Editing Insulin resistance

{{short description|Failure of cells to respond appropriately to insulin}}
{{more medical citations needed|date=October 2015}}
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'''Insulin resistance''' ('''IR''') is a [[pathological]] condition in which [[cell (biology)|cells]] in insulin-sensitive tissues in the body fail to respond normally to the hormone [[insulin]] or [[downregulation|downregulate]] insulin [[Insulin receptor|receptors]] in response to [[hyperinsulinemia]].

Insulin is a [[hormone]] that facilitates the transport of glucose from blood into cells, thereby reducing [[blood glucose]] (blood sugar). Insulin is released by the [[pancreas]] in response to [[carbohydrates]] consumed in the diet. In states of insulin resistance, the same amount of insulin does not have the same effect on glucose transport and blood sugar levels. There are many causes of insulin resistance and the underlying process is still not completely understood. [[Risk factor (epidemiology)|Risk factor]]s for insulin resistance include [[obesity]], [[sedentary lifestyle]], family history of [[diabetes]], various health conditions, and certain medications. Insulin resistance is considered a component of the [[metabolic syndrome]]. Insulin resistance can be improved or reversed with lifestyle approaches, such as weight reduction, exercise, and dietary changes.

There are multiple ways to measure insulin resistance such as fasting insulin levels or glucose tolerance tests, but these are not often used in clinical practice.

==Cause==
===Risk factors===
There are a number of risk factors for insulin resistance, including being overweight or obese or having a [[sedentary lifestyle]].<ref name=":4"/> Various genetic factors can increase risk, such as a family history of diabetes, and there are some specific medical conditions associated with insulin resistance, such as [[polycystic ovary syndrome]].<ref name=":4">{{cite web |publisher=[[National Institute of Diabetes and Digestive and Kidney Diseases]] |date=May 2018 |url=https://www.niddk.nih.gov/health-information/diabetes/overview/what-is-diabetes/prediabetes-insulin-resistance |title=Insulin Resistance & Prediabetes}}</ref>

The U.S. [[National Institute of Diabetes and Digestive and Kidney Diseases]] states that specific risks that may predispose an individual to insulin resistance can include:
* being aged 45 or older
* having African American, Alaska Native, American Indian, Asian American, Hispanic/Latino, Native Hawaiian, or Pacific Islander American ethnicity<ref group=Note name=Note01/>
* having health conditions such as high blood pressure and abnormal cholesterol levels
* having a history of gestational diabetes
* having a history of heart disease or stroke.<ref name=":4" />

In addition some medications and other health conditions can raise the risk.<ref name=":4" />

===Lifestyle factors===
Dietary factors are likely to contribute to insulin resistance. However, causative foods are difficult to determine given the limitations of nutrition research. Foods that have independently been linked to insulin resistance include those high in sugar with high [[Glycemic index|glycemic indices]], low in omega-3 and fiber, and which are [[hyperpalatable]] which increases risk of overeating.<ref name="fast_food">{{cite journal | vauthors = Isganaitis E, Lustig RH | title = Fast food, central nervous system insulin resistance, and obesity | journal = Arteriosclerosis, Thrombosis, and Vascular Biology | volume = 25 | issue = 12 | pages = 2451–62 | date = December 2005 | pmid = 16166564 | doi = 10.1161/01.ATV.0000186208.06964.91 | doi-access = free }}</ref> Overconsumption of fat- and sugar-rich meals and beverages have been proposed as a fundamental factor behind the [[metabolic syndrome]] epidemic.

Diet also has the potential to change the ratio of polyunsaturated to [[saturated fats|saturated]] phospholipids in cell membranes. The percentage of [[polyunsaturated fatty acids]] (PUFAs) is inversely correlated with insulin resistance.<ref>{{cite journal | vauthors = Haugaard SB, Madsbad S, Høy CE, Vaag A | title = Dietary intervention increases n-3 long-chain polyunsaturated fatty acids in skeletal muscle membrane phospholipids of obese subjects. Implications for insulin sensitivity | journal = Clinical Endocrinology | volume = 64 | issue = 2 | pages = 169–78 | date = February 2006 | pmid = 16430716 | doi = 10.1111/j.1365-2265.2006.02444.x | s2cid = 22878943 }}</ref> It is hypothesized that increasing cell membrane fluidity by increasing PUFA concentration might result in an enhanced number of insulin receptors, an increased affinity of insulin to its receptors, and reduced insulin resistance.<ref>{{cite journal | vauthors = Russo GL | title = Dietary n-6 and n-3 polyunsaturated fatty acids: from biochemistry to clinical implications in cardiovascular prevention | journal = Biochemical Pharmacology | volume = 77 | issue = 6 | pages = 937–46 | date = March 2009 | pmid = 19022225 | doi = 10.1016/j.bcp.2008.10.020 }}</ref>

[[Vitamin D]] deficiency has also been associated with insulin resistance.<ref name=Chiu_2004>{{cite journal | vauthors = Chiu KC, Chu A, Go VL, Saad MF | title = Hypovitaminosis D is associated with insulin resistance and beta cell dysfunction | journal = The American Journal of Clinical Nutrition | volume = 79 | issue = 5 | pages = 820–5 | date = May 2004 | pmid = 15113720 | doi = 10.1093/ajcn/79.5.820 | doi-access = free }}</ref>

Sedentary lifestyle increases the likelihood of development of insulin resistance.<ref>{{cite journal | vauthors = Ivy JL | title = Role of exercise training in the prevention and treatment of insulin resistance and non-insulin-dependent diabetes mellitus | journal = Sports Medicine | volume = 24 | issue = 5 | pages = 321–36 | date = November 1997 | pmid = 9368278 | doi = 10.2165/00007256-199724050-00004 | s2cid = 29053249 | place = Auckland, NZ }}</ref> In [[Epidemiology|epidemiological]] studies, higher levels of physical activity (more than 90 minutes per day) reduce the risk of diabetes by 28%.<ref name="pmid27510511">{{cite journal | vauthors = Kyu HH, Bachman VF, Alexander LT, Mumford JE, Afshin A, Estep K, Veerman JL, Delwiche K, Iannarone ML, Moyer ML, Cercy K, Vos T, Murray CJ, Forouzanfar MH | title = Physical activity and risk of breast cancer, colon cancer, diabetes, ischemic heart disease, and ischemic stroke events: systematic review and dose-response meta-analysis for the Global Burden of Disease Study 2013 | journal = BMJ | volume = 354 | issue = | pages = i3857 | date = August 2016 | pmid = 27510511 | pmc = 4979358 | doi = 10.1136/bmj.i3857 }}</ref>

