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 in fat cells results in hydrolysis of stored triglycerides, which elevates free fatty acids in the blood plasma. Insulin resistance in muscle reduces glucose uptake whereas insulin resistance in liver reduces glucose storage, with both effects serving to elevate blood glucose. High plasma levels of insulin and glucose due to insulin resistance often leads to metabolic syndrome and type 2 diabetes. eMedicine is an online clinical medical knowledge base that was founded in 1996. ... Medical Subject Headings (MeSH) is a huge controlled vocabulary (or metadata system) for the purpose of indexing journal articles and books in the life sciences. ... Insulin (from Latin insula, island, as it is produced in the Islets of Langerhans in the pancreas) is a polypeptide hormone that regulates carbohydrate metabolism. ... Fats consist of a wide group of compounds that are generally soluble in organic solvents and largely insoluble in water. ... A top-down view of skeletal muscle Muscle (from Latin musculus little mouse [1]) is contractile tissue of the body and is derived from the mesodermal layer of embryonic germ cells. ... The liver is an organ present in vertebrates and some other animals. ... Drawing of the structure of cork as it appeared under the microscope to Robert Hook from Micrographia which is the origin of the word cell. POOP Cells in culture, stained for keratin (red) and DNA (green). ... Hydrolysis is a chemical reaction or process in which a chemical compound reacts with water. ... Example of an unsaturated fat triglyceride. ... In chemistry, especially biochemistry, a fatty acid is a carboxylic acid often with a long unbranched aliphatic tail (chain), which is either saturated or unsaturated. ... Blood plasma is the liquid component of blood, in which the blood cells are suspended. ... Glucose (Glc), a monosaccharide (or simple sugar), is the most important carbohydrate in biology. ... Metabolic syndrome is a combination of medical disorders that increase ones risk for cardiovascular disease and diabetes. ... See diabetes mellitus for further general information on diabetes. ...

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 to a normal level (approximately 5 mmol/L (mM), or 90 mg/dL). In an insulin resistant person, normal levels of insulin do not trigger the signal for glucose absorption by muscle and adipose cells. To compensate for this, the pancreas in an insulin resistant individual releases much more insulin such that the cells are adequately triggered to absorb glucose. Occasionally, this can lead to a steep drop in blood sugar and a hypoglycemic reaction several hours after the meal. A porcine islet of Langerhans. ... The pancreas is an organ in the digestive and endocrine system (of vertebrates[2]). It is both exocrine (secreting pancreatic juice containing digestive enzymes) and endocrine (producing several important hormones, including insulin, glucagon, and somatostatin). ... A top-down view of skeletal muscle Muscle (from Latin musculus little mouse [1]) is contractile tissue of the body and is derived from the mesodermal layer of embryonic germ cells. ... Adipose tissue is an anatomical term for loose connective tissue composed of energy in the form of fat, although it also cushions and insulates the body. ... Glucose (Glc), a monosaccharide (or simple sugar), is the most important carbohydrate in biology. ... Glucose (Glc), a monosaccharide (or simple sugar), is the most important carbohydrate in biology. ... Hypoglycemia is a medical term referring to a pathologic state produced and usually defined by a lower than normal amount of sugar (glucose) in the blood. ...

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 adequate insulin to maintain normal blood sugar levels (euglycemia). The inability of the β-cells to produce more insulin in a condition of hyperglycemia is what characterizes the transition from insulin resistance to type 2 diabetes.^[1] Insulin (from Latin insula, island, as it is produced in the Islets of Langerhans in the pancreas) is a polypeptide hormone that regulates carbohydrate metabolism. ... Metabolic syndrome is a combination of medical disorders that increase ones risk for cardiovascular disease and diabetes. ... See diabetes mellitus for further general information on diabetes. ... Hyperglycemia or High Blood Sugar is a condition in which an excessive amount of glucose circulates in the blood plasma. ...

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). An infection is the detrimental colonization of a host organism by a foreign species. ... In medicine, tumor necrosis factor alpha (TNFα, cachexin or cachectin) is an important cytokine involved in systemic inflammation and the acute phase response. ... Acidosis is an increased acidity (i. ... The adipokines or adipocytokines are a group of cytokines (cell-to-cell signalling proteins) secreted by adipose tissue. ... Cytokines are a group of proteins and peptides that are used in organisms as signaling compounds. ... It has been suggested that Subcutaneous fat be merged into this article or section. ... Glucocorticoids are a class of steroid hormones characterised by an ability to bind with the cortisol receptor and trigger similar effects. ...

