Insulin resistance
Encyclopedia
Insulin resistance is a physiological condition where the natural hormone
insulin
becomes less effective at lowering blood sugars. 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 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 triglyceride
s. Increased mobilization of stored lipids in these cells elevates free fatty acid
s 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.
. 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 observed significant insulin resistance in rats after just 3 weeks on a high-fat diet. Large quantities of saturated, monounsaturated, and polyunsaturated (omega-6) fats all appear to be harmful to rats to some degree, compared to high-starch chow, 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. Insulin sensitivity is still negatively correlated with fat intake, and positively 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 (e.g.), 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 triglyceride
s 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 created equal (for example, the blood glucose level response to a fixed quantity of carbohydrates in baked potato
es 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; they assume 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 - 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.
An American study has shown that glucosamine
(often prescribed for joint problems) may cause insulin resistance.
Several 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 level apart from other contributing factors by itself may be a significant cause of insulin resistance.
Vitamin D
deficiency is also associated with insulin resistance.
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 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 transporter
s (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 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.
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 uncoupler
s, electron transport chain
inhibitors, or mitochondrial superoxide dismutase mimetics.
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 speculation.
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.
, starch
, etc.) causes blood glucose levels to increase. In a normal metabolism, the elevated blood glucose level makes beta (β) cells in the Islets of Langerhans
, located in the pancreas
, 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 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 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 Type 2 diabetes mellitus.
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 adipokine
s (the cytokine
s produced by adipose tissue
) in insulin resistance. Certain drugs may also be associated with insulin resistance (e.g., glucocorticoid
s).
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 protein
s 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 nonalcoholic 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 glucose production, both of which have the effect of exacerbating peripheral insulin resistance and increasing the likelihood of Type 2 diabetes mellitus.
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 glucose level reductions (glycemia) after a specific 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 less common. This form of insulin resistance is not what is being referred to in the metabolic syndrome.
Magnesium
(Mg) is present in living cells and its plasma concentration is remarkably constant in healthy subjects. Plasma and intracellular Mg concentrations are tightly regulated. Among the controlling mechanisms, 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. Poor intracellular Mg concentrations, as found in Type 2 diabetes mellitus 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 impairment in insulin action, and a worsening of insulin resistance in noninsulin-dependent diabetic and hypertensive patients. By contrast, in T2DM 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 T2DM patients are further supported by epidemiological studies showing that high daily Mg intake are predictive of a lower incidence of T2DM.
, 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/dl (140 to 197 mg/dl) is considered as Impaired Glucose Tolerance
(IGT) and a glycemia of greater than or equal to 11.1 mmol/dl (200 mg/dl) is considered Diabetes Mellitus
.
An 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).
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 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.
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.
. Low-glycemic index
or low-carbohydrate diets have also been shown to help. Both metformin
and the thiazolidinedione
s improve insulin resistance, but are only approved therapies for type 2 diabetes, not insulin resistance, per se. By contrast, growth hormone replacement therapy
may be associated with increased insulin resistance.
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 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 has found that carbohydrate deficit after exercise, but not energy deficit, contributed to insulin sensitivity increase.
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.
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 sensitivity, 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
.
One study found that chromium is necessary for maintaining normal glucose tolerance.
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.
Hormone
A hormone is a chemical released by a cell or a gland in one part of the body that sends out messages that affect cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism. In essence, it is a chemical messenger that transports a signal from one...
insulin
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
becomes less effective at lowering blood sugars. 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
Fat
Fats consist of a wide group of compounds that are generally soluble in organic solvents and generally insoluble in water. Chemically, fats are triglycerides, triesters of glycerol and any of several fatty acids. Fats may be either solid or liquid at room temperature, depending on their structure...
and muscle
Muscle
Muscle is a contractile tissue of animals and is derived from the mesodermal layer of embryonic germ cells. Muscle cells contain contractile filaments that move past each other and change the size of the cell. They are classified as skeletal, cardiac, or smooth muscles. Their function is to...
cells
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
require insulin to absorb glucose. When these cells fail to respond adequately to circulating insulin, blood glucose levels rise. The liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
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
Glucose
Glucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate...
uptake (and also local storage of glucose as glycogen
Glycogen
Glycogen is a molecule that serves as the secondary long-term energy storage in animal and fungal cells, with the primary energy stores being held in adipose tissue...
and triglycerides, respectively), whereas insulin resistance in liver cells results in reduced glycogen synthesis and storage and 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
Adipose tissue
In histology, adipose tissue or body fat or fat depot or just fat is loose connective tissue composed of adipocytes. It is technically composed of roughly only 80% fat; fat in its solitary state exists in the liver and muscles. Adipose tissue is derived from lipoblasts...