Studies have consistently shown that there is a link between insulin resistance and [[circadian rhythm]], with insulin sensitivity being higher in the morning and lower in the evening. A mismatch between the [[circadian rhythm]] and the meals schedule, such as in [[circadian rhythm disorder]]s, may increase insulin resistance.<ref>{{cite journal | vauthors = Stenvers DJ, Scheer FA, Schrauwen P, la Fleur SE, Kalsbeek A | title = Circadian clocks and insulin resistance | journal = Nature Reviews. Endocrinology | volume = 15 | issue = 2 | pages = 75–89 | date = February 2019 | pmid = 30531917 | doi = 10.1038/s41574-018-0122-1 | hdl = 20.500.11755/fdb8d77a-70e3-4ab7-a041-20b2303b418b | s2cid = 54449238 | url = https://pure.knaw.nl/ws/files/9742503/stenvers2019.pdf }}</ref>
<ref>{{cite journal | vauthors = Reutrakul S, Van Cauter E | title = Sleep influences on obesity, insulin resistance, and risk of type 2 diabetes | journal = Metabolism | volume = 84 | pages = 56–66 | date = July 2018 | pmid = 29510179 | doi = 10.1016/j.metabol.2018.02.010 }}</ref><ref>{{cite journal | vauthors = Mesarwi O, Polak J, Jun J, Polotsky VY | title = Sleep disorders and the development of insulin resistance and obesity | journal = Endocrinology and Metabolism Clinics of North America | volume = 42 | issue = 3 | pages = 617–34 | date = September 2013 | pmid = 24011890 | pmc = 3767932 | doi = 10.1016/j.ecl.2013.05.001 }}
* {{lay source |template=cite web|url= https://web.archive.org/web/20180823214749/http://advancedcardiosleep.com/blog/2673329-3-sleep-disorders-and-their-relationship-to-insulin-resistance/|title= 3 Sleep disorders and their relationship to insulin resistance|date= April 11, 2011 |website = Advanced Cardiovascular Sleep Disorder Center }}</ref>

Insufficient sleep has been shown to cause insulin resistance, and also increases the risk of developing metabolic diseases such as [[type 2 diabetes]] and obesity.<ref>{{Cite journal |last1=Sondrup |first1=Nina |last2=Termannsen |first2=Anne-Ditte |last3=Eriksen |first3=Jane N. |last4=Hjorth |first4=Mads F. |last5=Færch |first5=Kristine |last6=Klingenberg |first6=Lars |last7=Quist |first7=Jonas S. |date=2022-04-01 |title=Effects of sleep manipulation on markers of insulin sensitivity: A systematic review and meta-analysis of randomized controlled trials |journal=Sleep Medicine Reviews |volume=62 |pages=101594 |doi=10.1016/j.smrv.2022.101594 |pmid=35189549 |issn=1087-0792|doi-access=free }}</ref><ref>{{Cite journal |last1=Singh |first1=Trisha |last2=Ahmed |first2=Tarig H |last3=Mohamed |first3=Nusyba |last4=Elhaj |first4=Mohamed S |last5=Mohammed |first5=Zahir |last6=Paulsingh |first6=Christian N |last7=Mohamed |first7=Mohamed B |last8=Khan |first8=Safeera |title=Does Insufficient Sleep Increase the Risk of Developing Insulin Resistance: A Systematic Review |journal=Cureus |date=2022 |volume=14 |issue=3 |pages=e23501 |doi=10.7759/cureus.23501 |doi-access=free |issn=2168-8184 |pmc=9036496 |pmid=35494895}}</ref><ref>{{Cite journal |last1=Schmid |first1=Sebastian M |last2=Hallschmid |first2=Manfred |last3=Schultes |first3=Bernd |date=January 2015 |title=The metabolic burden of sleep loss |url=https://doi.org/10.1016/S2213-8587(14)70012-9 |journal=The Lancet Diabetes & Endocrinology |volume=3 |issue=1 |pages=52–62 |doi=10.1016/s2213-8587(14)70012-9 |pmid=24731536 |issn=2213-8587}}</ref>

===Medications===
Some medications are associated with insulin resistance including [[corticosteroid]]s, [[protease inhibitors]] (type of HIV medication),<ref name="pmid12626882">{{cite journal | vauthors = Fantry LE | title = Protease inhibitor-associated diabetes mellitus: a potential cause of morbidity and mortality | journal = J Acquir Immune Defic Syndr | volume = 32 | issue = 3 | pages = 243–4 | date = March 2003 | pmid = 12626882 | doi = 10.1097/00126334-200303010-00001 | doi-access = free }}</ref> and [[atypical antipsychotic]]s.<ref>{{cite journal | vauthors = Burghardt KJ, Seyoum B, Mallisho A, Burghardt PR, Kowluru RA, Yi Z | title = Atypical antipsychotics, insulin resistance and weight; a meta-analysis of healthy volunteer studies | journal = Progress in Neuro-Psychopharmacology & Biological Psychiatry | volume = 83 | pages = 55–63 | date = April 2018 | pmid = 29325867 | pmc = 5817633 | doi = 10.1016/j.pnpbp.2018.01.004 }}</ref>

===Exposure to light during sleep===
Being exposed to light during sleep has been shown to cause insulin resistance and increase heart rate.<ref>[https://news.feinberg.northwestern.edu/2022/03/14/exposure-to-artificial-light-during-sleep-may-increase-risk-of-heart-disease-and-diabetes/ Exposure to Artificial Light During Sleep May Increase Risk of Heart Disease and Diabetes]</ref>

===Hormones===
Many hormones can induce insulin resistance including [[cortisol]],<ref>{{cite journal | vauthors = Joseph JJ, Golden SH | title = Cortisol dysregulation: the bidirectional link between stress, depression, and type 2 diabetes mellitus | journal = Annals of the New York Academy of Sciences | volume = 1391 | issue = 1 | pages = 20–34 | date = March 2017 | pmid = 27750377 | pmc = 5334212 | doi = 10.1111/nyas.13217 | bibcode = 2017NYASA1391...20J }}</ref> [[growth hormone]], and [[human placental lactogen]].<ref>{{cite journal | vauthors = Newbern D, Freemark M | title = Placental hormones and the control of maternal metabolism and fetal growth | journal = Current Opinion in Endocrinology, Diabetes and Obesity | volume = 18 | issue = 6 | pages = 409–16 | date = December 2011 | pmid = 21986512 | doi = 10.1097/MED.0b013e32834c800d | s2cid = 24095227 }}</ref>

Cortisol counteracts [[insulin]] and can lead to increased hepatic [[gluconeogenesis]], reduced peripheral utilization of glucose, and increased insulin resistance.<ref name="brown">{{Cite book| vauthors = Brown DD|title=USMLE Step 1 Secrets|year=2003 |page=63}}</ref> It does this by decreasing the translocation of [[glucose transporter]]s (especially [[GLUT4]]) to the cell membrane.<ref>{{Cite book|vauthors = King MW|title= Lange Q&A USMLE Step 1|edition= 6th|page= [https://archive.org/details/langeqausmlestep0005unse/page/82 82]|isbn= 978-0-07-144578-8|year= 2005|publisher= McGraw-Hill Medical|location= New York|url-access= registration|url= https://archive.org/details/langeqausmlestep0005unse/page/82}}</ref><ref>{{cite journal | vauthors = Piroli GG, Grillo CA, Reznikov LR, Adams S, McEwen BS, Charron MJ, Reagan LP | title = Corticosterone impairs insulin-stimulated translocation of GLUT4 in the rat hippocampus | journal = Neuroendocrinology | volume = 85 | issue = 2 | pages = 71–80 | year = 2007 | pmid = 17426391 | doi = 10.1159/000101694 | s2cid = 38081413 }}</ref>

