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Insulin resistance (IR) is a physiological condition in which cells fail to respond to the normal actions of the hormone insulin. The body produces insulin, but the cells in the body become resistant to insulin and are unable to use it as effectively, leading to hyperglycemia. Beta cells in the pancreas subsequently increase their production of insulin, further contributing to hyperinsulinemia. This often remains undetected and can contribute to a diagnosis of Type 2 Diabetes.
One of insulin's functions is to regulate delivery of glucose into cells to provide them with energy. Insulin resistant cells cannot take in glucose, amino acids and fatty acids. Thus, glucose, fatty acids and amino acids 'leak' out of the cells. A decrease in insulin/glucagon ratio inhibits glycolysis which in turn decreases energy production. The resulting increase in blood glucose may raise levels outside the normal range and cause adverse health effects, depending on dietary conditions. Certain cell types such as fat and muscle cells require insulin to absorb glucose. When these cells fail to respond adequately to circulating insulin, blood glucose levels rise. The liver helps regulate glucose levels by reducing its secretion of glucose in the presence of insulin. This normal reduction in the liver’s glucose production may not occur in people with insulin resistance.
Insulin resistance in muscle and fat cells reduces glucose uptake (and also local storage of glucose as glycogen and triglycerides, respectively), whereas insulin resistance in liver cells results in reduced glycogen synthesis and storage and also a failure to suppress glucose production and release into the blood. Insulin resistance normally refers to reduced glucose-lowering effects of insulin. However, other functions of insulin can also be affected. For example, insulin resistance in fat cells reduces the normal effects of insulin on lipids and results in reduced uptake of circulating lipids and increased hydrolysis of stored triglycerides. Increased mobilization of stored lipids in these cells elevates free fatty acids in the blood plasma. Elevated blood fatty-acid concentrations (associated with insulin resistance and diabetes mellitus Type 2), reduced muscle glucose uptake, and increased liver glucose production all contribute to elevated blood glucose levels. High plasma levels of insulin and glucose due to insulin resistance are a major component of the metabolic syndrome. If insulin resistance exists, more insulin needs to be secreted by the pancreas. If this compensatory increase does not occur, blood glucose concentrations increase and type 2 diabetes occurs.
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These depend on poorly understood variations in individual biology and consequently may not be found with all people diagnosed with insulin resistance.
Several associated risk factors include the following:
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It is well known that insulin resistance commonly coexists with obesity. However, causal links between insulin resistance, obesity, and dietary factors are complex and controversial. It is possible that one of them arises first, and tends to cause the other; or that insulin resistance and excess body weight might arise independently as a consequence of a third factor, but end up reinforcing each other. Some population groups might be genetically predisposed to one or the other.
Dietary fat has long been implicated as a driver of insulin resistance. Studies on animals have observed significant insulin resistance in rats after just 3 weeks on a high-fat diet (59% fat, 20% carb.) Large quantities of saturated, monounsaturated, and polyunsaturated (omega-6) fats all appear to be harmful to rats to some degree, compared to large amounts of starch, but saturated fat appears to be the most effective at producing IR. This is partly caused by direct effects of a high-fat diet on blood markers, but, more significantly, ad libitum high-fat diet has the tendency to result in caloric intake that's far in excess of animals' energy needs, resulting in rapid weight gain. In humans, statistical evidence is more equivocal. Being insensitive to insulin is still positively correlated with fat intake, and negatively correlated with dietary fiber intake, but both these factors are also correlated with excess body weight.