reduces the normal effects of insulin on lipids and results in reduced uptake of circulating lipids and increased hydrolysis
Hydrolysis
Hydrolysis is a chemical reaction during which molecules of water are split into hydrogen cations and hydroxide anions in the process of a chemical mechanism. It is the type of reaction that is used to break down certain polymers, especially those made by condensation polymerization...
of stored triglyceride
Triglyceride
A triglyceride is an ester derived from glycerol and three fatty acids. There are many triglycerides, depending on the oil source, some are highly unsaturated, some less so....
s. Increased mobilization of stored lipids in these cells elevates free fatty acid
Fatty acid
In chemistry, especially biochemistry, a fatty acid is a carboxylic acid with a long unbranched aliphatic tail , which is either saturated or unsaturated. Most naturally occurring fatty acids have a chain of an even number of carbon atoms, from 4 to 28. Fatty acids are usually derived from...
s in the blood plasma
Blood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...
. 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
Metabolic syndrome
Metabolic syndrome is a combination of medical disorders that, when occurring together, increase the risk of developing cardiovascular disease and diabetes. It affects one in five people in the United States and prevalence increases with age...
. 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
Diabetes mellitus type 2
Diabetes mellitus type 2formerly non-insulin-dependent diabetes mellitus or adult-onset diabetesis a metabolic disorder that is characterized by high blood glucose in the context of insulin resistance and relative insulin deficiency. Diabetes is often initially managed by increasing exercise and...
occurs.
Signs and symptoms
These depend on poorly understood variations in individual biology and consequently may not be found with all people diagnosed with insulin resistance.- Fatigue.
- Brain fogginess and inability to focus.
- High blood sugar.
- Intestinal bloating – most intestinal gas is produced from carbohydrates in the diet, mostly those that humans cannot digest and absorb.
- Sleepiness, especially after meals.
- Weight gain, fat storage, difficulty losing weight – for most people, excess weight is from high fat storage; the fat in IR is generally stored in and around abdominal organs in both males and females. It is currently suspected that hormones produced in that 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 to control arterial wall tension throughout the body.
- Increased pro-inflammatory cytokines associated with cardiovascular disease.
- Depression. Due to the deranged metabolism resulting from insulin resistance, psychological effects, including depression, are not uncommon.
- Acanthosis nigricansAcanthosis nigricansAcanthosis nigricans is a brown to black, poorly defined, velvety hyperpigmentation of the skin. It is usually found in body folds, such as the posterior and lateral folds of the neck, the axilla, groin, umbilicus, forehead, and other areas.-Causes:...
. - Increased hunger.
Associated conditions
Several associated conditions include:- Genetic factors (inherited component):
- Family history with type 2 diabetes;
- Insulin receptorInsulin receptorIn molecular biology, the insulin receptor is a transmembrane receptor that is activated by insulin. It belongs to the large class of tyrosine kinase receptors....
mutations (Donohue SyndromeDonohue syndromeDonohue syndrome is an extremely rare and severe genetic disorder. Leprechaunism derives its name from the fact that those afflicted with the disease often have elfin features and are smaller than usual...
) - LMNALMNALamin A/C also known as LMNA is a protein that in humans is encoded by the LMNA gene. Lamin A/C belongs to the lamin family of proteins.-Function:...
mutations (Familial Partial LipodystrophyFamilial partial lipodystrophyFamilial partial lipodystrophy is an autosomal dominant skin condition characterized by the loss of subcutaneous fat.Type 1 is believed to be underdiagnosed.- References :...
) Insulin resistance may also be caused by the damage of liver cells having undergone a defect of insulin receptors in hepatocytes.
- Insulin receptor
- History of gestational diabetesGestational diabetesGestational diabetes is a condition in which women without previously diagnosed diabetes exhibit high blood glucose levels during pregnancy . It is widely accepted as a disease only in the United States, there is some question whether the condition is natural during pregnancy...
.
- Family history with type 2 diabetes;
- Particular physiological conditions and environmental factors:
- > 40–45 years of age;
- Sedentary lifestyle, due to lack of physical exercise and risk of obesityObesityObesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and/or increased health problems...
; - Stress;
- Tobacco smokingTobacco smokingTobacco smoking is the practice where tobacco is burned and the resulting smoke is inhaled. The practice may have begun as early as 5000–3000 BCE. Tobacco was introduced to Eurasia in the late 16th century where it followed common trade routes...