Based on the significant improvement in insulin sensitivity in humans after [[bariatric surgery]] and rats with surgical removal of the [[duodenum]],<ref>{{cite journal | vauthors = Garrido-Sanchez L, Murri M, Rivas-Becerra J, Ocaña-Wilhelmi L, Cohen RV, Garcia-Fuentes E, Tinahones FJ | title = Bypass of the duodenum improves insulin resistance much more rapidly than sleeve gastrectomy | journal = Surgery for Obesity and Related Diseases | volume = 8 | issue = 2 | pages = 145–50 | year = 2012 | pmid = 21570362 | doi = 10.1016/j.soard.2011.03.010 }}</ref><ref>{{cite news|url=http://www.mdedge.com/familypracticenews/article/109286/gastroenterology/duodenal-resurfacing-achieves-metabolic-benefits|title=Duodenal resurfacing achieves metabolic benefits in type 2 diabetes|vauthors =Goodman A|date=June 1, 2016|access-date=12 March 2017|agency=Family Practice News}}</ref> it has been proposed that some substance is produced in the [[mucosa]] of that initial portion of the small intestine that signals body cells to become insulin resistant. If the producing tissue is removed, the signal ceases and body cells revert to normal insulin sensitivity. No such substance has been found as yet, and the existence of such a substance remains speculative.{{Citation needed|date=October 2010}}

[[Leptin]] is a hormone produced from the ob gene and adipocytes.<ref name="pmid10766249">{{cite journal | vauthors = Friedman JM | title = Obesity in the new millennium | journal = Nature | volume = 404 | issue = 6778 | pages = 632–4 | date = April 2000 | pmid = 10766249 | doi = 10.1038/35007504 | s2cid = 4406498 | doi-access = free }}</ref> Its physiological role is to regulate hunger by alerting the body when it is full.<ref name=":2">{{cite journal | vauthors = Flier JS | title = Clinical review 94: What's in a name? In search of leptin's physiologic role | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 83 | issue = 5 | pages = 1407–13 | date = May 1998 | pmid = 9589630 | doi = 10.1210/jcem.83.5.4779 | doi-access = free }}</ref> Studies show that lack of leptin causes severe obesity and is strongly linked with insulin resistance.<ref>{{cite journal | vauthors = Elmquist JK, Maratos-Flier E, Saper CB, Flier JS | title = Unraveling the central nervous system pathways underlying responses to leptin | journal = Nature Neuroscience | volume = 1 | issue = 6 | pages = 445–50 | date = October 1998 | pmid = 10196541 | doi = 10.1038/2164 | s2cid = 7474447 }}</ref>

===Diseases===
[[PCOS|Polycystic ovary syndrome]]<ref>{{cite journal | vauthors = Nafiye Y, Sevtap K, Muammer D, Emre O, Senol K, Leyla M | title = The effect of serum and intrafollicular insulin resistance parameters and homocysteine levels of nonobese, nonhyperandrogenemic polycystic ovary syndrome patients on in vitro fertilization outcome | journal = Fertility and Sterility | volume = 93 | issue = 6 | pages = 1864–9 | date = April 2010 | pmid = 19171332 | doi = 10.1016/j.fertnstert.2008.12.024 | doi-access = free }}</ref> and [[NAFLD|non-alcoholic fatty liver disease (NAFLD)]] are associated with insulin resistance. [[Hepatitis C]] also makes people three to four times more likely to develop type 2 diabetes and insulin resistance.<ref name="pmid19962985">{{cite journal | vauthors = Milner KL, van der Poorten D, Trenell M, Jenkins AB, Xu A, Smythe G, Dore GJ, Zekry A, Weltman M, Fragomeli V, George J, Chisholm DJ | display-authors = 6 | title = Chronic hepatitis C is associated with peripheral rather than hepatic insulin resistance | journal = Gastroenterology | volume = 138 | issue = 3 | pages = 932–41.e1–3 | date = March 2010 | pmid = 19962985 | doi = 10.1053/j.gastro.2009.11.050 }}
* {{lay source |template = cite press release|url = https://www.sciencedaily.com/releases/2010/03/100309102519.htm|title = Surprising findings about Hepatitis C and insulin resistance|date = March 10, 2010 |website = Science Daily}}</ref>

=== Mitochondrial dysfunction ===
Multiple studies involving different methodology suggest that impaired function of [[Mitochondrion|mitochondria]] might play a pivotal role in the pathogenesis of insulin resistance.<ref>{{cite journal |last1=Turner |first1=N |last2=Heilbronn |first2=LK |title=Is mitochondrial dysfunction a cause of insulin resistance? |journal=Trends in Endocrinology and Metabolism |date=November 2008 |volume=19 |issue=9 |pages=324–30 |doi=10.1016/j.tem.2008.08.001 |pmid=18804383|s2cid=22469532 }}</ref><ref>{{cite journal |last1=Giebelstein |first1=J |last2=Poschmann |first2=G |last3=Højlund |first3=K |last4=Schechinger |first4=W |last5=Dietrich |first5=JW |last6=Levin |first6=K |last7=Beck-Nielsen |first7=H |last8=Podwojski |first8=K |last9=Stühler |first9=K |last10=Meyer |first10=HE |last11=Klein |first11=HH |title=The proteomic signature of insulin-resistant human skeletal muscle reveals increased glycolytic and decreased mitochondrial enzymes. |journal=Diabetologia |date=April 2012 |volume=55 |issue=4 |pages=1114–27 |doi=10.1007/s00125-012-2456-x |pmid=22282162|s2cid=5843657 |doi-access=free }}</ref> Mitochondrial dysfunction may result from the formation of [[reactive oxygen species]], genetic factors, aging, and reduced mitochondrial biogenesis.<ref>{{cite journal |last1=Kim |first1=JA |last2=Wei |first2=Y |last3=Sowers |first3=JR |title=Role of mitochondrial dysfunction in insulin resistance. |journal=Circulation Research |date=29 February 2008 |volume=102 |issue=4 |pages=401–14 |doi=10.1161/CIRCRESAHA.107.165472 |pmid=18309108|pmc=2963150 }}</ref> Important questions remain unsolved to date, however.<ref>{{cite journal |last1=Montgomery |first1=MK |last2=Turner |first2=N |title=Mitochondrial dysfunction and insulin resistance: an update. |journal=Endocrine Connections |date=March 2015 |volume=4 |issue=1 |pages=R1–R15 |doi=10.1530/EC-14-0092 |pmid=25385852|pmc=4261703 }}</ref> If confirmed by rigorous studies, a link between mitochondrial disorders and reduced insulin sensitivity might pave the way to new therapeutic approaches.<ref>{{cite journal |last1=Sergi |first1=D |last2=Naumovski |first2=N |last3=Heilbronn |first3=LK |last4=Abeywardena |first4=M |last5=O'Callaghan |first5=N |last6=Lionetti |first6=L |last7=Luscombe-Marsh |first7=N |title=Mitochondrial (Dys)function and Insulin Resistance: From Pathophysiological Molecular Mechanisms to the Impact of Diet. |journal=Frontiers in Physiology |date=2019 |volume=10 |pages=532 |doi=10.3389/fphys.2019.00532 |pmid=31130874 |pmc=6510277 |doi-access=free }}</ref>