The effect of dietary fat is largely or completely overridden if the high-fat diet is modified to contain nontrivial quantities (in excess of 5–10% of total fat intake) of polyunsaturated omega-3 fatty acids. This protective effect is most established with regard to the so-called "marine long-chain omega-3 fatty acids", EPA and DHA, found in fish oil; evidence in favor of other omega-3's, in particular, the most common vegetable-based omega-3 fatty acid, ALA, also exists, but it is more limited; some studies find ALA only effective among people with insufficient long-chain omega-3 intake, and some studies fail to find any effect at all (ALA can be partially converted into EPA and DHA by the human body, but the conversion rate is thought to be 10% or less, depending on diet and gender). The effect is thought to explain relatively low incidence of IR, type 2 diabetes, and obesity in polar foragers such as Alaskan Eskimos consuming their ancestral diet (which is very high in fat, but contains substantial amounts of omega-3). However, it is not strong enough to prevent IR in the typical modern Western diet. Unlike their omega-6 counterparts (which can be cheaply produced from a variety of sources, such as corn and soybeans), major sources of omega-3 fatty acids remain relatively rare and expensive. Consequently, the recommended average intake of omega-3 for adult men in the United States is only 1.6 grams/day, or less than 2% of total fat; the actual average consumption of omega-3 in the United States is around 1.3 grams/day, almost all of it in the form of ALA; EPA and DHA contributed less than 0.1 grams/day.
Elevated levels of free fatty acids and triglycerides in the blood stream and tissues have been found in many studies to contribute to diminished insulin sensitivity. Triglyceride levels are driven by a variety of dietary factors. They are correlated with excess body weight. They tend to rise due to overeating and fall during fat loss. At constant energy intake, triglyceride levels are positively correlated with trans fat intake and strongly inversely correlated with omega-3 intake. High-carbohydrate, low-fat diets were found by many studies to result in elevated triglycerides, in part due to higher production of VLDL from fructose and sucrose, and in part because increased carbohydrate intake tends to displace some omega-3 from the diet.
Several recent authors suggested that the intake of simple sugars, and particularly fructose, is also a factor that contributes to insulin resistance. Fructose is metabolized by the liver into triglycerides, and, as mentioned above, tends to raise their levels in the blood stream. Therefore, it may contribute to insulin resistance through the same mechanisms as the dietary fat. Just like fat, high levels of fructose and/or sucrose induce insulin resistance in rats, and, just like with fat, this insulin resistance is ameliorated by fish oil supplementation. One study observed that a low-fat diet high in simple sugars (but not in complex carbohydrates and starches) significantly stimulates fatty acid synthesis, primarily of the saturated fatty acid palmitate, therefore, paradoxically, resulting in the plasma fatty acid pattern that is similar to that produced by a high-saturated-fat diet. It should be pointed out that virtually all evidence of deleterious effects of simple sugars so far is limited to their concentrated formulations and sweetened beverages. In particular, very little is known about effects of simple sugars in whole fruit and vegetables. If anything, epidemiological studies suggest that their high consumption is associated with somewhat lower risk of IR and/or metabolic syndrome.
Yet another proposed mechanism involves the phenomenon known as leptin resistance. Leptin is a hormone that regulates long-term energy balance in many mammals. An important role of leptin is long-term inhibition of appetite in response to formation of body fat. This mechanism is known to be disrupted in many obese individuals: even though their leptin levels are commonly elevated, this does not result in reduction of appetite and caloric intake. Leptin resistance can be triggered in rats by ad libitum consumption of energy-dense, highly palatable foods over a period of several days. Chronic consumption of fructose in rats ultimately results in leptin resistance (however, this has only been demonstrated in a diet where fructose provided 60% of calories; the actual consumption by humans in a typical Western diet is several times lower.) Once leptin signalling has been disrupted, the individual becomes prone to further overeating, weight gain, and insulin resistance.
As elevated blood glucose levels are the primary stimulus for insulin secretion and production, habitually excessive carbohydrate intake is another likely contributor. This serves as a major motivation behind the low-carb family of diets. Furthermore, carbohydrates are not equally absorbed (for example, the blood glucose level response to a fixed quantity of carbohydrates in baked potatoes is about twice the response to the same quantity of carbohydrates in pumpernickel bread). Integrated blood glucose response to a fixed quantity of carbohydrates in a meal is known as glycemic index. Some diets are based on this concept, assuming that consumption of low-GI foods is less likely to result in insulin resistance and obesity. However, small to moderate amounts of simple sugars (i.e., sucrose, fructose, and glucose) in the typical developed-world diet seem to not have a causative effect on the development of insulin resistance.
