Editing Insulin resistance (section)

=== Molecular mechanism ===
At the molecular level, a cell senses insulin through insulin receptors, with the signal propagating through a signaling cascade collectively known as [[PI3K/AKT/mTOR pathway|PI3K/Akt/mTOR signaling pathway]].<ref name=":1">{{cite journal | vauthors = Wang G | title = Singularity analysis of the AKT signaling pathway reveals connections between cancer and metabolic diseases | journal = Physical Biology | volume = 7 | issue = 4 | pages = 046015 | date = December 2010 | pmid = 21178243 | doi = 10.1088/1478-3975/7/4/046015 | bibcode = 2010PhBio...7d6015W | s2cid = 40064689 }}</ref> Recent studies suggested that the pathway may operate as a [[Bistability#In biological and chemical systems|bistable]] switch under physiologic conditions for certain types of cells, and insulin response may well be a threshold phenomenon<!--Q7798100-->.<ref name=":0">{{cite journal | vauthors = Wang G | title = Raison d'être of insulin resistance: the adjustable threshold hypothesis | journal = Journal of the Royal Society, Interface | volume = 11 | issue = 101 | pages = 20140892 | date = December 2014 | pmid = 25320065 | pmc = 4223910 | doi = 10.1098/rsif.2014.0892 }}</ref><ref name=":1" /><ref>{{cite journal | vauthors = Wang G | title = Optimal homeostasis necessitates bistable control | journal = Journal of the Royal Society, Interface | volume = 9 | issue = 75 | pages = 2723–34 | date = October 2012 | pmid = 22535698 | pmc = 3427521 | doi = 10.1098/rsif.2012.0244 }}</ref> The pathway's sensitivity to insulin may be blunted by many factors such as lipolysis of free fatty acids,<ref>{{cite journal | vauthors = Lucidi P, Rossetti P, Porcellati F, Pampanelli S, Candeloro P, Andreoli AM, Perriello G, Bolli GB, Fanelli CG | display-authors = 6 | title = Mechanisms of insulin resistance after insulin-induced hypoglycemia in humans: the role of lipolysis | journal = Diabetes | volume = 59 | issue = 6 | pages = 1349–57 | date = June 2010 | pmid = 20299466 | pmc = 2874695 | doi = 10.2337/db09-0745 }}</ref> causing insulin resistance. From a broader perspective, however, sensitivity tuning (including sensitivity reduction) is a common practice for an organism to adapt to the changing environment or metabolic conditions.<ref>{{cite journal | vauthors = Wang G, Zhang M | title = Tunable ultrasensitivity: functional decoupling and biological insights | journal = Scientific Reports | volume = 6 | pages = 20345 | date = February 2016 | pmid = 26847155 | pmc = 4742884 | doi = 10.1038/srep20345 | bibcode = 2016NatSR...620345W }}</ref> Pregnancy, for example, entails significant metabolic changes, during which the mother must decrease the insulin sensitivity of her muscles to conserve more glucose for both the maternal and fetal brains. This adaptation can occur by elevating the response threshold, thereby delaying the onset of sensitivity. This is achieved through the secretion of [[placental growth factor]], which interferes with the interaction between [[insulin receptor substrate]] (IRS) and PI3K. This concept forms the basis of the adjustable threshold hypothesis of insulin resistance.<ref name=":0" />

Insulin resistance has been proposed to be a reaction to excess nutrition by [[superoxide dismutase]] in cell [[mitochondria]] that acts as an antioxidant defense mechanism. This link seems to exist under diverse causes of insulin resistance. It also is based on the finding that insulin resistance may be reversed rapidly by exposing cells to mitochondrial uncouplers, [[electron transport chain]] inhibitors, or mitochondrial [[superoxide dismutase mimetics]].<ref>{{cite journal | vauthors = Hoehn KL, Salmon AB, Hohnen-Behrens C, Turner N, Hoy AJ, Maghzal GJ, Stocker R, Van Remmen H, Kraegen EW, Cooney GJ, Richardson AR, James DE | display-authors = 6 | title = Insulin resistance is a cellular antioxidant defense mechanism | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 106 | issue = 42 | pages = 17787–92 | date = October 2009 | pmid = 19805130 | pmc = 2764908 | doi = 10.1073/pnas.0902380106 | bibcode = 2009PNAS..10617787H | doi-access = free }}</ref>