=== Inflammation ===
Acute or chronic inflammation, such as in infections, can cause insulin resistance. [[tumor necrosis factor-alpha|TNF-α]] is a cytokine that may promote insulin resistance by promoting [[lipolysis]], disrupting insulin signaling, and reducing the expression of GLUT4.<ref>{{cite journal | vauthors = Peraldi P, Spiegelman B | title = TNF-alpha and insulin resistance: summary and future prospects | journal = Molecular and Cellular Biochemistry | volume = 182 | issue = 1–2 | pages = 169–75 | date = May 1998 | pmid = 9609126 | doi = 10.1023/A:1006865715292 | s2cid = 32740002 }}</ref>

=== Genetics ===
Several genetic loci have been identified as associated with insulin insensitivity. These include variations in loci near the NAT2, GCKR, and IGFI genes, which are linked to insulin resistance. Further research has indicated that loci near these genes are correlated with insulin resistance. However, it is estimated that these loci only account for 25–44% of the genetic component of insulin resistance.<ref>{{cite journal | vauthors = Brown AE, Walker M | title = Genetics of Insulin Resistance and the Metabolic Syndrome | journal = Current Cardiology Reports | volume = 18 | issue = 8 | pages = 75 | date = August 2016 | pmid = 27312935 | pmc = 4911377 | doi = 10.1007/s11886-016-0755-4 }}</ref>

==Pathophysiology==
In normal metabolism, the elevated blood glucose instructs beta (β) cells in the [[Islets of Langerhans]], located in the [[pancreas]], to release insulin into the blood. The insulin makes insulin-sensitive tissues in the body (primarily skeletal [[muscle]] cells, [[adipose]] tissue, and [[liver]]) absorb [[glucose]] which provides energy as well as lowers blood glucose.<ref>{{cite news|url=https://www.economist.com/news/special-report/21568073-obesity-presents-big-challenge-governments-and-opportunity-drug-companies|title=A heavy burden|date=December 15, 2012|newspaper=The Economist|access-date=10 January 2013}}</ref> The beta cells reduce insulin output as the blood glucose level falls, allowing blood glucose to settle at a constant of approximately 5&nbsp;mmol/L (90&nbsp;mg/dL). In an ''insulin-resistant'' person, normal levels of insulin do not have the same effect in controlling blood glucose levels.

When the body produces insulin under conditions of insulin resistance, the cells are unable to absorb or use it as effectively and it stays in the bloodstream. Certain cell types such as [[fat]] and [[muscle]] cells require insulin to absorb glucose and when these cells fail to respond adequately to circulating insulin, blood glucose levels rise. The [[liver]] normally helps regulate glucose levels by reducing its secretion of glucose in the presence of insulin. However, in insulin resistance, this normal reduction in the liver's glucose production may not occur, further contributing to elevated blood glucose.<ref>{{cite web |date=Jun 2009 | url = https://www.sciencedaily.com/releases/2009/06/090621143236.htm |title= Science daily }}</ref>

Insulin resistance in [[adipose tissue|fat cells]] results in reduced uptake of circulating lipids and increased [[hydrolysis]] of stored [[triglyceride]]s. This leads to elevated free [[fatty acid]]s in the [[blood plasma]] and can further worsen insulin resistance.<ref name="pmid15910615">{{cite journal|vauthors=Schinner S, Scherbaum WA, Bornstein SR, Barthel A|date=June 2005|title=Molecular mechanisms of insulin resistance|journal=Diabetic Medicine|volume=22|issue=6|pages=674–82|doi=10.1111/j.1464-5491.2005.01566.x|pmid=15910615|s2cid=10680747}}</ref><ref>{{cite journal|vauthors=Koyama K, Chen G, Lee Y, Unger RH|date=October 1997|title=Tissue triglycerides, insulin resistance, and insulin production: implications for hyperinsulinemia of obesity|journal=The American Journal of Physiology|volume=273|issue=4|pages=E708-13|doi=10.1152/ajpendo.1997.273.4.E708|pmid=9357799}}</ref><ref name="PMC507380">{{cite journal|vauthors=Roden M, Price TB, Perseghin G, Petersen KF, Rothman DL, Cline GW, Shulman GI|date=June 1996|title=Mechanism of free fatty acid-induced insulin resistance in humans|journal=The Journal of Clinical Investigation|volume=97|issue=12|pages=2859–65|doi=10.1172/JCI118742|pmc=507380|pmid=8675698}}</ref> Since insulin is the primary hormonal signal for energy storage into [[fat cells]], which tend to retain their sensitivity in the face of hepatic and skeletal muscle resistance, insulin resistance stimulates the formation of new fatty tissue and accelerates weight gain.<ref name="fast_food" />

In states of insulin resistance, [[beta cell]]s in the [[pancreas]] increase their production of insulin. This causes [[hyperinsulinemia|high blood insulin]] (hyperinsulinemia) to compensate for the high blood glucose. During this compensated phase of insulin resistance, [[Pancreatic beta cell function|beta cell function]] is upregulated, insulin levels are higher, and blood glucose levels are still maintained. If compensatory insulin secretion fails, then either fasting (impaired fasting glucose) or postprandial (impaired glucose tolerance) glucose concentrations increase. Eventually, type 2 diabetes occurs when glucose levels become higher as the resistance increases and compensatory insulin secretion fails.<ref name="Medicine net">{{cite web|url=http://www.medicinenet.com/insulin_resistance/article.htm|title=Insulin resistance|publisher=Medicine net}}</ref><ref>{{cite report|url=https://www.diabeteshealth.com/news/insulin-resistance-leads-to-lada-latent-autoimmune-diabetes-in-adults|title=Insulin Resistance Leads to LADA|publisher=Diabetes Health|access-date=Feb 21, 2015|archive-date=April 14, 2015|archive-url=https://web.archive.org/web/20150414171256/https://www.diabeteshealth.com/news/insulin-resistance-leads-to-lada-latent-autoimmune-diabetes-in-adults/|url-status=dead}}</ref> The inability of the β-cells to produce sufficient insulin in a condition of hyperglycemia is what characterizes the transition from insulin resistance to type 2 diabetes.