; - CaffeineCaffeineCaffeine is a bitter, white crystalline xanthine alkaloid that acts as a stimulant drug. Caffeine is found in varying quantities in the seeds, leaves, and fruit of some plants, where it acts as a natural pesticide that paralyzes and kills certain insects feeding on the plants...
intake; - AlcoholAlcoholIn chemistry, an alcohol is an organic compound in which the hydroxy functional group is bound to a carbon atom. In particular, this carbon center should be saturated, having single bonds to three other atoms....
; - Pregnancy.
- Pathology:
- Obesity and Overweight (BMI > 25);
- Metabolic syndrome (Hyperlipidemia + HDL cholesterol level < 0.90 mmol/L or triglyceride level >2.82 mmol/L); Hypertension (>140/90 mmHg) or arteriosclerosis;
- Liver pathologies;
- Infection (Hepatitis CHepatitis CHepatitis C is an infectious disease primarily affecting the liver, caused by the hepatitis C virus . The infection is often asymptomatic, but chronic infection can lead to scarring of the liver and ultimately to cirrhosis, which is generally apparent after many years...
); - HaemochromatosisHaemochromatosisHaemochromatosis type 1 is a hereditary disease characterized by excessive intestinal absorption of dietary iron resulting in a pathological increase in total body iron stores. Humans, like most animals, have no means to excrete excess iron...
; - GastroparesisGastroparesisGastroparesis, also called delayed gastric emptying, is a medical condition consisting of a paresis of the stomach, resulting in food remaining in the stomach for a longer period of time than normal. Normally, the stomach contracts to move food down into the small intestine for digestion. The...
; - Polycystic ovary syndromePolycystic ovary syndromePolycystic ovary syndrome is one of the most common female endocrine disorders. PCOS is a complex, heterogeneous disorder of uncertain aetiology, but there is strong evidence that it can to a large degree be classified as a genetic disease....
(PCOS);
- Hypercortisolism (e.g., steroidSteroidA steroid is a type of organic compound that contains a characteristic arrangement of four cycloalkane rings that are joined to each other. Examples of steroids include the dietary fat cholesterol, the sex hormones estradiol and testosterone, and the anti-inflammatory drug dexamethasone.The core...
use or Cushing's diseaseCushing's diseaseCushing's disease is a cause of Cushing's Syndrome characterised by increased secretion of adrenocorticotropic hormone from the anterior pituitary. This is most often as a result of a pituitary adenoma...
); - MedicationMedicationA pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...
(e.g., glucosamineGlucosamineGlucosamine is an amino sugar and a prominent precursor in the biochemical synthesis of glycosylated proteins and lipids. Glucosamine is part of the structure of the polysaccharides chitosan and chitin, which compose the exoskeletons of crustaceans and other arthropods, cell walls in fungi and...
, rifampicinRifampicinRifampicin or rifampin is a bactericidal antibiotic drug of the rifamycin group. It is a semisynthetic compound derived from Amycolatopsis rifamycinica ...
, isoniazidIsoniazidIsoniazid , also known as isonicotinylhydrazine , is an organic compound that is the first-line antituberculosis medication in prevention and treatment. It was first discovered in 1912, and later in 1951 it was found to be effective against tuberculosis by inhibiting its mycolic acid...
, olanzapineOlanzapineOlanzapine is an atypical antipsychotic, approved by the FDA for the treatment of schizophrenia and bipolar disorder...
, risperidoneRisperidoneRisperidone is a second generation or atypical antipsychotic, sold under the trade name . It is used to treat schizophrenia , schizoaffective disorder, the mixed and manic states associated with bipolar disorder, and irritability in people with autism...
, progestogens, corticosteroidCorticosteroidCorticosteroids are a class of steroid hormones that are produced in the adrenal cortex. Corticosteroids are involved in a wide range of physiologic systems such as stress response, immune response and regulation of inflammation, carbohydrate metabolism, protein catabolism, blood electrolyte...
s, glucocorticoidGlucocorticoidGlucocorticoids are a class of steroid hormones that bind to the glucocorticoid receptor , which is present in almost every vertebrate animal cell...
s, methadoneMethadoneMethadone is a synthetic opioid, used medically as an analgesic and a maintenance anti-addictive for use in patients with opioid dependency. It was developed in Germany in 1937...
, many antiretrovirals).
Diet
It is well known that insulin resistance commonly coexists with obesityObesity
Obesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and/or increased health problems...
