolLink></jmol> in the proinsulin structure, is no longer connected to insulin after processing, but is secreted into the blood stream as so-called C-peptide. C-peptide has a role in diagnostics; it is used as a measure of how much insulin is made endogenously in patients who receive insulin as treatment (insulin is administered as mature protein, so it does not contain any C-peptide)<ref>https://en.wikipedia.org/wiki/C-peptide</ref>. | ||
===Storage=== | ===Storage=== | ||
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===Receptor interaction=== | ===Receptor interaction=== | ||
The insulin receptor belongs to the class of tyrosine kinase receptors | The insulin receptor belongs to the class of [[tyrosine kinase]] receptors. Many of these receptors occur as monomers that dimerize upon ligand binding, bringing the intracellular tytrosine kinase domains (the endodomains) into close vicinity. In contrast, the insulin receptor (just like the closely related [[IGF1#Stimulating_interaction_:_IGF-1_-_IGF-1R|IGF-1 receptor]]) is a dimer even in the absence of ligand, crosslinked by disulfide bridges. The unliganded receptor ectodomain has the shape of a Λ (an inverted V), keeping the transmembrane segments and the endodomains at a distance. | ||
Cryo-electronmicroscopy studies have shown a [http://proteopedia.org/wiki/images/0/05/LambdaTee.gif Λ to T transition] when insulin binds. One structure resolves four <scene name='82/821037/Spacefilling/5'>insulin binding sites</scene> (1, 1', 2, 2') per receptor dimer<ref name="ecto">DOI:10.1101/679233 </ref> (coordinates not yet available). Contacts with insulin are distinct in site 1 vs. site 2, as are the conformations of insulin<ref>PMID:25092300</ref>. For comparison to the initial scene, here is another view of the <scene name='82/821037/Ribbon/2'>contact residues</scene>. | [[Cryo-EM|Cryo-electronmicroscopy]] studies have shown a [http://proteopedia.org/wiki/images/0/05/LambdaTee.gif Λ to T transition] when insulin binds. One structure resolves four <scene name='82/821037/Spacefilling/5'>insulin binding sites</scene> (1, 1', 2, 2') per receptor dimer<ref name="ecto">DOI:10.1101/679233 </ref> (coordinates not yet available). Contacts with insulin are distinct in site 1 vs. site 2, as are the conformations of insulin<ref>PMID:25092300</ref>. For comparison to the initial scene, here is another view of the <scene name='82/821037/Ribbon/2'>contact residues</scene>. | ||
<scene name='82/821037/Receptor_bound/1'>Binding sites 1 and 1'</scene> had already been characterized in previous structures<ref>PMID:29512653</ref><ref name="gutmann"/>. Insulin makes contacts with both the N-terminal domain and the CT alpha helix, structural elements that are far apart in the unliganded conformation. Thus, binding of insulin in site 1 requires a large structural rearrangement that activates the tyrosine kinase activity of the endodomain by bringing the two kinase domains close for autophosphorylation. | <scene name='82/821037/Receptor_bound/1'>Binding sites 1 and 1'</scene> had already been characterized in previous structures<ref>PMID:29512653</ref><ref name="gutmann"/>. Insulin makes contacts with both the N-terminal domain <jmol> | ||
<jmolLink> | |||
<script> select *:A; selectionHalos ON; delay 0.5;selectionHalos OFF; </script> | |||
<text>(☼)</text> | |||
</jmolLink> | |||
</jmol> and the CT alpha helix <jmol> | |||
<jmolLink> | |||
<script> select *:P; selectionHalos ON; delay 0.5;selectionHalos OFF; </script> | |||
<text>(☼)</text> | |||
</jmolLink> | |||
</jmol>, structural elements that are far apart in the unliganded conformation. Thus, binding of insulin in site 1 requires a large structural rearrangement that activates the tyrosine kinase activity of the endodomain by bringing the two kinase domains close for autophosphorylation. | |||
</StructureSection> | </StructureSection> | ||
==Insulin 3D structures== | |||
[[Insulin 3D Structures]] | |||
==See also== | ==See also== | ||