Insulin resistance is strongly associated with intestinal-derived [[Apolipoprotein B|apoB-48]] production rate in insulin-resistant subjects and type 2 diabetics.<ref>{{Cite journal|title= Chylomicrons: Advances in biology, pathology, laboratory testing, and therapeutics|url=https://www.researchgate.net/publication/293638020|journal= Clinica Chimica Acta|year=2016 |doi=10.1016/j.cca.2016.02.004 |last1=Julve |first1=Josep |last2=Martín-Campos |first2=Jesús M. |last3=Escolà-Gil |first3=Joan Carles |last4=Blanco-Vaca |first4=Francisco |volume=455 |pages=134–148 |pmid=26868089 }}</ref> Insulin resistance often is found in people with visceral adiposity, hypertension, hyperglycemia, and [[dyslipidemia]] involving elevated triglycerides, small dense [[low-density lipoprotein]] (sdLDL) particles, and decreased [[high-density lipoprotein]] (HDL) cholesterol levels. With respect to visceral adiposity, a great deal of evidence suggests two strong links with insulin resistance. First, unlike subcutaneous adipose tissue, visceral adipose cells produce significant amounts of proinflammatory [[cytokines]] such as tumor necrosis factor-alpha ([[TNF-a]]), and [[Interleukins]]-1 and −6, etc. In numerous experimental models, these proinflammatory cytokines disrupt normal insulin action in fat and muscle cells and may be a major factor in causing the whole-body insulin resistance observed in patients with visceral adiposity. Much of the attention on production of proinflammatory cytokines has focused on the IKK-beta/[[NF-kappa-B]] pathway, a protein network that enhances transcription of inflammatory markers and mediators that may cause insulin resistance. Second, visceral adiposity is related to an accumulation of fat in the liver, a condition known as [[non-alcoholic fatty liver disease]] (NAFLD). The result of NAFLD is an excessive release of free fatty acids into the bloodstream (due to increased lipolysis), and an increase in hepatic breakdown of glycogen stores into glucose ([[glycogenolysis]]), both of which have the effect of exacerbating peripheral insulin resistance and increasing the likelihood of [[T2DM|Type 2 diabetes mellitus]].{{Citation needed|date=October 2010}}

The excessive expansion of adipose tissue that tends to occur under sustainedly positive energy balance (as in overeating) has been postulated by [[Antonio Vidal-Puig|Vidal-Puig]] to induce lipotoxic and inflammatory effects that may contribute to causing insulin resistance and its accompanying disease states.<ref name="pmid29596053">{{cite journal | vauthors = Caprio S, Pierpont B, Kursawe R | title = The "adipose tissue expandability" hypothesis: a potential mechanism for insulin resistance in obese youth | journal = Horm Mol Biol Clin Investig | volume = 33 | issue = 2 | pages = | date = March 2018 | pmid = 29596053 | doi = 10.1515/hmbci-2018-0005 | s2cid = 4515780}}</ref>

Also, insulin resistance often is associated with a [[hypercoagulable state]] (impaired [[fibrinolysis]]) and increased inflammatory cytokine levels.<ref name="nagaev">{{cite journal | vauthors = Nagaev I, Bokarewa M, Tarkowski A, Smith U | title = Human resistin is a systemic immune-derived proinflammatory cytokine targeting both leukocytes and adipocytes | journal = PLOS ONE | volume = 1 | issue = 1| pages = e31 | date = December 2006 | pmid = 17183659 | pmc = 1762367 | doi = 10.1371/journal.pone.0000031 | bibcode = 2006PLoSO...1...31N | doi-access = free }}</ref> <!-- The paper states the contrary: that in humans the cytokine resistin is neither related to insulin resistance nor produced by adipose tissue. Besides, the paper does not mention anything about the hypercoagulable state or fibrinolysis. -->

=== 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>

==Diagnosis==
===Glucose tolerance testing===
During a [[glucose tolerance test]] (GTT), which may be used to diagnose diabetes mellitus, a fasting patient takes a 75&nbsp;gram oral dose of glucose. Then blood glucose levels are measured over the following two hours.

Interpretation is based on [[WHO]] guidelines. After two hours a [[blood sugar|glycemia]] less than 7.8&nbsp;mmol/L (140&nbsp;mg/dL) is considered normal, a glycemia of between 7.8 and 11.0&nbsp;mmol/L (140 to 197&nbsp;mg/dL) is considered as [[impaired glucose tolerance]] (IGT), and a glycemia of greater than or equal to 11.1&nbsp;mmol/L (200&nbsp;mg/dL) is considered [[diabetes mellitus]].

An [[oral glucose tolerance test]] (OGTT) may be normal or mildly abnormal in simple insulin resistance. Often, there are raised glucose levels in the early measurements, reflecting the loss of a postprandial peak (after the meal) in insulin production. Extension of the testing (for several more hours) may reveal a [[hypoglycemia|hypoglycemic]] "dip," that is a result of an overshoot in insulin production after the failure of the physiologic postprandial insulin response.{{Citation needed|date=October 2010}}

===Fasting insulin levels===
A fasting serum insulin level greater than 29 microIU/mL or 174 pmol/L indicates insulin resistance.<ref name="pmid30318910">{{cite journal | vauthors = Knopp JL, Holder-Pearson L, Chase JG | title = Insulin Units and Conversion Factors: A Story of Truth, Boots, and Faster Half-Truths | journal = J Diabetes Sci Technol | volume = 13 | issue = 3 | pages = 597–600 | date = May 2019 | pmid = 30318910 | pmc = 6501531 | doi = 10.1177/1932296818805074 }}</ref>{{Failed verification|date=January 2024|reason=this paper has no discussion about insulin resistance at all: it's a paper about the proper conversion of mass-based to bioactivity-based measures of insulin}} The same levels apply three hours after the last meal.

===Hyperinsulinemic euglycemic clamp===
The [[gold standard (test)|gold standard]] for investigating and quantifying insulin resistance is the "hyperinsulinemic euglycemic clamp," so-called because it measures the amount of [[glucose]] necessary to compensate for an increased [[insulin]] level without causing [[hypoglycemia]].<ref name = Anders_1979>{{cite journal | vauthors = DeFronzo RA, Tobin JD, Andres R | title = Glucose clamp technique: a method for quantifying insulin secretion and resistance | journal = The American Journal of Physiology | volume = 237 | issue = 3 | pages = E214-23 | date = September 1979 | pmid = 382871 | doi = 10.1152/ajpendo.1979.237.3.e214 | s2cid = 7192984 }}</ref> It is a type of [[glucose clamp technique]]. The test is rarely performed in clinical care, but is used in medical research, for example, to assess the effects of different medications. The rate of glucose infusion commonly is referred to in diabetes literature as the GINF value.<ref name="Muniyappa">{{cite journal | vauthors = Muniyappa R, Lee S, Chen H, Quon MJ | title = Current approaches for assessing insulin sensitivity and resistance in vivo: advantages, limitations, and appropriate usage | journal = American Journal of Physiology. Endocrinology and Metabolism | volume = 294 | issue = 1 | pages = E15-26 | date = January 2008 | pmid = 17957034 | doi = 10.1152/ajpendo.00645.2007 | s2cid = 848540 }}</ref>

