Insulin resistance
54448
225681943
2008-07-14T21:45:38Z
Ianmc
50870
[[WP:UNDO|Undid]] revision 225384977 by [[Special:Contributions/69.118.197.140|69.118.197.140]] ([[User talk:69.118.197.140|talk]])first spelling was correct
{{Infobox_Disease |
Name = Insulin resistance |
Image = |
Caption = |
DiseasesDB = |
ICD10 = |
ICD9 = |
ICDO = |
OMIM = |
MedlinePlus = |
eMedicineSubj = med |
eMedicineTopic = 1173 |
MeshName = Insulin+Resistance |
MeshNumber = C18.452.394.968.500 |
}}
'''Insulin resistance''' is the condition in which normal amounts of [[insulin]] are inadequate to produce a normal [[insulin response]] from [[fat]], [[muscle]] and [[liver]] [[cell (biology)|cells]]. Insulin resistance in [[adipose tissue|fat cells]] reduces the effects of insulin and results in elevated [[hydrolysis]] of stored [[triglyceride]]s in the absence of measures which either increase insulin sensitivity or which provide additional insulin. Increased mobilization of stored lipids in these cells elevates free [[fatty acid]]s in the [[blood plasma]]. Insulin resistance in muscle cells reduces [[glucose]] uptake (and so local storage of glucose as [[glycogen]]), whereas insulin resistance in liver cells reduces storage of glycogen, making it unavailable for release into the blood when blood insulin levels fall (normally only when blood glucose levels are low). Both cause elevated blood glucose levels. High plasma levels of insulin and glucose due to insulin resistance often lead to [[metabolic syndrome]] and [[diabetes mellitus type 2|type 2 diabetes]], including its complications.
==Symptoms of IR==
# Fatigue.
# Brain fogginess and inability to focus. Sometimes the fatigue is physical, but often it is mental.
# Low blood sugar. Mild, brief periods of low blood sugar are normal during the day, especially if meals are not eaten on a regular schedule; they are normally raised by mobilization of glucose into the blood from stored glycogen made from blood glucose previously taken by liver cells. But prolonged hypoglycemia, with some of the symptoms listed here, especially physical and mental fatigue, is not normal. Feeling agitated, jittery, moody, nauseous, or having a headache is common in insulin resistance, commonly with rapid relief once food is eaten.
# Intestinal bloating. Most intestinal gas is produced from carbohydrates in the diet. Insulin resistance sufferers who eat carbohydrates sometimes suffer from gas.
# Sleepiness. Many people with insulin resistance get sleepy immediately after eating a meal containing more than 20% or 30% carbohydrates.
# Weight gain, fat storage, difficulty losing weight. For most people, too much weight is too much fat. The fat in IR is generally stored in and around abdominal organs in both males and females. It is currently suspected that hormonal effects from such fat are a precipitating cause of insulin resistance.
# Increased blood triglyceride levels.
# Increased blood pressure. Many people with hypertension are either diabetic or pre-diabetic and have elevated insulin levels due to insulin resistance. One of insulin's effects is on arterial walls throughout the body.
# Depression. Because of the deranged metabolism resulting from insulin resistance, psychological effects are not uncommon. Depression is said to be the prevalent psychological symptom.**
==Pathophysiology==
In a person with normal metabolism, insulin is released from the beta (β) cells of the [[Islets of Langerhans]] located in the [[pancreas]] after eating ("postprandial"), and it signals insulin-sensitive tissues in the body (e.g., [[muscle]], [[adipose]]) to absorb [[glucose]] to lower blood glucose. The beta cells reduce their insulin output as blood glucose levels fall, with the result that blood glucose is maintained at approximately 5 mmol/L (mM) (90 mg/dL). In an ''insulin-resistant'' person, normal levels of insulin do not have the same effect on muscle and adipose cells, with the result that glucose levels stay higher than normal. To compensate for this, the pancreas in an insulin-resistant individual is stimulated to release more insulin. The elevated insulin levels have additional effects (see [[insulin]]) which further cause biological effects throughout the body.
