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07-SEPTEMBER-2008 03:17:44 - Insulin resistance Insulin resistance Classification and external resources eMedicine med/1173 MeSH 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. Contents 1 Symptoms of IR 2 Pathophysiology 3 Investigation 3.1 Fasting Insulin Levels 3.2 Glucose tolerance testing GTT 3.3 Measuring Insulin Resistance 3.4 Alternatives 4 Causes of insulin resistance 5 Associated Conditions 6 Treatment 7 History 8 References 9 See also 10 External links 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.1 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.2 This leads to a greater need for insulin, which again leads to fewer glucose receptors. Exercise reverses this process in muscle tissue3, 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. 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.4 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.5 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.6 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. 7 Inflammation also contributes to insulin resistance. Mice without JNK1-signaling do not develop insulin resistance under dietary conditions that normally produce it.8 9 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.10 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.11 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.121314 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.15 One study found that chromium is necessary for maintaining normal glucose tolerance. 16 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 17, and confirmed by Sir Harold Percival Himsworth of the University College Hospital Medical Center in London in 1936.18 References symptoms list was quoted in part from various websites that are trying to educate the public about the illness, but were ed for accuracy. ^ McGarry J 2002. Banting lecture 2001: dysregulation of fatty acid metabolism in the etiology of type 2 diabetes. Diabetes 51 1: 7-18. doi:10.2337/diabetes.51.1.7. PMID 11756317. ^ J R Flores-Riveros 1993. Insulin down-regulates expression of the insulin-responsive glucose transporter GLUT4 gene: effects on transcription and mRNA turnover 90 2: 512-516. ^ Paul S. MacLean_2002 2002. Exercise-Induced Transcription of the Muscle Glucose Transporter GLUT 4 Gene. Biochemical and Biophysical Research Communications 292 2: 409-414. doi:10.1006/bbrc.2002.6654. ^ DeFronzo R, Tobin J, Andres R 1979. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol 237 3: E214-23. PMID 382871. ^ Wallace T, Levy J, Matthews D 2004. Use and abuse of HOMA modeling. Diabetes Care 27 6: 1487-95. doi:10.2337/diacare.27.6.1487. PMID 15161807. ^ Pham, T; Cornea A; Blick KE; Jenkins A; Scofield RHMD 2007. Oral Glucosamine in Doses Used to Treat Osteoarthritis Worsens Insulin Resistance. The American Journal of the Medical Sciences 333 6: 333-339. doi:10.1097/MAJ.0b013e318065bdbe. PMID 17570985. Retrieved on 2007-11-11. ^ Jeff Unger. Intensive Management of Type 2 Diabetes. Emergency Medicine. Retrieved on 2008-01-13. ^ Solinas Giovanni et al 2007-11-07. JNK1 in Hematopoietically Derived Cells Contributes to Diet-Induced Inflammation and Insulin Resistance without Affecting Obesity. Cell Metabolism, 6: 386-397. doi:10.1016/j.cmet.2007.09.011. Retrieved on 2008-01-11. ^ UCSD Researchers Discover Inflammation, Not Obesity, Cause of Insulin Resistance. Retrieved on 2008-01-12. ^ Bramnert M, Segerlantz M, Laurila E, Daugaard JR, Manhem P, Groop L 2003. Growth hormone replacement therapy induces insulin resistance by activating the glucose-fatty acid cycle. The Journal Of Clinical Endocrinology Metabolism 88 4: 1455-1463. doi:10.1210/jc.2002-020542. PMID 12679422. ^ Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, Nathan DM; Diabetes Prevention Program Research Group 2002. