Insulin resistance

Last updated
Insulin resistance
Specialty Endocrinology

Insulin resistance (IR) is a pathological condition in which cells fail to respond normally to the hormone insulin. [1]

Cell (biology) The basic structural and functional unit of all organisms; the smallest unit of life.

The cell is the basic structural, functional, and biological unit of all known living organisms. A cell is the smallest unit of life. Cells are often called the "building blocks of life". The study of cells is called cell biology or cellular biology.

Insulin mammalian protein found in Homo sapiens

Insulin is a peptide hormone produced by beta cells of the pancreatic islets; it is considered to be the main anabolic hormone of the body. It regulates the metabolism of carbohydrates, fats and protein by promoting the absorption of carbohydrates, especially glucose from the blood into liver, fat and skeletal muscle cells. In these tissues the absorbed glucose is converted into either glycogen via glycogenesis or fats (triglycerides) via lipogenesis, or, in the case of the liver, into both. Glucose production and secretion by the liver is strongly inhibited by high concentrations of insulin in the blood. Circulating insulin also affects the synthesis of proteins in a wide variety of tissues. It is therefore an anabolic hormone, promoting the conversion of small molecules in the blood into large molecules inside the cells. Low insulin levels in the blood have the opposite effect by promoting widespread catabolism, especially of reserve body fat.


To prevent hyperglycemia and noticeable organ damage over time, [2] the body produces insulin when glucose starts to be released into the bloodstream, primarily from the digestion of carbohydrates in the diet. Under normal conditions of insulin reactivity, this insulin response triggers glucose being taken into body cells, to be used for energy, and inhibits the body from using fat for energy, thereby causing the concentration of glucose in the blood to decrease as a result, staying within the normal range even when a large amount of carbohydrates is consumed.

Hyperglycemia Too much blood sugar, usually because of diabetes

Hyperglycemia, is a condition in which an excessive amount of glucose circulates in the blood plasma. This is generally a blood sugar level higher than 11.1 mmol/l (200 mg/dl), but symptoms may not start to become noticeable until even higher values such as 15–20 mmol/l (~250–300 mg/dl). A subject with a consistent range between ~5.6 and ~7 mmol/l is considered slightly hyperglycemic, while above 7 mmol/l is generally held to have diabetes. For diabetics, glucose levels that are considered to be too hyperglycemic can vary from person to person, mainly due to the person's renal threshold of glucose and overall glucose tolerance. On average however, chronic levels above 10–12 mmol/L can produce noticeable organ damage over time.

Glucose A simple form of sugar

Glucose (also called dextrose) is a simple sugar with the molecular formula C6H12O6. Glucose is the most abundant monosaccharide, a subcategory of carbohydrates. Glucose is mainly made by plants and most algae during photosynthesis from water and carbon dioxide, using energy from sunlight. There it is used to make cellulose in cell walls, which is the most abundant carbohydrate. In energy metabolism, glucose is the most important source of energy in all organisms. Glucose for metabolism is partially stored as a polymer, in plants mainly as starch and amylopectin and in animals as glycogen. Glucose circulates in the blood of animals as blood sugar. The naturally occurring form of glucose is D-glucose, while L-glucose is produced synthetically in comparatively small amounts and is of lesser importance.

Blood specialized bodily fluid in animals

Blood is a body fluid in humans and other animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells.

Carbohydrates comprise simple sugars, i.e. monosaccharides, such as glucose and fructose, disaccharides, such as cane sugar, and polysaccharides, e.g. starches. Fructose, which is metabolised into triglycerides in the liver, stimulates insulin production through another mechanism, and can have a more potent effect than other carbohydrates. A habitually high intake of carbohydrates, and particularly fructose, e.g. with sweetened beverages, contributes to insulin resistance and has been linked to weight gain and obesity. [3] [4] [5] If excess blood sugar is not sufficiently absorbed by cells even in the presence of insulin, the increase in the level of blood sugar can result in the classic hyperglycemic triad of polyphagia (increased appetite), polydipsia (increased thirst) and polyuria (increased urination).

Fructose A simple ketonic monosaccharide found in many plants

Fructose, or fruit sugar, is a simple ketonic monosaccharide found in many plants, where it is often bonded to glucose to form the disaccharide sucrose. It is one of the three dietary monosaccharides, along with glucose and galactose, that are absorbed directly into blood during digestion. Fructose was discovered by French chemist Augustin-Pierre Dubrunfaut in 1847. The name "fructose" was coined in 1857 by the English chemist William Allen Miller. Pure, dry fructose is a sweet, white, odorless, crystalline solid, and is the most water-soluble of all the sugars. Fructose is found in honey, tree and vine fruits, flowers, berries, and most root vegetables.