The most common type of [[insulin]] resistance is associated with a disease state known as [[metabolic syndrome]]. Insulin resistance can progress to full [[type 2 diabetes]]. This is often seen when [[hyperglycemia]] develops after a meal, when pancreatic β-cells are unable to produce sufficient insulin to maintain normal blood sugar levels ([[euglycemia]]). 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.<ref name = McGarry_2002>{{cite journal |author=McGarry J |title=Banting lecture 2001: dysregulation of fatty acid metabolism in the etiology of type 2 diabetes |journal=Diabetes |volume=51 |issue=1 |pages=7–18 |year=2002 |pmid=11756317 |doi=10.2337/diabetes.51.1.7}}</ref>
Various disease states make the body tissues more resistant to the actions of insulin. Examples include [[infection]] (mediated by the cytokine [[tumor necrosis factor-alpha|TNFα]]) and [[acidosis]]. Recent research is investigating the roles of [[adipokine]]s (the [[cytokine]]s produced by [[adipose tissue]]) in insulin resistance. Certain drugs may also be associated with insulin resistance (e.g., [[glucocorticoid]]s).
Elevated blood levels of glucose — regardless of cause — leads to increased [[glycation]] of [[protein]]s with changes (only a few of which are known) in protein function throughout the body.
Insulin resistance is often found in people with visceral adiposity (i.e., a high degree of fatty tissue underneath the abdominal muscle wall - as distinct from subcutaneous adiposity or fat between the skin and the muscle wall), hypertension, hyperglycemia and dyslipidemia involving elevated triglycerides, small dense low-density lipoprotein (sdLDL) particles, and decreased HDL cholesterol levels.
Insulin resistance is also often associated with a hypercoagulable state (impaired fibrinolysis) and increased inflammatory cytokine levels.
Insulin resistance is also occasionally found in patients who use insulin. In this case, the production of antibodies against insulin leads to lower-than-expected falls of glucose levels (glycemia) after a given dose of insulin. With the development of human insulin and analogues in the 1980s and the decline in the use of animal insulins (e.g., pork, beef), this type of insulin resistance has become very uncommon.
==Investigation==
===Fasting Insulin Levels===
A fasting serum insulin level of greater than the upper limit of normal for the assay used (approximately 60pmol/L) is considered evidence of insulin resistance.
===Glucose tolerance testing (GTT)===
During a [[glucose tolerance test]], which may be used to diagnose diabetes mellitus, a fasted patient takes a 75 gram oral dose of glucose. Blood glucose levels are then measured over the following 2 hours.
Interpretation is based on WHO guidelines. After 2 hours a [[Glycemia]] less than 7.8 mmol/L is considered normal, a glycaemia of between 7.8 to 11.0 is considered as Impaired Glucose Tolerance (IGT) and a glycaemia of greater than or equal to 11.1 is considered [[Diabetes Mellitus]].
OGTT can 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 (after the meal) peak in insulin production. Extension of the testing (for several more hours) may reveal a [[hypoglycemia|hypoglycemic]] "dip," which is a result of an overshoot in insulin production after the failure of the physiologic postprandial insulin response.
===Measuring Insulin Resistance===
'''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 |author=DeFronzo R, Tobin J, Andres R |title=Glucose clamp technique: a method for quantifying insulin secretion and resistance |journal=Am J Physiol |volume=237 |issue=3 |pages=E214–23 |year=1979 |pmid=382871}}</ref> 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 is commonly referred to in diabetes literature as the GINF value.
The procedure takes about 2 hours. Through a [[peripheral vein]], [[insulin]] is infused at 10-120 mU per m<small><sup>2</sup></small> 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 mmol/l. The rate of glucose infusion is determined by checking the [[blood sugar]] levels every 5 to 10 minutes. Low-dose insulin infusions are more useful for assessing the response of the liver, whereas high-dose insulin infusions are useful for assessing peripheral (i.e., muscle and fat) insulin action.
The rate of glucose infusion during the last 30 minutes of the test determines insulin sensitivity. If high levels (7.5 mg/min or higher) are required, the patient is insulin-sensitive. Very low levels (4.0 mg/min or lower) indicate that the body is resistant to insulin action. Levels between 4.0 and 7.5 mg/min are not definitive and suggest "impaired glucose tolerance," an early sign of insulin resistance.
This basic technique can be significantly enhanced by the use of glucose tracers. Glucose can be labeled with either stable or radioactive atoms. Commonly-used tracers are 3-<sup><small>3</small></sup>H glucose (radioactive), 6,6 <sup><small>2</small></sup>H-glucose (stable) and 1-<sup><small>13</small></sup>C Glucose (stable). Prior to beginning the hyperinsulinemic period, a 3h tracer infusion enables one to determine the basal rate of glucose production. During the clamp, the plasma tracer concentrations enable the calculation of whole-body insulin-stimulated glucose metabolism, as well as the production of glucose by the body (i.e., endogenous glucose production).
'''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.
