Editing Beta cell (section)

== Insulin secretion ==
[[File:Insulin secretion.png|alt=A diagram of the Consensus Model of glucose-stimulated insulin secretion|thumb|262x262px|The triggering pathway of glucose-stimulated insulin secretion]]
In beta cells, insulin release is stimulated primarily by glucose present in the blood.<ref name="Boland_2017"/> As circulating glucose levels rise, such as after ingesting a meal, insulin is secreted in a dose-dependent fashion.<ref name="Boland_2017" /> This system of release is commonly referred to as glucose-stimulated insulin secretion (GSIS).<ref>{{cite journal | vauthors = Komatsu M, Takei M, Ishii H, Sato Y | title = Glucose-stimulated insulin secretion: A newer perspective | journal = Journal of Diabetes Investigation | volume = 4 | issue = 6 | pages = 511–516 | date = November 2013 | pmid = 24843702 | pmc = 4020243 | doi = 10.1111/jdi.12094 }}</ref> There are four key events to the triggering pathway of GSIS: [[Glucose transporter|GLUT]] dependent glucose uptake, glucose metabolism, [[ATP-sensitive potassium channel|K<sub>ATP</sub> channel]] closure, and the opening of voltage gated calcium channels causing insulin granule fusion and exocytosis.<ref name="Kalwat_2017">{{cite journal | vauthors = Kalwat MA, Cobb MH | title = Mechanisms of the amplifying pathway of insulin secretion in the β cell | journal = Pharmacology & Therapeutics | volume = 179 | pages = 17–30 | date = November 2017 | pmid = 28527919 | pmc = 7269041 | doi = 10.1016/j.pharmthera.2017.05.003 }}</ref><ref name="Ramadan_2011">{{cite journal | vauthors = Ramadan JW, Steiner SR, O'Neill CM, Nunemaker CS | title = The central role of calcium in the effects of cytokines on beta-cell function: implications for type 1 and type 2 diabetes | journal = Cell Calcium | volume = 50 | issue = 6 | pages = 481–490 | date = December 2011 | pmid = 21944825 | pmc = 3223281 | doi = 10.1016/j.ceca.2011.08.005 }}</ref>

[[Voltage dependent calcium channel|Voltage-gated calcium channels]] and [[ATP sensitive potassium ion channel|ATP-sensitive potassium ion channels]] (K<sub>ATP</sub> channels) are embedded in the plasma membrane of beta cells.<ref name="Ramadan_2011" /><ref name="Ashcroft_1990">{{cite journal | vauthors = Ashcroft FM, Rorsman P | title = ATP-sensitive K+ channels: a link between B-cell metabolism and insulin secretion | journal = Biochemical Society Transactions | volume = 18 | issue = 1 | pages = 109–111 | date = February 1990 | pmid = 2185070 | doi = 10.1042/bst0180109 }}</ref> Under non-glucose stimulated conditions, the K<sub>ATP</sub> channels are open and the voltage gated calcium channels are closed.<ref name="Boland_2017" /><ref name=":0">{{cite journal | vauthors = Ashcroft FM, Rorsman P | title = K(ATP) channels and islet hormone secretion: new insights and controversies | journal = Nature Reviews. Endocrinology | volume = 9 | issue = 11 | pages = 660–669 | date = November 2013 | pmid = 24042324 | doi = 10.1038/nrendo.2013.166 | pmc = 5890885 }}</ref> Via the K<sub>ATP</sub> channels, potassium ions move out of the cell, down their concentration gradient, making the inside of the cell more negative with respect to the outside (as potassium ions carry a positive charge).<ref name="Boland_2017" /> At rest, this creates a [[potential difference]] across the cell surface membrane of -70mV.<ref name="MacDonald_2005">{{cite journal | vauthors = MacDonald PE, Joseph JW, Rorsman P | title = Glucose-sensing mechanisms in pancreatic beta-cells | journal = Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences | volume = 360 | issue = 1464 | pages = 2211–2225 | date = December 2005 | pmid = 16321791 | pmc = 1569593 | doi = 10.1098/rstb.2005.1762 }}</ref>