Elevated blood levels of glucose regardless of cause leads to increased glycation of proteins. Glycation is the result of a sugar-reducing molecule, such as fructose or glucose, bonding to a protein or lipid molecule without the controlling action of an enzyme. ... A representation of the 3D structure of myoglobin, showing coloured alpha helices. ...

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 resisance 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. A glucose tolerance test in medical practice is the administration of glucose to determine how quickly it is cleared from the blood. ...

Interpretation is based on WHO guidelines, but glycemia greater than or equal to 11.1mmol/L at 2 hours or greater than or equal to 7.0mmol/L fasting is diagnostic for diabetes mellitus. Glycemia is the concentration of glucose in the blood. ...

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. Hypoglycemia (hypoglycæmia in the UK) is a medical term referring to a pathologic state produced by a lower than normal amount of sugar (glucose) in the blood. ...

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.^[2] 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. In medicine, a gold standard test is the diagnostic test that is regarded as definitive in determining whether an individual has a disease process. ... Glucose (Glc), a monosaccharide (or simple sugar), is the most important carbohydrate in biology. ... Insulin (from Latin insula, island, as it is produced in the Islets of Langerhans in the pancreas) is a polypeptide hormone that regulates carbohydrate metabolism. ... Hypoglycemia (hypoglycæmia in the UK) is a medical term referring to a pathologic state produced by a lower than normal amount of sugar (glucose) in the blood. ...

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 5-10minutes. 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. Peripheral Veins are the veins that are the veins leading back towards the heart from the organs below the stomach and also from the muscles in the arms, hands, legs and feet. ... Insulin (from Latin insula, island, as it is produced in the Islets of Langerhans in the pancreas) is a polypeptide hormone that regulates carbohydrate metabolism. ... A minute is a unit of time equal to 1/60th of an hour and to 60 seconds. ... An intravenous drip in a hospital Intravenous therapy or IV therapy is the administration of liquid substances directly into a vein. ... Glucose (Glc), a monosaccharide (or simple sugar), is the most important carbohydrate in biology. ... In medicine, blood sugar is a term used to refer to levels of glucose in the blood. ... A minute is a unit of time equal to 1/60th of an hour and to 60 seconds. ...

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 25mcg of sandosatin in 5ml of normal saline over 3-5 min IV as an initial bolus and then will be infused continuously with an intravenous infusion of somatostatin (0.27microgm/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 1/2 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 correllate 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.^[3] Hypoglycemia (hypoglycæmia in the UK) is a medical term referring to a pathologic state produced by a lower than normal amount of sugar (glucose) in the blood. ... The homeostatic model assessment (HOMA) is a method used to quantify insulin resistance. ... Fasting is primarily the act of willingly abstaining from some or all food, drink, or both, for a period of time. ... Insulin (from Latin insula, island, as it is produced in the Islets of Langerhans in the pancreas) is a polypeptide hormone that regulates carbohydrate metabolism. ... Glucose (Glc), a monosaccharide (or simple sugar), is the most important carbohydrate in biology. ...

Causes of insulin resistance

The cause of the vast majority of cases of insulin resistance remains unknown. [NIRC ED: While technically correct in the absence of proof from replicable scientific studies, one factor is highly implicated by epidemiological evidence: insulin resistance is coded in the genetics of about 10% of the population. This is inferred from the genetic risk inherent in indisputable family patterns of diabetes and heart disease occurence, two of insulin resistance's bad outcomes. Further, there is scientific evidence that insulin resistance is probably triggered, and certainly enhanced, by excess weight.]

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)