Patients initially receive 25 mcg of octreotide (Sandostatin) in 5 ml of normal saline over 3 to 5 min IV as an initial bolus, and then will be infused continuously with an intravenous infusion of somatostatin (0.27μgm/m<small><sup>2</sup></small>/min) to suppress endogenous insulin and glucose secretion. Insulin and 20% glucose is then infused at rates of 32 and 267mg/m<sup><small>2</small></sup>/min, respectively. Blood glucose is checked at zero, 30, 60, 90, and 120 minutes, and then every 10 minutes for the last half-hour of the test. These last 4 values are averaged to determine the steady-state plasma glucose level. Subjects with an SSPG greater than 150mg/dl are considered to be insulin-resistant.
===Alternatives===
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), and a more recent method is the QUICKI (quantitative insulin sensitivity check index). Both employ [[fasting]] [[insulin]] and [[glucose]] levels to calculate insulin resistance, and both correlate reasonably with the results of clamping studies. Wallace ''et al'' point out that QUICKI is the [[logarithm]] of the value from one of the HOMA equations.<ref name=Wallace_2004>{{cite journal |author=Wallace T, Levy J, Matthews D |title=Use and abuse of HOMA modeling |journal=Diabetes Care |volume=27 |issue=6 |pages=1487–95 |year=2004 |pmid=15161807 | doi = 10.2337/diacare.27.6.1487 <!--Retrieved from CrossRef by DOI bot-->}}</ref>
==Causes of insulin resistance==
The cause of the vast majority of cases of insulin resistance remains unknown. There is clearly an inherited component, as sharply increased rates of insulin resistance and Type 2 diabetes are found in those with close relatives who have developed Type 2 diabetes. However, there are some grounds for suspecting that insulin resistance is related to a high-carbohydrate diet. An American study has shown that [[glucosamine]] (often prescribed for joint problems) may cause insulin resistance.<ref name=Pham2007>{{cite journal
| author = Pham, T
| coauthors = Cornea A; Blick KE; Jenkins A; Scofield RHMD
| year = 2007
| title = Oral Glucosamine in Doses Used to Treat Osteoarthritis Worsens Insulin Resistance
| journal = The American Journal of the Medical Sciences
| volume = 333
| pmid =17570985
| issue = 6
| pages = 333–339
| url = http://www.amjmedsci.com/pt/re/ajms/fulltext.00000441-200706000-00003.htm
| accessdate = 2007-11-11
| doi = 10.1097/MAJ.0b013e318065bdbe
}}</ref>
Insulin resistance has also been linked to [[PCOS]] (<u>p</u>oly<u>c</u>ystic <u>o</u>vary <u>s</u>yndrome) as either causing it or being caused by it. Further studies are in progress. Other studies have also linked to the increased amounts of fructose (e.g., in HFCS — <u>h</u>igh <u>f</u>ructose <u>c</u>orn <u>s</u>yrup, currently the least expensive nutritive sweetener available in industrial quantities), its fructose causing changes in blood lipid profiles, among other things. The high amounts of ordinary sucrose (i.e., table sugar) in the typical developed-world diet is also suspected of having some causative effect on the development of insulin resistance (sucrose is 1/2 fructose, which may account for the effect, if any). IR has certainly risen in step with the increase in sugar consumption and the substantial commercial useage of HFCS since its introduction to the food trades.
At the cellular level, down-regulation of insulin receptors occurs due to high circulating insulin amounts, apparently independently of insulin resistance. <ref name="titleEmergency Medicine">
{{cite web
|url=http://www.emedmag.com/html/pre/fea/features/101501.asp
|publisher=Emergency Medicine
|title=Intensive Management of Type 2 Diabetes
|author=Jeff Unger
|accessdate=2008-01-13
|format=
|work=
}}</ref>
Inflammation also contributes to insulin resistance. Mice without [[C-Jun N-terminal kinases|JNK1]]-signaling do not develop insulin resistance under dietary conditions that normally produce it.<ref name=Solinas >
{{cite journal
|url=http://www.cellmetabolism.org/content/article/abstract?uid=PIIS1550413107002926
|title=JNK1 in Hematopoietically Derived Cells Contributes to Diet-Induced Inflammation and Insulin Resistance without Affecting Obesity
|author=Solinas Giovanni ''et al''
|journal=Cell Metabolism,
|volume=6
|pages=386–397
|date=2007-11-07
|accessdate=2008-01-11
|doi=10.1016/j.cmet.2007.09.011
}}</ref>
<ref name="titleDiabetes News from dLife.com: UCSD Researchers Discover Inflammation, Not Obesity, Cause of Insulin Resistance">
{{cite web |url=http://www.dlife.com/diabetes-news/2007/11/ucsd_researchers_discover_infl.html |title=UCSD Researchers Discover Inflammation, Not Obesity, Cause of Insulin Resistance |accessdate=2008-01-12 |format= |work=}}</ref>
Some research has shed light on a complex interaction between elevated free fatty acids and inflammatory cytokines seen in obesity activating Protein Kinase C isoform theta. PKC Theta inhibits Insulin Receptor Substrate (IRS) activation and hence prevents glucose up-take in response to insulin. <!-- <ref name="titleMolecular mechanisms of insulin resistance.">{{cite web |url=http://www.blackwell-synergy.com/doi/full/10.1111/j.1464-5491.2005.01566.x?cookieSet=1 -->
Recent research and experimentation has uncovered a non-obesity related connection to insulin resistance and Type 2 diabetes. It has long been observed that patients who have had some kinds of bariatric surgery have increased insulin sensitivity and even remission of Type 2 diabetes. It was discovered that diabetic / insulin resistant non obese rats whose proximal small intestine and duodenum has been surgically removed also experienced increased insulin sensitivity and remission of Type 2 diabetes. This suggested similar surgery in humans, and early reports in prominent medical journals (January 08) are that the same effect is seen in humans, at least the small number who have participated in the experimental surgical program. The speculation is that some substance is produced in that portion of the small intestine which 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, so its existance remains speculation.