Once established, insulin resistance would result in increased circulating levels of insulin. Since insulin is the primary hormonal signal for energy storage into fat cells, which tend to retain their sensitivity in the face of hepatic and skeletal muscle resistance, IR stimulates the formation of new fatty tissue and accelerates weight gain.
Another possible explanation is that both insulin resistance and obesity often have the same cause, a systematic overeating, which has the potential to lead to insulin resistance and obesity due to repeated administration of excess levels of glucose, which stimulate insulin secretion; excess levels of fructose, which raise triglyceride levels in the bloodstream; and fats, which can be easily absorbed by the adipose cells and tend to end up as fatty tissue in a hypercaloric diet. Some scholars go as far as to claim that neither insulin resistance, nor obesity are really metabolic disorders per se, but simply adaptive responses to sustained caloric surplus, intended to protect bodily organs from lipotoxicity (unsafe levels of lipids in the bloodstream and tissues): "Obesity should therefore not be regarded as a pathology or disease, but rather as the normal, physiologic response to sustained caloric surplus… As a consequence of the high level of lipid accumulation in insulin target tissues including skeletal muscle and liver, it has been suggested that exclusion of glucose from lipid-laden cells is a compensatory defense against further accumulation of lipogenic substrate." Fast food meals typically possess several characteristics, all of which have independently been linked to IR: they are energy-dense, palatable, and cheap, increasing risk of overeating and leptin resistance; they are simultaneously high in dietary fat and fructose, and low in omega-3; and they usually have high glycemic indices. Consumption of fast food has been proposed as a fundamental factor behind the metabolic syndrome epidemic and all its constituents.
Studies show that high levels of cortisol within the bloodstream from the digestion of animal protein can contribute to the development of insulin resistance. Additionally, animal protein, because of its high content of purine, causes blood pH to become acidic. Several studies conclude that high uric acid levels, apart from other contributing factors, by itself may be a significant cause of insulin resistance.
Sedentary lifestyle increases the likelihood of development of insulin resistance. It's been estimated that each 500 kcal/week increment in physical activity related energy expenditure reduces the lifetime risk of type 2 diabetes by 6%. A different study found that vigorous exercise at least once a week reduced the risk of type 2 diabetes in women by 33%.
At the cellular level, much of the variance in insulin sensitivity between untrained, non-diabetic humans can be explained by two mechanisms: differences in phospholipid profiles of skeletal muscle cell membranes, and in intramyocellular lipid (ICML) stores within these cells. High levels of lipids in the bloodstream have the potential to result in accumulation of triglycerides and their derivatives within muscle cells, which activate proteins Kinase C-ε and C-θ, ultimately reducing the glucose uptake at any given level of insulin. This mechanism is quite fast-acting and can induce insulin resistance within days or even hours in response to a large lipid influx. Draining the intracellular reserves, on the other hand, is more challenging: moderate caloric restriction alone, even over a period of several months, appears to be ineffective, and it must be combined with physical exercise to have any effect. However, a 2011 study found that a severe ultra-low-calorie diet, limiting patients to 600 calories/day for a period of 2 months, without explicit exercise targets, was capable of reversing insulin resistance and type 2 diabetes.)
In the long term, diet has the potential to change the ratio of polyunsaturated to saturated phospholipids in cell membranes, correspondingly changing cell membrane fluidity; full impact of such changes is not fully understood, but it is known that the percentage of polyunsaturated phospholipids is strongly inversely correlated with insulin resistance. It is hypothesized that increasing cell membrane fluidity by increasing PUFA concentration might result in an enhanced number of insulin receptors, an increased affinity of insulin to its receptors and a reduced insulin resistance, and vice versa.