. 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 observed significant insulin resistance in rats after just 3 weeks on a high-fat diet. Large quantities of saturated, monounsaturated, and polyunsaturated (omega-6) fats all appear to be harmful to rats to some degree, compared to high-starch chow, 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. Insulin sensitivity is still negatively correlated with fat intake, and positively 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
Eicosapentaenoic acid
Eicosapentaenoic acid is an omega-3 fatty acid. In physiological literature, it is given the name 20:5. It also has the trivial name timnodonic acid...
and DHA
Docosahexaenoic acid
Docosahexaenoic acid is an omega-3 fatty acid that is a primary structural component of the human brain and retina. In chemical structure, DHA is a carboxylic acid with a 22-carbon chain and six cis double bonds; the first double bond is located at the third carbon from the omega end...
, found in fish oil; evidence in favor of other omega-3's, in particular, the most common vegetable-based omega-3 fatty acid, ALA
Alpha-linolenic acid
α-Linolenic acid is an organic compound found in many common vegetable oils. In terms of its structure, it is named all-cis-9,12,15-octadecatrienoic acid. In physiological literature, it is given the name 18:3 ....
, also exists (e.g.), 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 triglyceride
Triglyceride
A triglyceride is an ester derived from glycerol and three fatty acids. There are many triglycerides, depending on the oil source, some are highly unsaturated, some less so....
s 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
Trans fat
Trans fat is the common name for unsaturated fat with trans-isomer fatty acid. Because the term refers to the configuration of a double carbon-carbon bond, trans fats are sometimes monounsaturated or polyunsaturated, but never saturated....
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
Fructose
Fructose, or fruit sugar, is a simple monosaccharide found in many plants. It is one of the three dietary monosaccharides, along with glucose and galactose, that are absorbed directly into the bloodstream during digestion. Fructose was discovered by French chemist Augustin-Pierre Dubrunfaut in 1847...
, 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
Leptin
Leptin is a 16 kDa protein hormone that plays a key role in regulating energy intake and energy expenditure, including appetite and metabolism. It is one of the most important adipose derived hormones...
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 created equal (for example, the blood glucose level response to a fixed quantity of carbohydrates in baked potato
Potato
The potato is a starchy, tuberous crop from the perennial Solanum tuberosum of the Solanaceae family . The word potato may refer to the plant itself as well as the edible tuber. In the region of the Andes, there are some other closely related cultivated potato species...
es is about twice the response to the same quantity of carbohydrates in pumpernickel
Pumpernickel
Pumpernickel is a type of very heavy, slightly sweet rye bread traditionally made with coarsely ground rye. It is often made with a combination of rye flour and whole rye berries. It has been long associated with the Westphalia region of Germany. The first written mention of the black bread of...
bread). Integrated blood glucose response to a fixed quantity of carbohydrates in a meal is known as glycemic index
Glycemic index
The glycemic index, glycaemic index, or GI is a measure of the effects of carbohydrates on blood sugar levels. Carbohydrates that break down quickly during digestion and release glucose rapidly into the bloodstream have a high GI; carbohydrates that break down more slowly, releasing glucose more...
. Some diets are based on this concept; they assume 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 - 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
Fast food
Fast food is the term given to food that can be prepared and served very quickly. While any meal with low preparation time can be considered to be fast food, typically the term refers to food sold in a restaurant or store with preheated or precooked ingredients, and served to the customer in a...
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.
An American study has shown that glucosamine
Glucosamine
Glucosamine is an amino sugar and a prominent precursor in the biochemical synthesis of glycosylated proteins and lipids. Glucosamine is part of the structure of the polysaccharides chitosan and chitin, which compose the exoskeletons of crustaceans and other arthropods, cell walls in fungi and...
(often prescribed for joint problems) may cause insulin resistance.
Several studies show that high levels of cortisol
Cortisol
Cortisol is a steroid hormone, more specifically a glucocorticoid, produced by the adrenal gland. It is released in response to stress and a low level of blood glucocorticoids. Its primary functions are to increase blood sugar through gluconeogenesis; suppress the immune system; and aid in fat,...
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 level apart from other contributing factors by itself may be a significant cause of insulin resistance.
Vitamin D
Vitamin D
Vitamin D is a group of fat-soluble secosteroids. In humans, vitamin D is unique both because it functions as a prohormone and because the body can synthesize it when sun exposure is adequate ....
deficiency is also associated with insulin resistance.
Sedentary lifestyle
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%.Cellular
At the cellular level, much of the variance in insulin sensitivity between untrained, non-diabetic humans is explained by two mechanisms: differences in phospholipidPhospholipid
Phospholipids are a class of lipids that are a major component of all cell membranes as they can form lipid bilayers. Most phospholipids contain a diglyceride, a phosphate group, and a simple organic molecule such as choline; one exception to this rule is sphingomyelin, which is derived from...