Sweetened beverage

A sweetened beverage is any beverage with added sugar. It has been described as "liquid candy". Consumption of sweetened beverages has been linked to weight gain, obesity, and associated health risks. According to the CDC, consumption of sweetened beverages is also associated with unhealthy behaviors like smoking, not getting enough sleep and exercise, and eating fast food often and not enough fruits regularly.

Weight gain

Weight gain is an increase in body weight. This can involve an increase in muscle mass, fat deposits, excess fluids such as water or other factors. Weight gain can be a symptom of a serious medical condition.

Avoiding carbohydrates and sugars, a no-carbohydrate diet or fasting can reverse insulin resistance. [6] [7]

Fasting is the willing abstinence or reduction from some or all food, drink, or both, for a period of time. An absolute fast or dry fasting is normally defined as abstinence from all food and liquid for a defined period. Other fasts may be partially restrictive, limiting only particular foods or substances, or be intermittent.


When the body produces insulin under conditions of insulin resistance, the cells are resistant to the insulin and are unable to use it as effectively, leading to high blood sugar. Beta cells in the pancreas subsequently increase their production of insulin, further contributing to a high blood insulin level. This often remains undetected and can contribute to the development of type 2 diabetes, obesity or latent autoimmune diabetes of adults. [8] Although this type of chronic insulin resistance is harmful, during acute illness it is actually a well-evolved protective mechanism.

Beta cells are a type of cell found in pancreatic islets that synthesize and secrete insulin and amylin. Beta cells make up 50–70% of the cells in human islets. In patients with type I or type II diabetes, beta-cell mass and function are diminished, leading to insufficient insulin secretion and hyperglycemia.

Pancreas glandular organ in the digestive system and endocrine system of vertebrates or mixed gland because this count in exocrine and endocrine system . It secrete both enzymes and and proteins.

The pancreas is an organ of the digestive system and endocrine system of vertebrates. In humans, it is located in the abdomen behind the stomach.

Hyperinsulinemia condition in which there are excess levels of insulin circulating in the blood relative to the level of glucose

Hyperinsulinemia, is a condition in which there are excess levels of insulin circulating in the blood relative to the level of glucose. While it is often mistaken for diabetes or hyperglycaemia, hyperinsulinemia can result from a variety of metabolic diseases and conditions. While hyperinsulinemia is often seen in people with early stage type 2 diabetes mellitus, it is not the cause of the condition and is only one symptom of the disease. Type 1 diabetes only occurs when pancreatic beta-cell function is impaired. Hyperinsulinemia can be seen in a variety of conditions including diabetes mellitus type 2, in neonates and in drug induced hyperinsulinemia. It can also occur in congenital hyperinsulism, including nesidioblastosis.

Recent investigations have revealed that insulin resistance helps to conserve the brain's glucose supply by preventing muscles from taking up excessive glucose. [1] In theory, insulin resistance should even be strengthened under harsh metabolic conditions such as pregnancy, during which the expanding fetal brain demands more glucose.

People who develop type 2 diabetes usually pass through earlier stages of insulin resistance and prediabetes, although those often go undiagnosed. Insulin resistance is a syndrome (a set of signs and symptoms) resulting from reduced insulin activity; it is also part of a larger constellation of symptoms called the metabolic syndrome.

Insulin resistance may also develop in patients who have recently experienced abdominal or bariatric procedures. [9] This acute form of insulin resistance that may result post-operatively tends to increase over the short term, with sensitivity to insulin typically returning to patients after about five days. [10]

Associated risk factors

Several associated risk factors include the following:


Molecular mechanism

Insulin resistance implies that the body's cells (primarily muscle) lose sensitivity to insulin, a hormone secreted by the pancreas to promote glucose utilization. At the molecular level, a cell senses insulin through insulin receptors, with the signal propagating through a cascade of molecules collectively known as PI3K/Akt/mTOR signaling pathway. [17] Recent studies suggested that the pathway may operate as a bistable switch under physiologic conditions for certain types of cells, and insulin response may well be a threshold phenomenon. [1] [17] [18] The pathway's sensitivity to insulin may be blunted by many factors such as free fatty acids, [19] causing insulin resistance. From a broader perspective, however, sensitivity tuning (including sensitivity reduction) is a common practice for an organism to adapt to the changing environment or metabolic conditions. [20] Pregnancy, for example, is a prominent change of metabolic conditions, under which the mother has to reduce her muscles' insulin sensitivity to spare more glucose for the brains (the mother's brain and the fetal brain). This can be achieved through raising the response threshold (i.e., postponing the onset of sensitivity) by secreting placental growth factor to interfere with the interaction between insulin receptor substrate (IRS) and PI3K, which is the essence of the so-called adjustable threshold hypothesis of insulin resistance. [1]


It is well known that insulin regulates the conversion of carbohydrates into fats (triglycerides) by promoting the absorption of, especially, glucose from the blood into fat cells. [21] The intake of simple sugars, and particularly fructose, is a factor that contributes to insulin resistance. [3] Fructose is metabolized by the liver into triglycerides, and, as mentioned above, tends to raise their levels in the blood stream.