Ageing or aging is the process of getting older. ... Haemochromatosis, also spelled hemochromatosis, is a hereditary disease characterized by improper processing by the body of dietary iron which causes iron to accumulate in a number of body tissues, eventually causing organ dysfunction. ... Polycystic ovary syndrome (PCOS, also known clinically as Stein-Leventhal syndrome), is an endocrine disorder that affects 5–10% of women. ... Cushings syndrome or hypercortisolism is an endocrine disorder caused by excessive levels of the endogenous corticosteroid hormone cortisol. ... Steroid skeleton of lanosterol. ... Cushings syndrome or hypercortisolism is an endocrine disorder caused by excessive levels of the endogenous corticosteroid hormone cortisol. ... It has been suggested that Blockbuster drug be merged into this article or section. ... Rifampicin (INN) (IPA: ) or rifampin (USAN) is a bacteriocidal antibiotic drug of the rifamycin group. ... Isoniazid (also called isonicotinyl hydrazine or isonicotinic acid hydrazide); abbreviated INH or just H. Isoniazid is a first-line antituberculous medication used in the prevention and treatment of tuberculosis. ... Olanzapine (oh-LAN-za-peen, sold as Zyprexa®, Zyprexa Zydis®, or in combination with fluoxetine, as Symbyax®) was the third atypical antipsychotic to gain approval by the Food and Drug Administration (FDA) and has become one of the most commonly used atypical antipsychotics. ... Risperdal tablets Risperidone (sold under the trade names Belivon, Rispen and Risperdal in the United States) is an atypical antipsychotic medication developed by Janssen Pharmaceutica. ... Progestagens (also spelled progestogens or gestagens) are hormones similar in effect to progesterone, the only natural progestagen. ... Functional group of an alcohol molecule. ... Methadone is a synthetic opioid, used medically as an analgesic and in the treatment of narcotic addiction. ... In molecular biology, the insulin receptor is a transmembrane receptor that is activated by insulin. ... Donohue Syndrome (also known as Leprechaunism) is an extremely rare medical condition. ... LMNA is a lamin gene associated with Emery-Dreifuss muscular dystrophy. ...

Therapy

The primary treatment for insulin resistance is exercise and weight loss. In some individuals, a low glycemic index 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. [NIRC ED: Nevertheless, metformin, the 8th most often prescribed drug in the US, is often prescribed for pre-diabetes and insulin resistance despite FDA instructions.] By contrast, growth hormone replacement therapy may be associated with increased insulin resistance.^[4] The term Exercise can refer to: Physical exercise such as running or strength training Exercise (options), the financial term for enacting and terminating a contract Category: ... Weight loss, in the context of medicine or health, is a reduction of the total body weight, which can mean loss of fluid, muscle, bone mass, or fat. ... Glycemic index (also glycaemic index, GI) is a ranking system for carbohydrates based on their immediate effect on blood glucose levels. ... Metformin (INN; trade names Glucophage, Diabex, Diaformin, Fortamet, Riomet, Glumetza and others) is an anti-diabetic drug from the biguanide class of oral hypoglycemic agents. ... The medication class of thiazolidinedione was introduced in the late 1990s as an adjunctive therapy for diabetes mellitus (type II) and related diseases. ... Growth hormone (GH) is a protein hormone secreted by the pituitary gland which stimulates growth and cell reproduction. ...

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.^[5] [NIRC ED: However, the same study showed that combining exercise, improved diet and metformin produced the most dramatic results.] Metformin (INN; trade names Glucophage, Diabex, Diaformin, Fortamet, Riomet, Glumetza and others) is an anti-diabetic drug from the biguanide class of oral hypoglycemic agents. ...

Monounsaturated fatty acids (like unsaturated fats) promote insulin resistance, whereas polyunsaturated fatty acids can increase insulin sensitivity.^[6][7][8] In nutrition, monounsaturated fats are fatty acids with one double-bonded carbon in the molecule, with all of the others single-bonded carbons, in contrast to polyunsaturated fatty acids which have more than one double bond. ... An unsaturated fat is a fat or fatty acid in which there are one or more double bonds in the fatty acid chain. ... // In nutrition, polyunsaturated fat is an abbreviation of polyunsaturated fatty acid. ...

There are scientific studies showing that chromium picolinate can increase insulin sensitivity, especially in type 2 diabetics, but other studies show no effect. The results are controversial. Chromium picolinate is a bright red solid that is the chromium (III) salt of picolinic acid. ...

Naturopathic approaches to insulin resistance have been advocated including supplementation of vanadium, bitter melon (momordica) and gymnema sylvestra. There is little, if any, scientific support for any of these supplements.

History

The concept that insulin resistance may be the underlying cause of diabetes mellitus type 2 was first advanced by Sir Harold Percival Himsworth of the University College Hospital Medical Center in London in 1936.^[9] For the disease characterized by excretion of large amounts of very dilute urine, see diabetes insipidus. ... Sir Harold Percival (Harry) Himsworth (19 May 1905 - 1 November 1993) was a British scientist, best known for his medical research on diabetes mellitus. ... 1936 (MCMXXXVI) was a leap year starting on Wednesday (link will take you to calendar). ...

References

The New England Journal of Medicine (NEJM) is a peer-reviewed medical journal published by the Massachusetts Medical Society with the highest impact factor for a general medical journal. ...

External links

• Insulin resistance at the Open Directory Project
• Insulin Resistance Information