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 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
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
, and contributes to hyperglycemia-causing hepatic gluconeogenesis
Gluconeogenesis
Gluconeogenesis is a metabolic pathway that results in the generation of glucose from non-carbohydrate carbon substrates such as lactate, glycerol, and glucogenic amino acids....
and inhibits the peripheral utilization of glucose which eventually leads to insulin resistance. It does this by decreasing the translocation of glucose transporter
Glucose transporter
Glucose transporters are a wide group of membrane proteins that facilitate the transport of glucose over a plasma membrane. Because glucose is a vital source of energy for all life these transporters are present in all phyla...
s (especially GLUT4
GLUT4
Glucose transporter type 4, also known as GLUT4, is a protein that in humans is encoded by the GLUT4 gene. GLUT4 is the insulin-regulated glucose transporter found in adipose tissues and striated muscle that is responsible for insulin-regulated glucose translocation into the cell...
) 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
C-Jun N-terminal kinases
c-Jun N-terminal kinases , were originally identified as kinases that bind and phosphorylate c-Jun on Ser-63 and Ser-73 within its transcriptional activation domain. They belong to the mitogen-activated protein kinase family, and are responsive to stress stimuli, such as cytokines, ultraviolet...
-signaling do not develop insulin resistance under dietary conditions that normally produce it.
Rare Type 2 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.
Molecular
Insulin resistance has been proposed at a molecular level to be a reaction to excess nutrition by superoxide dismutaseSuperoxide dismutase
Superoxide dismutases are a class of enzymes that catalyze the dismutation of superoxide into oxygen and hydrogen peroxide. As such, they are an important antioxidant defense in nearly all cells exposed to oxygen...
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 uncoupler
Uncoupling protein
An uncoupling protein is a mitochondrial inner membrane protein that can dissipate the proton gradient before it can be used to provide the energy for oxidative phosphorylation.There are five types known in mammals:* UCP1, also known as thermogenin* UCP2...
s, electron transport chain
Electron transport chain
An electron transport chain couples electron transfer between an electron donor and an electron acceptor with the transfer of H+ ions across a membrane. The resulting electrochemical proton gradient is used to generate chemical energy in the form of adenosine triphosphate...
inhibitors, or mitochondrial superoxide dismutase mimetics.
Disease
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 surgeryBariatric surgery
Bariatric surgery includes a variety of procedures performed on people who are obese. Weight loss is achieved by reducing the size of the stomach with an implanted medical device or through removal of a portion of the stomach or by resecting and re-routing the small intestines...
have increased insulin sensitivity and even remission of Type 2 diabetes. It was discovered that diabetic / insulin resistant non obese rats whose duodenum
Duodenum
The duodenum is the first section of the small intestine in most higher vertebrates, including mammals, reptiles, and birds. In fish, the divisions of the small intestine are not as clear and the terms anterior intestine or proximal intestine may be used instead of 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 speculation.
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.
HCV and Insulin Resistance
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."Pathophysiology
Any food or drink containing glucose (or the digestible carbohydrates that contain it, such as sucroseSucrose
Sucrose is the organic compound commonly known as table sugar and sometimes called saccharose. A white, odorless, crystalline powder with a sweet taste, it is best known for its role in human nutrition. The molecule is a disaccharide composed of glucose and fructose with the molecular formula...
, starch
Starch
Starch or amylum is a carbohydrate consisting of a large number of glucose units joined together by glycosidic bonds. This polysaccharide is produced by all green plants as an energy store...
, etc.) causes blood glucose levels to increase. In a normal metabolism, the elevated blood glucose level makes beta (β) cells in the Islets of Langerhans
Islets of Langerhans
The islets of Langerhans are the regions of the pancreas that contain its endocrine cells. Discovered in 1869 by German pathological anatomist Paul Langerhans at the age of 22, the islets of Langerhans constitute approximately 1 to 2% of the mass of the pancreas...
, located in the pancreas
Pancreas
The pancreas is a gland organ in the digestive and endocrine system of vertebrates. It is both an endocrine gland producing several important hormones, including insulin, glucagon, and somatostatin, as well as a digestive organ, secreting pancreatic juice containing digestive enzymes that assist...