The procedure takes about two hours. Through a [[peripheral vein]], [[insulin]] is infused at 10–120 mU per m<sup>2</sup> per [[minute]]. In order to compensate for the insulin [[intravenous|infusion]], [[glucose]] 20% is infused to maintain blood sugar levels between 5 and 5.5&nbsp;mmol/L. The rate of glucose infusion is determined by checking the [[blood sugar]] levels every five to ten minutes.<ref name="Muniyappa" />

The insulin sensitivity is determined by the rate of glucose infusion during the last thirty minutes of the test. If high levels (7.5&nbsp;mg/min or higher) are needed, the patient is considered insulin-sensitive. Conversely, very low levels (4.0&nbsp;mg/min or lower) indicate insulin resistance. Levels falling between 4.0 and 7.5&nbsp;mg/min are not conclusive and suggest "impaired glucose tolerance," which is an early indication of insulin resistance.<ref name="Muniyappa" />

This fundamental technique can be greatly enhanced through the utilization of glucose tracers. Glucose can be labeled with either stable or radioactive atoms. Commonly employed tracers include 3-3H glucose (radioactive), 6,6 2H-glucose (stable), and 1-13C glucose (stable). Prior to initiating the hyperinsulinemic phase, a 3-hour tracer infusion allows for the determination of the basal rate of glucose production. Throughout the clamp, the plasma tracer concentrations facilitate the computation of whole-body insulin-stimulated glucose metabolism, as well as the production of glucose by the body. (i.e., endogenous glucose production).<ref name="Muniyappa" />

===Modified insulin suppression test===
Another measure of insulin resistance is the modified insulin suppression test developed by [[Gerald Reaven]] at Stanford University. The test correlates well with the euglycemic clamp, with less operator-dependent error. This test has been used to advance the large body of research relating to the metabolic syndrome.<ref name = "Muniyappa" />

Patients initially receive 25 μg of [[octreotide]] (Sandostatin) in 5 mL of normal saline over 3 to 5 minutes via intravenous infusion (IV) as an initial bolus, and then, are infused continuously with an intravenous infusion of [[somatostatin]] (0.27 μg/m<sup>2</sup>/min) to suppress endogenous insulin and glucose secretion. Next, insulin and 20% glucose are infused at rates of 32 and 267&nbsp;mg/m<sup>2</sup>/min, respectively. Blood glucose is checked at zero, 30, 60, 90, and 120 minutes, and thereafter, every 10 minutes for the last half-hour of the test. These last four values are averaged to determine the steady-state plasma glucose level (SSPG). Subjects with an SSPG greater than 150&nbsp;mg/dL are considered to be insulin-resistant.<ref name="Muniyappa" />

===Static function tests===
Given the complicated nature of the "clamp" technique (and the potential dangers of [[hypoglycemia]] in some patients), alternatives have been sought to simplify the measurement of insulin resistance. The first was the [[homeostatic model assessment|Homeostatic Model Assessment]] (HOMA),<ref name="pmid3899825">{{cite journal | vauthors = Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC | title = Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man | journal = Diabetologia | volume = 28 | issue = 7 | pages = 412–9 | date = July 1985 | pmid = 3899825 | doi = 10.1007/BF00280883 | s2cid = 24872571 | doi-access = free }}</ref> and more recent methods include the [[Quantitative insulin sensitivity check index]] (QUICKI)<ref name="pmid10902785">{{cite journal | vauthors = Katz A, Nambi SS, Mather K, Baron AD, Follmann DA, Sullivan G, Quon MJ | title = Quantitative insulin sensitivity check index: a simple, accurate method for assessing insulin sensitivity in humans | journal = J Clin Endocrinol Metab | volume = 85 | issue = 7 | pages = 2402–10 | date = July 2000 | pmid = 10902785 | doi = 10.1210/jcem.85.7.6661 | s2cid = 7612943 | doi-access = free }}</ref> and [[SPINA-GR]], a measure for insulin sensitivity.<ref name="pmid36271244">{{cite journal | vauthors = Dietrich JW, Dasgupta R, Anoop S, Jebasingh F, Kurian ME, Inbakumari M, Boehm BO, Thomas N | title = SPINA Carb: a simple mathematical model supporting fast in-vivo estimation of insulin sensitivity and beta cell function | journal = Sci Rep | volume = 12 | issue = 1 | pages = 17659 | date = October 2022 | pmid = 36271244 | doi = 10.1038/s41598-022-22531-3 | pmc = 9587026 | bibcode = 2022NatSR..1217659D }}</ref> All of these calculated markers employ [[fasting]] [[insulin]] and [[glucose]] levels to calculate insulin resistance, and all correlate reasonably with the results of clamping studies.

====Interpretation of results====
** HOMA-IR < 2: normal insulin sensitivity
** HOMA-IR > 2: possible insulin resistance
** HOMA-IR > 2,5: probable insulin resistance
** HOMA-IR > 5: typical results for type 2 diabetes<ref>{{cite web |last1=DocCheck |title=Homeostasis Model Assessment |url=https://flexikon.doccheck.com/de/Homeostasis_Model_Assessment |website=DocCheck Flexikon |language=de}}</ref>
** SPINA-GR 1,41–9,00&nbsp;mol/s: normal insulin sensitivity
** SPINA-GR ≤ 1,40&nbsp;mol/s: insulin resistance
** SPINA-GR < 1,35&nbsp;mol/s: typical results for type 2 diabetes<ref name="pmid36271244"/>

==Prevention and management==
Maintaining a healthy body weight and engaging in regular physical activity can help mitigate the risk of developing insulin resistance.<ref name=":4" />

The primary treatment for insulin resistance is [[exercise]] and [[weight loss]].<ref>{{cite journal | vauthors = Davidson LE, Hudson R, Kilpatrick K | title = Effects of Exercise Modality on Insulin Resistance and Functional Limitation in Older Adults | journal = Archives of Internal Medicine | publisher = JAMA | date=Jan 2009 | volume = 169 | issue = 2 | pages = 122–131 | url = https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/414732 | doi=10.1001/archinternmed.2008.558 | pmid = 19171808 | access-date = 17 Sep 2020 | doi-access = }}</ref> Both [[metformin]] and [[thiazolidinedione]]s improve insulin sensitivity. Metformin is approved for prediabetes and type 2 diabetes and has become one of the more commonly prescribed medications for insulin resistance.<ref>{{cite journal | vauthors = Giannarelli R, Aragona M, Coppelli A, Del Prato S | title = Reducing insulin resistance with metformin: the evidence today | journal = Diabetes & Metabolism | volume = 29 | issue = 4 Pt 2 | pages = 6S28–35 | date = September 2003 | pmid = 14502098 | doi = 10.1016/s1262-3636(03)72785-2 }}</ref>