Many stressing factors can lead to increased cortisol in the bloodstream. Cortisol counteracts insulin, and contributes to hyperglycemia-causing hepatic gluconeogenesis and inhibits the peripheral utilization of glucose which eventually leads to insulin resistance. It does this by decreasing the translocation of glucose transporters (especially GLUT4) to the cell membrane.
Although inflammation is often caused by cortisol, inflammation by itself also seems to be implicated in causing insulin resistance. Mice without JNK1-signaling do not develop insulin resistance under dietary conditions that normally produce it.
Rare type 2 diabetes cases sometimes use high levels of exogenous insulin. As short term overdosing of insulin causes short term insulin resistance, it has been hypothesized that chronic high dosing contributes to more permanent insulin resistance.
Insulin resistance has been proposed at a molecular level to be a reaction to excess nutrition by superoxide dismutase in cell mitochondria that acts as an antioxidant defense mechanism. This link seems to exist under diverse causes of insulin resistance. It is also based on the finding that insulin resistance can be rapidly reversed by exposing cells to mitochondrial uncouplers, electron transport chain inhibitors, or mitochondrial superoxide dismutase mimetics.
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 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 8) 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 that signals body cells to become insulin resistant. If the producing tissue is removed, the signal ceases and body cells revert to normal insulin sensitivity. No such substance has been found as yet, so its existence remains speculative.
Hepatitis C also makes people three to four times more likely to develop type 2 diabetes and insulin resistance. In addition, "people with Hepatitis C who develop diabetes probably have susceptible insulin-producing cells, and would probably get it anyway – but much later in life. The extra insulin resistance caused by Hepatitis C apparently brings on diabetes at 35 or 40, instead of 65 or 70."
Any food or drink containing glucose (or the digestible carbohydrates that contain it, such as sucrose, starch, etc.) causes blood glucose levels to increase. In normal metabolism, the elevated blood glucose level instructs beta (β) cells in the Islets of Langerhans, located in the pancreas, to release insulin into the blood. The insulin, in turn, makes insulin-sensitive tissues in the body (primarily skeletal muscle cells, adipose tissue, and liver) absorb glucose, and thereby lower the blood glucose level. The beta cells reduce insulin output as the blood glucose level falls, allowing blood glucose to settle at a constant of approximately 5 mmol/L (mM) (90 mg/dL). In an insulin-resistant person, normal levels of insulin do not have the same effect in controlling blood glucose levels. During the compensated phase on insulin resistance insulin levels are higher, and blood glucose levels are still maintained. If compensatory insulin secretion fails, then either fasting (impaired fasting glucose) or postprandial (impaired glucose tolerance) glucose concentrations increase. Eventually, type 2 diabetes occurs when glucose levels become higher throughout the day as the resistance increases and compensatory insulin secretion fails. The elevated insulin levels also have additional effects (see insulin) that cause further abnormal biological effects throughout the body.
The most common type of insulin resistance is associated with overweight and obesity in a condition known as the metabolic syndrome. Insulin resistance often progresses to full Type 2 diabetes mellitus (T2DM). 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) in the face of insulin resistance. The inability of the β-cells to produce sufficient insulin in a condition of hyperglycemia is what characterizes the transition from insulin resistance to T2DM.
Various disease states make 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 leads to a kind of insulin resistance; every time a cell is exposed to insulin, the production of GLUT4 (type four glucose receptors) on the cell's membrane decreases somewhat. In the presence of a higher than usual level of insulin (generally caused by insulin resistance), this down-regulation acts as a kind of positive feedback, increasing the need for insulin. Exercise reverses this process in muscle tissue, but if it is left unchecked, it can contribute to insulin resistance.
Elevated blood levels of glucose — regardless of cause — lead to increased glycation of proteins with changes, only a few of which are understood in any detail, in protein function throughout the body.