, release insulin into the blood. The insulin, in turn, makes insulin-sensitive tissues in the body (primarily skeletal muscle
Muscle
Muscle is a contractile tissue of animals and is derived from the mesodermal layer of embryonic germ cells. Muscle cells contain contractile filaments that move past each other and change the size of the cell. They are classified as skeletal, cardiac, or smooth muscles. Their function is to...
cells, adipose tissue, and liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
) absorb glucose
Glucose
Glucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate...
, 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 have additional effects (see insulin
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
) that cause further abnormal biological effects throughout the body.
The most common type of insulin
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
resistance is associated with overweight and obesity in a condition known as metabolic syndrome
Metabolic syndrome
Metabolic syndrome is a combination of medical disorders that, when occurring together, increase the risk of developing cardiovascular disease and diabetes. It affects one in five people in the United States and prevalence increases with age...
. Insulin resistance often progresses to full Type 2 diabetes mellitus (T2DM). This is often seen when hyperglycemia
Hyperglycemia
Hyperglycemia or Hyperglycæmia, or high blood sugar, is a condition in which an excessive amount of glucose circulates in the blood plasma. This is generally a glucose level higher than 13.5mmol/l , but symptoms may not start to become noticeable until even higher values such as 15-20 mmol/l...
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 Type 2 diabetes mellitus.
Various disease states make body tissues more resistant to the actions of insulin. Examples include infection
Infection
An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...
(mediated by the cytokine TNFα) and acidosis
Acidosis
Acidosis is an increased acidity in the blood and other body tissue . If not further qualified, it usually refers to acidity of the blood plasma....
. Recent research is investigating the roles of adipokine
Adipokine
The adipokines or adipocytokines are cytokines secreted by adipose tissue.Members include:* chemerin* interleukin-6...
s (the cytokine
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
s produced by adipose tissue
Adipose tissue
In histology, adipose tissue or body fat or fat depot or just fat is loose connective tissue composed of adipocytes. It is technically composed of roughly only 80% fat; fat in its solitary state exists in the liver and muscles. Adipose tissue is derived from lipoblasts...
) in insulin resistance. Certain drugs may also be associated with insulin resistance (e.g., glucocorticoid
Glucocorticoid
Glucocorticoids are a class of steroid hormones that bind to the glucocorticoid receptor , which is present in almost every vertebrate animal cell...
s).
Insulin itself leads to a kind of insulin resistance; every time a cell is exposed to insulin, the production of GLUT4
GLUT4
Glucose transporter type 4, also known as GLUT4, is a protein that in humans is encoded by the GLUT4 gene. GLUT4 is the insulin-regulated glucose transporter found in adipose tissues and striated muscle that is responsible for insulin-regulated glucose translocation into the cell...
(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
Glycation
Glycation is the result of the bonding of a protein or lipid molecule with a sugar molecule, such as fructose or glucose, without the controlling action of an enzyme. All blood sugars are reducing molecules. Glycation may occur either inside the body or outside the body...
of protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
s 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
Dyslipidemia
Dyslipidemia or dyslipidaemia is an abnormal amount of lipids in the blood. In developed countries, most dyslipidemias are hyperlipidemias; that is, an elevation of lipids in the blood, often due to diet and lifestyle. The prolonged elevation of insulin levels can lead to 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 nonalcoholic 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 glucose production, both of which have the effect of exacerbating peripheral insulin resistance and increasing the likelihood of Type 2 diabetes mellitus.
Insulin resistance is also often associated with a hypercoagulable state (impaired fibrinolysis
Fibrinolysis
Fibrinolysis is a process that prevents blood clots from growing and becoming problematic. This process has two types: primary fibrinolysis and secondary 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 glucose level reductions (glycemia) after a specific 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 less common. This form of insulin resistance is not what is being referred to in the metabolic syndrome.
Magnesium
Magnesium
Magnesium is a chemical element with the symbol Mg, atomic number 12, and common oxidation number +2. It is an alkaline earth metal and the eighth most abundant element in the Earth's crust and ninth in the known universe as a whole...
(Mg) is present in living cells and its plasma concentration is remarkably constant in healthy subjects. Plasma and intracellular Mg concentrations are tightly regulated. Among the controlling mechanisms, 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. Poor intracellular Mg concentrations, as found in Type 2 diabetes mellitus 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 impairment in insulin action, and a worsening of insulin resistance in noninsulin-dependent diabetic and hypertensive patients. By contrast, in T2DM 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 T2DM patients are further supported by epidemiological studies showing that high daily Mg intake are predictive of a lower incidence of T2DM.