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. New England Journal of Medicine 346 6: 393-403. doi:10.1056/NEJMoa012512. PMID 11832527. ^ Lovejoy, JC 2002. The influence of dietary fat on insulin resistance. Current Diabetes Reports 2 5: 435-440. doi:10.1007/s11892-002-0098-y. PMID 12643169. ^ Fukuchi S 2004. Role of Fatty Acid Composition in the Development of Metabolic Disorders in Sucrose-Induced Obese Rats. Experimental Biology and Medicine 229 6: 486-493. PMID 15169967. ^ Storlien LH 1996. Dietary fats and insulin action. Diabetologica 39 6: 621-631. doi:10.1007/BF00418533. PMID 8781757. ^ Harinantenaina L 2006. Momordica charantia constituents and antidiabetic screening of the isolated major compounds. Chemical Pharmaceutical Bulletin Tokyo 54 7: 1017-21. doi:10.1248/cpb.54.1017. PMID 16819222. ^ Article: Chromium Critical for Glucose Tolerance by Judy McBride, USDA 1999 ^ Falta W, Boller R 1931. Insularer und insulinresistenter Diabetes. Klin Wochenschr 10: 438-443. ^ Himsworth HP 1936. Diabetes mellitus: its differentiation into insulin-sensitive and insulin-insensitive types. Lancet 1: 127-130. doi:10.1016/S0140-67360136134-2. See also Chronic Somogyi rebound External links The National Insulin Resistance Council Insulin resistance at the Open Directory Project Insulin Resistance Information Simple assessment of insulin sensitivity and secretion Chromum Critical in Glucose Tolerance USDA Article v d e Endocrine pathology: endocrine diseases E00-35, 240-259 Pancreas/ glucose metabolism Diabetes mellitus types: type 1, type 2, MODY, complications: coma, angiopathy, ketoacidosis, nephropathy, neuropathy, retinopathy Hypoglycemia - Hyperinsulinism - Zollinger-Ellison syndrome - insulin receptor Rabson-Mendenhall syndrome - Insulin resistance Hypothalamic/ pituitary axes Pituitary Hyperpituitarism Acromegaly, Hyperprolactinaemia, SIADH Hypopituitarism Sheehan's syndrome, Kallmann syndrome, Growth hormone deficiency, Diabetes insipidus Adiposogenital dystrophy - Empty sella syndrome - Pituitary apoplexy - ACTH deficiency Thyroid Hypothyroidism Iodine deficiency, Cretinism, Congenital hypothyroidism, Goitre, Myxedema Hyperthyroidism Graves disease, Toxic multinodular goitre, Teratoma with thyroid tissue or Struma ovarii Thyroiditis De Quervain's thyroiditis, Hashimoto's thyroiditis, Riedel's thyroiditis Euthyroid sick syndrome - Thyroid hormone resistance - Thyroid nodule Parathyroid Hypoparathyroidism Pseudohypoparathyroidism - Hyperparathyroidism Primary, Secondary, Tertiary Adrenal Adrenocortical hyperfunction: Cushing's syndrome Nelson's syndrome, Pseudo-Cushing's syndrome - Hyperaldosteronism Conn syndrome, Bartter syndrome CAH Lipoid, 3β, 11β, 17α, 21α Adrenal insufficiency Addison's disease, Waterhouse-Friderichsen syndrome - Hypoaldosteronism Gonads ovarian Polycystic ovary syndrome, Premature ovarian failure testicular 5-alpha-reductase deficiency, 17-beta-hydroxysteroid dehydrogenase deficiency general Hypogonadism, Delayed puberty, Precocious puberty Other Androgen insensitivity syndrome - Autoimmune polyendocrine syndrome - Carcinoid syndrome - Gigantism - Short stature Laron syndrome, Psychogenic dwarfism - Multiple endocrine neoplasia 1, 2 - Progeria - Woodhouse-Sakati syndrome - thymus Abscess of thymus, Thymus hyperplasia see also congenital, neoplasia Retrieved from http://en..org/wiki/Insulin_resistance Categories: Diabetes Views Article Discussion this page History Personal tools Log in / create account Navigation Main page Contents Featured content Current events Random article Search Go Search Interaction Community portal Recent changes Contact Donate to Help Toolbox What links here Related changes Upload file Special pages Printable version Permanent link Cite this page Languages Afrikaans Deutsch 한국어 Bahasa Indonesia 日本語 Polski Português Suomi Türkçe 中文 This page was last modified on 27 August 2008, at 18:27
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