Insulin resistance is often found in people with visceral adiposity (i.e., a high degree of fatty tissue within the abdomen — as distinct from subcutaneous adiposity or fat between the skin and the muscle wall, especially elsewhere on the body, such as hips or thighs), hypertension, hyperglycemia and dyslipidemia involving elevated triglycerides, small dense low-density lipoprotein (sdLDL) particles, and decreased HDL cholesterol levels. With respect to visceral adiposity, a great deal of evidence suggests two strong links with insulin resistance. First, unlike subcutaneous adipose tissue, visceral adipose cells produce significant amounts of proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-a), and Interleukins-1 and -6, etc. In numerous experimental models, these proinflammatory cytokines disrupt normal insulin action in fat and muscle cells, and may be a major factor in causing the whole-body insulin resistance observed in patients with visceral adiposity. Much of the attention on production of proinflammatory cytokines has focused on the IKK-beta/NF-kappa-B pathway, a protein network that enhances transcription of inflammatory markers and mediators that can cause insulin resistance. Second, visceral adiposity is related to an accumulation of fat in the liver, a condition known as non-alcoholic fatty liver disease (NAFLD). The result of NAFLD is an excessive release of free fatty acids into the bloodstream (due to increased lipolysis), and an increase in hepatic glycogenolysis and hepatic glucose production, both of which have the effect of exacerbating peripheral insulin resistance and increasing the likelihood of Type 2 diabetes mellitus.
A fasting serum insulin level of greater than the upper limit of normal for the assay used (approximately 60 pmol/L) is considered evidence of insulin resistance.
During a glucose tolerance test, which may be used to diagnose diabetes mellitus, a fasting 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 (140 mg/dl) is considered normal, a glycemia of between 7.8 to 11.0 mmol/L (140 to 197 mg/dl) is considered as impaired glucose tolerance (IGT) and a glycemia of greater than or equal to 11.1 mmol/L (200 mg/dl) is considered diabetes mellitus.
An oral glucose tolerance test (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.
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. It is a type of glucose clamp technique. The test is rarely performed in clinical care, but is used in medical research, for example, to assess the effects of different medications. The rate of glucose infusion 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).
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 are infused continuously with an intravenous infusion of somatostatin (0.27 μgm/m2/min) to suppress endogenous insulin and glucose secretion. Insulin and 20% glucose is then infused at rates of 32 and 267 mg/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 (SSPG). Subjects with an SSPG greater than 150 mg/dl are considered to be insulin-resistant.
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 Quantitative insulin sensitivity check index (QUICKI). 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.
The primary treatment for insulin resistance is exercise and weight loss. Research shows that a low-carb diet can help. Both metformin and the thiazolidinediones improve insulin resistance, but are only approved therapies for type 2 diabetes, not for insulin resistance. By contrast, growth hormone replacement therapy may be associated with increased insulin resistance.
Metformin has become one of the more commonly prescribed medications for insulin resistance, and as of 2014[update] a newer drug, exenatide (marketed as Byetta), has become available. Exenatide has not been approved in the UK except for use in diabetics, but often reduces insulin resistance in healthy individuals by the same mechanism as it does in diabetics.
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. One 2009 study found that carbohydrate deficit after exercise, but not energy deficit, contributed to insulin sensitivity increase.
Resistant starch from high-amylose corn has been shown to reduce insulin resistance in healthy individuals, and in individuals with type 2 diabetes. Animal studies demonstrate that it cannot reverse insulin resistance, but that it reduces the development of insulin resistance.
Some types of monounsaturated fatty acids, saturated, and trans fats promote insulin resistance. Some types of polyunsaturated fatty acids (omega-3) can moderate the progression of insulin resistance into type 2 diabetes. However, omega-3 fatty acids appear to have limited ability to reverse insulin resistance, and they cease to be efficacious once type 2 diabetes is established.
Caffeine intake limits insulin action, but not enough to increase blood-sugar levels in healthy persons. People who already have diabetes II can see a small increase in levels if they take 2 or 21/2 cups of coffee per day.
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, and confirmed as contributary by Sir Harold Percival Himsworth of the University College Hospital Medical Centre in London in 1936. However, type 2 diabetes does not occur unless there is concurrent failure of compensatory insulin secretion.