Fasting insulin levels
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.Glucose tolerance testing (GTT)
During a glucose tolerance testGlucose tolerance test
A glucose tolerance test is a medical test in which glucose is given and blood samples taken afterward to determine how quickly it is cleared from the blood. The test is usually used to test for diabetes, insulin resistance, and sometimes reactive hypoglycemia and acromegaly, or rarer disorders of...
, 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
Glycemia
Glycemia means the presence, or the level, of glucose in one's blood. Related words include:* Hyperglycemia, an unusually high concentration of sugar in the blood* Hypoglycemia, an unusually low concentration of sugar in the blood...
less than 7.8 mmol/L (140 mg/dl) is considered normal, a glycemia of between 7.8 to 11.0 mmol/dl (140 to 197 mg/dl) is considered as Impaired Glucose Tolerance
Impaired glucose tolerance
Impaired glucose tolerance is a pre-diabetic state of dysglycemia that is associated with insulin resistance and increased risk of cardiovascular pathology. IGT may precede type 2 diabetes mellitus by many years...
(IGT) and a glycemia of greater than or equal to 11.1 mmol/dl (200 mg/dl) is considered Diabetes Mellitus
Diabetes mellitus
Diabetes mellitus, often simply referred to as diabetes, is a group of metabolic diseases in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced...
.
An 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
Hypoglycemia
Hypoglycemia or hypoglycæmia is the medical term for a state produced by a lower than normal level of blood glucose. The term literally means "under-sweet blood"...
"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 clampThe gold standard
Gold standard (test)
In medicine and statistics, gold standard test refers to a diagnostic test or benchmark that is the best available under reasonable conditions. It does not have to be necessarily the best possible test for the condition in absolute terms...
for investigating and quantifying insulin resistance is the "hyperinsulinemic euglycemic clamp," so-called because it measures the amount of glucose
Glucose
Glucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate...
necessary to compensate for an increased insulin
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
level without causing hypoglycemia
Hypoglycemia
Hypoglycemia or hypoglycæmia is the medical term for a state produced by a lower than normal level of blood glucose. The term literally means "under-sweet blood"...
. It is a type of glucose clamp technique
Glucose clamp technique
Glucose clamp technique is a method for quantifying insulin secretion and resistance. It is used to measure either how well an individual metabolizes glucose or how sensitive an individual is to insulin.Two types of clamps are quite commonly used...
. 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
Peripheral vein
Peripheral Veins are the veins not in the chest or abdomen . These veins lead deoxygenated blood from the capillaries in the extremities back to the heart....
, insulin
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
is infused at 10-120 mU per m2 per minute
Minute
A minute is a unit of measurement of time or of angle. The minute is a unit of time equal to 1/60th of an hour or 60 seconds. In the UTC time scale, a minute on rare occasions has 59 or 61 seconds; see leap second. The minute is not an SI unit; however, it is accepted for use with SI units...
. In order to compensate for the insulin infusion, glucose
Glucose
Glucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate...
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
Blood sugar
The blood sugar concentration or blood glucose level is the amount of glucose present in the blood of a human or animal. Normally in mammals, the body maintains the blood glucose level at a reference range between about 3.6 and 5.8 mM , or 64.8 and 104.4 mg/dL...
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 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.
Alternatives
Given the complicated nature of the "clamp" technique (and the potential dangers of hypoglycemiaHypoglycemia
Hypoglycemia or hypoglycæmia is the medical term for a state produced by a lower than normal level of blood glucose. The term literally means "under-sweet blood"...
in some patients), alternatives have been sought to simplify the measurement of insulin resistance. The first was the Homeostatic Model Assessment
Homeostatic model assessment
The homeostatic model assessment is a method used to quantify insulin resistance and beta-cell function. It was first described under the name HOMA by Matthews et al. in 1985.-Derivation:...
(HOMA), and a more recent method is the Quantitative insulin sensitivity check index (QUICKI). Both employ fasting
Fasting
Fasting is primarily the act of willingly abstaining from some or all food, drink, or both, for a period of time. An absolute fast is normally defined as abstinence from all food and liquid for a defined period, usually a single day , or several days. Other fasts may be only partially restrictive,...
insulin
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
and glucose
Glucose
Glucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate...
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
Logarithm
The logarithm of a number is the exponent by which another fixed value, the base, has to be raised to produce that number. For example, the logarithm of 1000 to base 10 is 3, because 1000 is 10 to the power 3: More generally, if x = by, then y is the logarithm of x to base b, and is written...
of the value from one of the HOMA equations.