The ''Diabetes Prevention Program'' (DPP) showed that exercise and diet were nearly twice as effective as [[metformin]] at reducing the risk of progressing to type 2 diabetes.<ref name="Knowler_2002">{{cite journal | vauthors = Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, Nathan DM | title = Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin | journal = The New England Journal of Medicine | volume = 346 | issue = 6 | pages = 393–403 | date = February 2002 | pmid = 11832527 | pmc = 1370926 | doi = 10.1056/NEJMoa012512 }}</ref> However, the participants in the DPP trial regained about 40% of the weight that they had lost at the end of 2.8 years, resulting in a similar incidence of diabetes development in both the lifestyle intervention and the control arms of the trial.<ref>{{cite journal | vauthors = Kahn R | title = Reducing the impact of diabetes: is prevention feasible today, or should we aim for better treatment? | journal = Health Affairs | volume = 31 | issue = 1 | pages = 76–83 | date = January 2012 | pmid = 22232097 | doi = 10.1377/hlthaff.2011.1075 | doi-access = }}</ref> In epidemiological studies, higher levels of physical activity (more than 90 minutes per day) reduce the risk of diabetes by 28%.<ref name="BMJ2016">{{cite journal|vauthors=Kyu HH, Bachman VF, Alexander LT, Mumford JE, Afshin A, Estep K, Veerman JL, Delwiche K, Iannarone ML, Moyer ML, Cercy K, Vos T, Murray CJ, Forouzanfar MH|date=August 2016|title=Physical activity and risk of breast cancer, colon cancer, diabetes, ischemic heart disease, and ischemic stroke events: systematic review and dose-response meta-analysis for the Global Burden of Disease Study 2013|journal=BMJ|volume=354|pages=i3857|doi=10.1136/bmj.i3857|pmc=4979358|pmid=27510511}}</ref>

Furthermore, physical training has also generally been seen to be an effective antagonist of insulin resistance in obese or overweight children and adolescents (under the age of 19).<ref name="Marson 211–218"/> As per the 2016 systematic review and meta-analysis conducted by Marson et al., aerobic exercise is associated with fasting insulin reduction; however, resistance and combined exercise are not.<ref name="Marson 211–218">{{cite journal | vauthors = Marson EC, Delevatti RS, Prado AK, Netto N, Kruel LF | title = Effects of aerobic, resistance, and combined exercise training on insulin resistance markers in overweight or obese children and adolescents: A systematic review and meta-analysis | journal = Prev Med | volume = 93 | issue = | pages = 211–218 | date = December 2016 | pmid = 27773709 | doi = 10.1016/j.ypmed.2016.10.020 }}</ref> The authors caution against demeaning the importance of resistance and combined exercise, as this type of training is generally less researched than aerobic training.<ref name="Marson 211–218"/> Overall, physical training can be used in both adolescents and adults to prevent the progression of insulin resistance and future possible metabolic and cardiovascular disease.

[[Resistant starch]] from high-amylose corn, [[amylomaize]], has been shown to reduce insulin resistance in healthy individuals, in individuals with insulin resistance, and in individuals with type 2 diabetes.<ref>{{cite journal | vauthors = Keenan MJ, Zhou J, Hegsted M, Pelkman C, Durham HA, Coulon DB, Martin RJ | title = Role of resistant starch in improving gut health, adiposity, and insulin resistance | journal = Advances in Nutrition | volume = 6 | issue = 2 | pages = 198–205 | date = March 2015 | pmid = 25770258 | pmc = 4352178 | doi = 10.3945/an.114.007419 }}</ref>

Some types of [[Polyunsaturated fat|polyunsaturated fatty acids]] ([[omega-3]]) may moderate the progression of insulin resistance into type 2 diabetes,<ref name=Lovejoy_2002>{{cite journal | vauthors = Lovejoy JC | title = The influence of dietary fat on insulin resistance | journal = Current Diabetes Reports | volume = 2 | issue = 5 | pages = 435–40 | date = October 2002 | pmid = 12643169 | doi = 10.1007/s11892-002-0098-y | s2cid = 31329463 }}
</ref><ref name = Fukuchi_2004>
{{cite journal | vauthors = Fukuchi S, Hamaguchi K, Seike M, Himeno K, Sakata T, Yoshimatsu H | title = Role of fatty acid composition in the development of metabolic disorders in sucrose-induced obese rats | journal = Experimental Biology and Medicine | volume = 229 | issue = 6 | pages = 486–93 | date = June 2004 | pmid = 15169967 | doi = 10.1177/153537020422900606 | s2cid = 20966659 }}
</ref><ref name = Storlien_1996>
{{cite journal | vauthors = Storlien LH, Baur LA, Kriketos AD, Pan DA, Cooney GJ, Jenkins AB, Calvert GD, Campbell LV | display-authors = 6 | title = Dietary fats and insulin action | journal = Diabetologia | volume = 39 | issue = 6 | pages = 621–31 | date = June 1996 | pmid = 8781757 | doi = 10.1007/BF00418533 | s2cid = 33171616 }}
</ref> however, omega-3 fatty acids appear to have limited ability to reverse insulin resistance, and they cease to be efficacious once type 2 diabetes is established.<ref>
{{cite journal | vauthors = Delarue J, LeFoll C, Corporeau C, Lucas D | title = N-3 long chain polyunsaturated fatty acids: a nutritional tool to prevent insulin resistance associated to type 2 diabetes and obesity? | journal = Reproduction, Nutrition, Development | volume = 44 | issue = 3 | pages = 289–99 | year = 2004 | pmid = 15460168 | doi = 10.1051/rnd:2004033 | doi-access = free }}
</ref>

==History==
The concept that insulin resistance may be the underlying cause of [[diabetes mellitus]] type 2 was first advanced by Professor Wilhelm Falta and published in Vienna in 1931,<ref name=Falta_1931>{{cite journal |vauthors =Falta W, Boller R |title=Insulärer und Insulinresistenter Diabetes |journal=Klinische Wochenschrift |volume=10 |pages=438–43 |year=1931 |doi=10.1007/BF01736348 |issue=10|s2cid=32359074 }}</ref> and confirmed as contributory by Sir [[Harold Percival Himsworth]] of the University College Hospital Medical Centre in London in 1936;<ref name=Himsworth_1936>{{cite journal |vauthors = Himsworth H |title=Diabetes mellitus: its differentiation into insulin-sensitive and insulin insensitive types |journal=The Lancet |volume=227 |pages=127–30 |year=1936 |doi=10.1016/S0140-6736(01)36134-2 |issue=5864}}</ref> however, type 2 diabetes does not occur unless there is concurrent failure of compensatory insulin secretion.<ref name=Nolan_2010>{{cite journal | vauthors = Nolan CJ | title = Failure of islet β-cell compensation for insulin resistance causes type 2 diabetes: what causes non-alcoholic fatty liver disease and non-alcoholic steatohepatitis? | journal = Journal of Gastroenterology and Hepatology | volume = 25 | issue = 10 | pages = 1594–7 | date = October 2010 | pmid = 20880166 | doi = 10.1111/j.1440-1746.2010.06473.x | doi-access = free }}</ref>