==Associated Conditions==
Several associated conditions include
* Abnormally Sedentary Lifestyle, whether the result of the effects of [[aging]] on the body or lack of physical exercise (both of which can also produce [[obesity]])
* [[Haemochromatosis]]
* [[Polycystic ovarian syndrome]] (PCOS)
* [[Hypercortisolism]] (e.g., [[steroid]] use or [[Cushing's disease]])
* [[Medication|Drugs]] (e.g., [[rifampicin]], [[isoniazid]], [[olanzapine]], [[risperidone]], [[progestogen]]s, many antiretrovirals, possibly [[alcohol]], [[methadone]])
* Genetic causes
**[[Insulin receptor]] mutations ([[Donohue Syndrome]])
**[[LMNA]] mutations ([[Familial Partial Lipodystrophy]])
Insulin resistance may also be caused by the damage of liver cells having undergone a defect of insulin receptors in hepatocytes.
==Treatment==
The primary treatment for insulin resistance is [[exercise]] and [[weight loss]]. In some individuals, a low-[[glycemic index]] or a low-carbohydrate diet may also help. Both [[metformin]] and the [[thiazolidinedione]]s improve insulin resistance, but are only approved therapies for type 2 diabetes, not insulin resistance, ''per se''. By contrast, [[Growth hormone treatment|growth hormone replacement therapy]] may be associated with increased insulin resistance.<ref name=Bramnert_2003>{{cite journal | author=Bramnert M, Segerlantz M, Laurila E, Daugaard JR, Manhem P, Groop L | title=Growth hormone replacement therapy induces insulin resistance by activating the glucose-fatty acid cycle | journal=The Journal Of Clinical Endocrinology & Metabolism| year=2003| volume=88 | issue=4 | pages=1455–1463 | url=http://jcem.endojournals.org/cgi/content/full/88/4/1455 | pmid=12679422 | doi=10.1210/jc.2002-020542}}</ref>
Metformin has become one of the more commonly prescribed medications for IR, and currently a newer drug, [[exenatide]] (marketed as Byetta), is being used. Exenatide has not been approved except for use in diabetics, but often improves IR by the same mechanism as it does diabetes. It also has been used to aid in weight loss for diabetics and those with IR, and is being studied for this use as well as for weight loss in people who have gained weight while on antidepressants. The ''Diabetes Prevention Program'' 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 | author=Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, Nathan DM; Diabetes Prevention Program Research Group | title=Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin | journal=[[New England Journal of Medicine]]| year=2002 | volume=346 | issue=6 | pages=393–403 | url=http://content.nejm.org/cgi/content/abstract/346/6/393 | pmid=11832527 | doi=10.1056/NEJMoa012512}}</ref>
Many people with IR currently follow the lead of some diabetics, and add cinnamon in therapeutic doses to their diet to help control blood sugar. This has the danger of increasing the risk of bleeding, since many commercial cinnamon preparations are actually from <i>[[cassia]]</i>, which also has anticoagulants, though true [[cinnamon]] <i>cinnamomum sp. zeylonicum</i>, or <i>sp. verum</i>, does not.
