Insulin resistance

Infobox_Disease
Name = Insulin resistance


Caption =
DiseasesDB =
ICD10 =
ICD9 =
ICDO =
OMIM =
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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 cells. Insulin resistance (IR) in fat cells reduces the effects of insulin and results in elevated hydrolysis of stored triglycerides 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 acids 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 type 2 diabetes, including its complications.

ymptoms 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.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]

Various disease states make the body tissues more resistant to the actions of insulin. Examples include infection (mediated by the cytokine TNFα) and acidosis. Recent research is investigating the roles of adipokines (the cytokines produced by adipose tissue) in insulin resistance. Certain drugs may also be associated with insulin resistance (e.g., glucocorticoids).

Insulin itself can lead to insulin resistance; every time a cell is exposed to insulin, the production of GLUT4 (type four glucose receptors) on the cell's membrane is decreased. [ cite journal | author=J R Flores-Riveros |title=Insulin down-regulates expression of the insulin-responsive glucose transporter (GLUT4) gene: effects on transcription and mRNA turnover |journal PNAS |volume=90 |issue=2 |pages=512-516 |year=1993] This leads to a greater need for insulin, which again leads to fewer glucose receptors. Exercise reverses this process in muscle tissue [ cite journal | author=Paul S. MacLean_2002 |title=Exercise-Induced Transcription of the Muscle Glucose Transporter (GLUT 4) Gene |journal=Biochemical and Biophysical Research Communications |volume=292 |issue=2 |pages=409-414 |year=2002 |doi=10.1006/bbrc.2002.6654] , but if left unchecked, it can spiral into insulin resistance.

Elevated blood levels of glucose — regardless of cause — leads to increased glycation of proteins 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.

Magnesium (Mg) is one of the most abundant ions present in living cells and its plasma concentration is remarkably constant in healthy subjects. Plasma and intracellular Mg concentrations are tightly regulated by several factors. Among them, insulin seems to be one of the most important. In vitro and in vivo studies have demonstrated that insulin may modulate the shift of Mg from extracellular to intracellular space. Intracellular Mg concentration has also been shown to be effective in modulating insulin action (mainly oxidative glucose metabolism), offset calcium-related excitation-contraction coupling, and decrease smooth cell responsiveness to depolarizing stimuli. A poor intracellular Mg concentration, as found in noninsulin-dependent diabetes mellitus (NIDDM) and in hypertensive patients, may result in a defective tyrosine-kinase activity at the insulin receptor level and exaggerated intracellular calcium concentration. Both events are responsible for the impairment in insulin action and a worsening of insulin resistance in noninsulin-dependent diabetic and hypertensive patients. By contrast, in NIDDM patients daily Mg administration, restoring a more appropriate intracellular Mg concentration, contributes to improve insulin-mediated glucose uptake. The benefits deriving- from daily Mg supplementation in NIDDM patients are further supported by epidemiological studies showing that high daily Mg intake are predictive of a lower incidence of NIDDM.

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 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 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.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] 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 m² per minute. In order to compensate for the insulin 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 3-³H glucose (radioactive), 6,6 ²H-glucose (stable) and 1-¹³C 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/m²/min) to suppress endogenous insulin and glucose secretion. Insulin and 20% glucose is then infused at rates of 32 and 267mg/m²/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 (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.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 ]

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.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 ] Insulin resistance has also been linked to PCOS (polycystic ovary syndrome) 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 — high fructose corn syrup, 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). Insulin resistance has certainly risen in step with the increase in sugar consumption and the substantial commercial usage 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. 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=] Inflammation also contributes to insulin resistance. Mice without JNK1-signaling do not develop insulin resistance under dietary conditions that normally produce it.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] 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=]

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.

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 existence 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)
* Drugs (e.g., rifampicin, isoniazid, olanzapine, risperidone, progestogens, 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 thiazolidinediones improve insulin resistance, but are only approved therapies for type 2 diabetes, not insulin resistance, "per se". By contrast, growth hormone replacement therapy may be associated with increased insulin resistance.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] Metformin has become one of the more commonly prescribed medications for insulin resistance, 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 insulin resistance by the same mechanism as it does diabetes. It also has been used to aid in weight loss for diabetics and those with insulin resistance, 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.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]

Many people with insulin resistance 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 most commercial cinnamon preparations are actually from "cassia", which also has anticoagulants, though true cinnamon "cinnamomum sp. zeylonicum", or "sp. verum", does not.

Some types of Monounsaturated fatty acids and saturated fats appear to promote insulin resistance, whereas some types of polyunsaturated fatty acids (omega-3) can increase insulin sensitivity.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 ] 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] 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 ]

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.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]

One study found that chromium is necessary for maintaining normal glucose tolerance. [Article: Chromium Critical for Glucose Tolerance by Judy McBride, USDA 1999 ]

Daily Mg administration, restoring a appropriate intracellular Mg concentration, contributes to improve insulin-mediated glucose uptake. High daily Mg intake are predictive of a lower incidence of NIDDM.

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 in1931 cite journal | author = Falta W, Boller R | title = Insularer und insulinresistenter Diabetes | journal = Klin Wochenschr | year = 1931 | volume = 10 | pages = 438–443 | url= | doi = ] , and confirmed by Sir Harold Percival Himsworth of the University College Hospital Medical Center in London in 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 ]

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.

ee 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.realfoodnutrients.com/db/trials8.htm Chromum Critical in Glucose Tolerance USDA Article]