=== Adaptive explanations ===
Some scholars go as far as to claim that neither insulin resistance, nor obesity really are metabolic disorders ''per se'', but simply adaptive responses to sustained caloric surplus, intended to protect bodily organs from [[lipotoxicity]] (unsafe levels of lipids in the bloodstream and tissues): "Obesity should therefore not be regarded as a [[pathology]] or disease, but rather as the normal, physiologic response to sustained caloric surplus... As a consequence of the high level of lipid accumulation in insulin target tissues including skeletal muscle and liver, it has been suggested that exclusion of glucose from lipid-laden cells is a compensatory defense against further accumulation of lipogenic substrate."<ref>{{cite journal | vauthors = Unger RH, Scherer PE | title = Gluttony, sloth and the metabolic syndrome: a roadmap to lipotoxicity | journal = Trends in Endocrinology and Metabolism | volume = 21 | issue = 6 | pages = 345–52 | date = June 2010 | pmid = 20223680 | pmc = 2880185 | doi = 10.1016/j.tem.2010.01.009 }}</ref>

Other prevailing thoughts that insulin resistance can be an evolutionary adaptation include the [[thrifty gene hypothesis]]. This hypothesis raises the point that if there is a genetic component to insulin resistance and Type 2 diabetes, these phenotypes should be selected against.<ref name=":3">{{cite journal | vauthors = Neel JV | title = Diabetes mellitus: a "thrifty" genotype rendered detrimental by "progress"? | journal = American Journal of Human Genetics | volume = 14 | issue = 4 | pages = 353–62 | date = December 1962 | pmid = 13937884 | pmc = 1932342 }}</ref> Yet, there has been an increase in mean insulin resistance in both the normoglycemic population as well as the diabetic population.<ref>{{cite journal | vauthors = Ioannou GN, Bryson CL, Boyko EJ | title = Prevalence and trends of insulin resistance, impaired fasting glucose, and diabetes | journal = Journal of Diabetes and Its Complications | volume = 21 | issue = 6 | pages = 363–70 | date = 2007-11-01 | pmid = 17967708 | doi = 10.1016/j.jdiacomp.2006.07.005 }}</ref>

J.V. Neel posits that in ancient human ancestors, during periods of heightened famine, genes facilitating increased glucose storage would have conferred an advantage. However, in today's modern environment, this is no longer the case.<ref name=":3" />

Evidence contradicts Neel's hypothesis in studies of the Pima Indians, which suggest that individuals with higher insulin sensitivity tended to have higher weights, whereas those with insulin resistance tended to weigh less on average within this demographic.<ref>{{cite journal | vauthors = Swinburn BA, Nyomba BL, Saad MF, Zurlo F, Raz I, Knowler WC, Lillioja S, Bogardus C, Ravussin E | display-authors = 6 | title = Insulin resistance associated with lower rates of weight gain in Pima Indians | journal = The Journal of Clinical Investigation | volume = 88 | issue = 1 | pages = 168–73 | date = July 1991 | pmid = 2056116 | pmc = 296017 | doi = 10.1172/JCI115274 }}</ref>

Modern hypotheses propose that insulin [[metabolism]] serves as a socio-ecological adaptation, with insulin serving as the mechanism for allocating energy to different body components and insulin sensitivity being an adaptation to regulate this energy allocation. The Behavioral Switch Hypothesis suggests that insulin resistance leads to two methods of altering reproductive and behavioral strategies. These strategies are termed "r to K" and "soldier to diplomat." The "r to K" strategy involves directing insulin through the placenta to the fetus, resulting in weight gain in the fetus but not the mother, indicating an increase in parental investment (K strategy). In the "soldier to diplomat" strategy, the insensitivity of skeletal muscle to insulin could redirect glucose to the brain, which does not require insulin receptors. This has been shown to enhance cognitive development across various studies.<ref>{{cite journal | vauthors = Watve MG, Yajnik CS | title = Evolutionary origins of insulin resistance: a behavioral switch hypothesis | journal = BMC Evolutionary Biology | volume = 7 | pages = 61 | date = April 2007 | issue = 1 | pmid = 17437648 | pmc = 1868084 | doi = 10.1186/1471-2148-7-61 | bibcode = 2007BMCEE...7...61W | doi-access = free }}</ref>

== See also ==
{{col div|colwidth=40em}}
* [[Pancreatic beta cell function]]
* [[Chronic Somogyi rebound]]
* [[Hyperinsulinemia]]
* [[Resistin]]
* [[Chronic stress]]
* [[Inflammation#Interleukins and obesity|Systemic inflammation]]
* [[Circadian rhythm#Obesity and diabetes|Circadian rhythm disruption]]
* [[Advanced glycation end-products]]
* [[Polycystic ovary syndrome]]
{{colend}}

==Notes==
{{reflist|group=Note|refs=
<ref name=Note01>The practice of using ethnicity or race as a risk factor for diseases is not scientifically sound and has led to historic over/underdiagnosis in marginalized communities.</ref>
}}

== References ==
{{Reflist |2}}

== Further reading ==
{{refbegin}}
* {{cite journal | vauthors = Reaven GM | title = The insulin resistance syndrome: definition and dietary approaches to treatment | journal = Annual Review of Nutrition | volume = 25 | pages = 391–406 | year = 2005 | pmid = 16011472 | doi = 10.1146/annurev.nutr.24.012003.132155 | s2cid = 24849146 | type = review }}
* {{cite journal | vauthors = Rao G | title = Insulin resistance syndrome | journal = American Family Physician | volume = 63 | issue = 6 | pages = 1159–63, 1165–6 | date = March 2001 | pmid = 11277552 | url = http://www.aafp.org/afp/2001/0315/p1159.html | type = review | place = US }}
{{refend}}

== External links ==
{{Medical resources
| DiseasesDB =
| ICD10 =
| ICD9 =
| ICDO =
| OMIM =
| MedlinePlus =
| eMedicineSubj = med
| eMedicineTopic = 1173
}}
* {{Cite book | url = http://diabetes.niddk.nih.gov/dm/pubs/insulinresistance/ | title = Diabetes | contribution = Insulin resistance | publisher = NIH | location = US | access-date = 2013-04-25 | archive-date = 2015-05-13 | archive-url = https://web.archive.org/web/20150513011234/http://diabetes.niddk.nih.gov/DM/pubs/insulinresistance/ | url-status = dead }}

{{diabetes}}
{{Disease of the pancreas and glucose metabolism}}
{{Authority control}}

{{DEFAULTSORT:Insulin Resistance}}
[[Category:Diabetes]]