Some types of [[Monounsaturated fat|Monounsaturated fatty acids]] and saturated fats appear to promote insulin resistance, whereas some types of [[Polyunsaturated fat|polyunsaturated fatty acids]] ([[omega-3]]) can increase insulin sensitivity.<ref name=Lovejoy_2002>{{cite journal | author=Lovejoy, JC | title=The influence of dietary fat on insulin resistance | journal=Current Diabetes Reports | year=2002 | volume=2 | issue=5 | pages= 435–440 | pmid=12643169 | doi = 10.1007/s11892-002-0098-y <!--Retrieved from CrossRef by DOI bot-->}}</ref><ref name=Fukuchi_2004>{{cite journal | author=Fukuchi S | title=Role of Fatty Acid Composition in the Development of Metabolic Disorders in Sucrose-Induced Obese Rats | journal=Experimental Biology and Medicine | year=2004 | volume=229 | issue=6 | pages= 486–493 | url=http://www.ebmonline.org/cgi/content/full/229/6/486 | pmid=15169967}}</ref><ref name=Storlien_1996>{{cite journal | author=Storlien LH | title=Dietary fats and insulin action | journal=Diabetologica | year=1996 | volume=39 | issue=6 | pages=621–631 | pmid=8781757 | doi = 10.1007/BF00418533 <!--Retrieved from CrossRef by DOI bot-->}}</ref>
There are scientific studies showing that vanadium (e.g., as [[vanadyl sulfate]]) and chromium (e.g., in [[chromium picolinate]] and GTF formulations) in reasonable doses have reportedly also shown some efficacy in improving IR, but these effects are controversial.
Naturopathic approaches to insulin resistance have been advocated including supplementation of vanadium (but see preceding paragraph), bitter melon ([[Momordica]], but reportedly dangerous if not used with care), and [[Gymnema sylvestre]].<ref name=Harinantenaina_2006>{{cite journal | author=Harinantenaina L | title=Momordica charantia constituents and antidiabetic screening of the isolated major compounds | journal=Chemical & Pharmaceutical Bulletin (Tokyo) | year=2006 | volume=54 | issue=7 | pages= 1017–21 | url=http://www.jstage.jst.go.jp/article/cpb/54/7/54_1017/_article | pmid=16819222 | doi=10.1248/cpb.54.1017}}</ref>
==History==
The concept that insulin resistance may be the underlying cause of [[diabetes mellitus]] type 2 was first advanced by Prof. Wilhelm Falta and published in Vienna in[[1931]] <ref name=Falta_1931>{{cite journal | author = Falta W, Boller R | title = Insularer und insulinresistenter Diabetes | journal = Klin Wochenschr | year = 1931 | volume = 10 | pages = 438–443 | url= | doi = }}</ref>, and confirmed by Sir [[Harold Percival Himsworth]] of the University College Hospital Medical Center in London in [[1936]].<ref name=Himsworth_1936>{{cite journal | author = Himsworth HP | title = Diabetes mellitus: its differentiation into insulin-sensitive and insulin-insensitive types | journal = Lancet | year = 1936 | volume = 1 | pages = 127–130 | url= | doi = 10.1016/S0140-6736(01)36134-2 }}</ref>
==References==
* symptoms list was quoted in part from various websites that are trying to educate the public about the illness, but were edited for accuracy.
<!-- ---------------------------------------------------------------
See http://en.wikipedia.org/wiki/Wikipedia:Footnotes for a
discussion of different citation methods and how to generate
footnotes using the <ref> & </ref> tags and the {{Reflist}} template
-------------------------------------------------------------------- -->
{{Reflist|2}}
==See also==
* [[Chronic Somogyi rebound]]
==External links==
* [http://www.insulinresistancecouncil.org The National Insulin Resistance Council]
* [http://search.dmoz.org/cgi-bin/search?search=Insulin+resistance Insulin resistance] at the [[Open Directory Project]]
* [http://www.online-diabetes-information.com/insulin/insulin-resistance/ Insulin Resistance Information]
* [http://www.d4pro.com/idm/site/simple_assessment_of_insulin____.htm Simple assessment of insulin sensitivity and secretion]
* [http://www.healthynerd.com/2006/08/02/bitter-melon-prickly-pear-cactus-reduce-glucose-levels-of-type-2-diabetics/ Bitter Melon, Prickly Pear Cactus, Address Insulin Resistance]
[[Category:Diabetes]]
[[af:Insulienweerstandigheid]]
[[de:Insulinresistenz]]
[[ko:인슐린 저항성]]
[[id:Penolakan insulin]]
[[ja:インスリン抵抗性]]
[[pl:Insulinooporność]]
[[pt:Resistência à insulina]]
[[fi:Insuliiniresistenssi]]
[[tr:İnsülin direnci]]
[[zh:胰岛素抵抗]]