When the glucose concentration outside the cell is high, glucose molecules move into the cell by [[facilitated diffusion]], down its concentration gradient through [[glucose transporter]]s (GLUT).<ref>{{cite journal | vauthors = De Vos A, Heimberg H, Quartier E, Huypens P, Bouwens L, Pipeleers D, Schuit F | title = Human and rat beta cells differ in glucose transporter but not in glucokinase gene expression | journal = The Journal of Clinical Investigation | volume = 96 | issue = 5 | pages = 2489–2495 | date = November 1995 | pmid = 7593639 | pmc = 185903 | doi = 10.1172/JCI118308 }}</ref> Rodent beta cells primarily express the [[GLUT2]] isoform, whereas human beta cells, although also expressing GLUT2, mainly make use of [[GLUT1]] and [[GLUT3]] isoforms.<ref>{{cite journal | vauthors = Berger C, Zdzieblo D | title = Glucose transporters in pancreatic islets | journal = Pflugers Archiv | volume = 472 | issue = 9 | pages = 1249–1272 | date = September 2020 | pmid = 32394191 | pmc = 7462922 | doi = 10.1007/s00424-020-02383-4 }}</ref><ref>{{cite journal | vauthors = Rorsman P, Ashcroft FM | title = Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men | journal = Physiological Reviews | volume = 98 | issue = 1 | pages = 117–214 | date = January 2018 | pmid = 29212789 | doi = 10.1152/phy }}</ref> Since beta cells use [[glucokinase]] to catalyze the first step of [[glycolysis]], metabolism only occurs around physiological [[blood glucose]] levels and above.<ref name="Boland_2017" /> Metabolism of glucose produces [[Adenosine triphosphate|ATP]], which increases the ATP to [[Adenosine diphosphate|ADP]] ratio.<ref name="JCI2015">{{cite journal | vauthors = Santulli G, Pagano G, Sardu C, Xie W, Reiken S, D'Ascia SL, Cannone M, Marziliano N, Trimarco B, Guise TA, Lacampagne A, Marks AR | title = Calcium release channel RyR2 regulates insulin release and glucose homeostasis | journal = The Journal of Clinical Investigation | volume = 125 | issue = 5 | pages = 1968–1978 | date = May 2015 | pmid = 25844899 | pmc = 4463204 | doi = 10.1172/JCI79273 }}</ref>

The K<sub>ATP</sub> channels close when the ATP to ADP ratio rises.<ref name="Ashcroft_1990" /> The closure of the K<sub>ATP</sub> channels causes the outward potassium ion current to diminish, leading to inward currents of potassium ions dominating.<ref name=":0" /> As a result, the potential difference across the membrane becomes more positive (as potassium ions accumulate inside the cell).<ref name="MacDonald_2005" /> This change in potential difference opens the [[voltage-gated calcium channels]], which allows calcium ions from outside the cell to move into the cell down their concentration gradient.<ref name="MacDonald_2005" /> When the calcium ions enter the cell, they cause [[vesicle (biology)|vesicles]] containing insulin to move to, and fuse with, the cell surface membrane, releasing insulin by [[exocytosis]] into the pancreatic capillaries.<ref>{{cite journal | vauthors = Lang V, Light PE | title = The molecular mechanisms and pharmacotherapy of ATP-sensitive potassium channel gene mutations underlying neonatal diabetes | journal = Pharmacogenomics and Personalized Medicine | volume = 3 | pages = 145–161 | year = 2010 | pmid = 23226049 | pmc = 3513215 | doi = 10.2147/PGPM.S6969 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Edgerton DS, Kraft G, Smith M, Farmer B, Williams PE, Coate KC, Printz RL, O'Brien RM, Cherrington AD | title = Insulin's direct hepatic effect explains the inhibition of glucose production caused by insulin secretion | journal = JCI Insight | volume = 2 | issue = 6 | pages = e91863 | date = March 2017 | pmid = 28352665 | pmc = 5358484 | doi = 10.1172/jci.insight.91863 }}</ref><ref name=":1">{{cite journal | vauthors = Jansson L, Barbu A, Bodin B, Drott CJ, Espes D, Gao X, Grapensparr L, Källskog Ö, Lau J, Liljebäck H, Palm F, Quach M, Sandberg M, Strömberg V, Ullsten S, Carlsson PO | title = Pancreatic islet blood flow and its measurement | journal = Upsala Journal of Medical Sciences | volume = 121 | issue = 2 | pages = 81–95 | date = May 2016 | pmid = 27124642 | doi = 10.3109/03009734.2016.1164769 | pmc = 4900068 }}</ref> The venous blood then eventually empties into the hepatic portal vein.<ref name=":1" />

In addition to the triggering pathway, the amplifying pathway can cause increased insulin secretion without a further increase in intracellular calcium levels. The amplifying pathway is modulated by byproducts of glucose metabolism along with various intracellular signaling pathways; [[incretin]] hormone signaling being one important example.<ref name="Kalwat_2017" /><ref>{{cite journal | vauthors = Holst JJ, Gasbjerg LS, Rosenkilde MM | title = The Role of Incretins on Insulin Function and Glucose Homeostasis | journal = Endocrinology | volume = 162 | issue = 7 | pages = bqab065 | date = July 2021 | pmid = 33782700 | pmc = 8168943 | doi = 10.1210/endocr/bqab065 }}</ref>