Management
The primary treatment for insulin resistance is exercise and weight lossWeight loss
Weight loss, in the context of medicine, health or physical fitness, is a reduction of the total body mass, due to a mean loss of fluid, body fat or adipose tissue and/or lean mass, namely bone mineral deposits, muscle, tendon and other connective tissue...
. Low-glycemic index
Glycemic index
The glycemic index, glycaemic index, or GI is a measure of the effects of carbohydrates on blood sugar levels. Carbohydrates that break down quickly during digestion and release glucose rapidly into the bloodstream have a high GI; carbohydrates that break down more slowly, releasing glucose more...
or low-carbohydrate diets have also been shown to help. Both metformin
Metformin
Metformin is an oral antidiabetic drug in the biguanide class. It is the first-line drug of choice for the treatment of type 2 diabetes, in particular, in overweight and obese people and those with normal kidney function. Its use in gestational diabetes has been limited by safety concerns...
and the thiazolidinedione
Thiazolidinedione
The thiazolidinediones , also known as glitazones, are a class of medications used in the treatment of diabetes mellitus type 2. They were introduced in the late 1990s.- Mechanism of action :...
s improve insulin resistance, but are only approved therapies for type 2 diabetes, not insulin resistance, per se. By contrast, growth hormone replacement therapy
Growth hormone treatment
Growth hormone treatment refers to the use of growth hormone in medical treatment. Growth hormone is a peptide hormone secreted by the pituitary gland that stimulates growth and cell reproduction. In the past, growth hormone was extracted from human pituitary glands. GH is now produced by...
may be associated with increased insulin resistance.
Metformin has become one of the more commonly prescribed medications for insulin resistance, and currently a newer drug, exenatide
Exenatide
Exenatide is a medication approved in April 2005 for the treatment of diabetes mellitus type 2. It belongs to the group of incretin mimetics and is manufactured by Amylin Pharmaceuticals and Eli Lilly and Company....
(marketed as Byetta), is being used. Exenatide has not been approved except for use in diabetics, but often improves 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
Metformin
Metformin is an oral antidiabetic drug in the biguanide class. It is the first-line drug of choice for the treatment of type 2 diabetes, in particular, in overweight and obese people and those with normal kidney function. Its use in gestational diabetes has been limited by safety concerns...
at reducing the risk of progressing to type 2 diabetes. One 2009 study has found that carbohydrate deficit after exercise, but not energy deficit, contributed to insulin sensitivity increase.
Some types of Monounsaturated fatty acids
Monounsaturated fat
In biochemistry and nutrition, monounsaturated fats or MUFA are fatty acids that have one double bond in the fatty acid chain and all of the remainder of the carbon atoms in the chain are single-bonded...
, saturated, and trans fats promote insulin resistance. Some types of polyunsaturated fatty acids
Polyunsaturated fat
In nutrition, polyunsaturated fat, or polyunsaturated fatty acid, are fatty acids in which more than one carbon–carbon double bond exists within the representative molecule. That is, the molecule has two or more points on its structure capable of supporting hydrogen atoms not currently part of the...
(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.
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 sensitivity, but these effects are controversial.
Naturopathic approaches to insulin resistance have been advocated including supplementation of vanadium (but see preceding paragraph), bitter melon (Momordica
Momordica
Momordica is a genus of about 60 species of annual or perennial climbers herbaceous or rarely small shrubs belonging to the family Cucurbitaceae, natives of tropical and subtropical Africa and Asia and Australia...
, but reportedly dangerous if not used with care), and Gymnema sylvestre
Gymnema sylvestre
Gymnema sylvestre is a herb native to the tropical forests of southern and central India where it has been used as a natural treatment for diabetes for nearly two millennia.-Description:...
.
One study found that chromium is necessary for maintaining normal glucose tolerance.
History
The concept that insulin resistance may be the underlying cause of diabetes mellitusDiabetes mellitus
Diabetes mellitus, often simply referred to as diabetes, is a group of metabolic diseases in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced...
type 2 was first advanced by Prof. Wilhelm Falta and published in Vienna in 1931, and confirmed as contributary by Sir Harold Percival Himsworth
Harold Percival Himsworth
Sir Harold Percival Himsworth, KCB was a British scientist, best known for his medical research on diabetes mellitus.-Early life:...
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.
External links
- Insulin resistance at the Open Directory ProjectOpen Directory ProjectThe Open Directory Project , also known as Dmoz , is a multilingual open content directory of World Wide Web links. It is owned by Netscape but it is constructed and maintained by a community of volunteer editors.ODP uses a hierarchical ontology scheme for organizing site listings...
- The National Insulin Resistance Council