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. [22]

Insulin resistance and type 2 diabetes are associated with excess body weight. [23] A 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 may be absorbed easily by the adipose cells, and tend to end up as fatty tissue in a hypercaloric diet.[ citation needed ] Some scholars go as far as to claim that neither insulin resistance, nor obesity really are 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." [24]

Fast food meals combined with drinks containing sugar typically possess several characteristics, all of which have independently been linked to IR: they are sugar rich, palatable, and cheap, increasing risk of overeating and leptin resistance; simultaneously, they are high in dietary fat and fructose, and low in omega-3 and fiber; and they usually have high glycemic indices. [22] Overconsumption of cheap sugar-rich meals and beverages have been proposed as a fundamental factor behind the metabolic syndrome epidemic and all its constituents.

Vitamin D deficiency also is associated with insulin resistance. [25]

Elevated levels of free fatty acids and triglycerides in the blood stream and tissues also have been found in many studies to occur in states of insulin resistance. [26] [27] [28] [29] Triglyceride levels are driven by a variety of dietary factors.

In studies on animals caloric intake that is far in excess of animals' energy needs results in rapid weight gain and significant insulin resistance after just three weeks (in rats). [30] [26]

Sedentary lifestyle

Sedentary lifestyle increases the likelihood of development of insulin resistance. [31] [32] It has been estimated that each 500 kcal/week increment in physical activity related energy expenditure, reduces the lifetime risk of type 2 diabetes by 9%. [33] A different study found that vigorous exercise at least once a week reduced the risk of type 2 diabetes in women by 33%. [34]

Protease inhibitors

Protease inhibitors found in HIV drugs are linked to insulin resistance. [35]

Cellular level

At the cellular level, much of the variance in insulin sensitivity between untrained, non-diabetic humans may be explained by two mechanisms: differences in phospholipid profiles of skeletal muscle cell membranes, and in intramyocellular lipid (ICML) stores within these cells. [36] 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. [27] [37] This mechanism is quite fast-acting and may induce insulin resistance within days or even hours in response to a large lipid influx. [38] 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, [39] [40] and it must be combined with physical exercise to have any effect.

In the long term, diet has the potential to change the ratio of polyunsaturated to saturated phospholipids in cell membranes, correspondingly changing cell membrane fluidity; full impact of such changes is not fully understood, but it is known that the percentage of polyunsaturated phospholipids is strongly inversely correlated with insulin resistance. [41] 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. [42]

Many stressing factors may lead to increased cortisol in the bloodstream. Cortisol counteracts insulin, contributes to hyperglycemia-causing hepatic gluconeogenesis, [43] and inhibits the peripheral utilization of glucose, which eventually leads to insulin resistance. [43] It does this by decreasing the translocation of glucose transporters (especially GLUT4) to the cell membrane. [44] [45]

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. [46] [47] Recent study have found out the specific role of the MLK family of protein in the activation of JNK during obesity and insulin resistance. [48]

Rare type 2 diabetes cases sometimes use high levels of exogenous insulin. As short-term overdosing of insulin causes short-term insulin resistance, it has been hypothesized that chronic high dosing contributes to more permanent insulin resistance.[ citation needed ]


At a molecular level, insulin resistance has been proposed to be a reaction to excess nutrition by superoxide dismutase in cell mitochondria that acts as an antioxidant defense mechanism. This link seems to exist under diverse causes of insulin resistance. It also is based on the finding that insulin resistance may be reversed rapidly by exposing cells to mitochondrial uncouplers, electron transport chain inhibitors, or mitochondrial superoxide dismutase mimetics. [49]


Recent research and experimentation has uncovered a non-obesity related connection to insulin resistance and type 2 diabetes. It has long been observed that patients who have had some kinds of bariatric surgery have increased insulin sensitivity and even remission of type 2 diabetes. It was discovered that diabetic/insulin resistant non-obese rats whose duodenum has been removed surgically, also experienced increased insulin sensitivity [50] and remission of type 2 diabetes. This suggested similar surgery in humans, and early reports in prominent medical journals [51] 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 the mucosa of that initial 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, and the existence of such a substance remains speculative.[ citation needed ]

Insulin resistance is associated with PCOS. [52]

HCV and insulin resistance

Hepatitis C also makes people three to four times more likely to develop type 2 diabetes and insulin resistance. [15] In addition, "people with Hepatitis C who develop diabetes probably have susceptible insulin-producing cells, and probably would get it anyway, but much later in life. [15] The extra insulin resistance caused by Hepatitis C apparently brings on diabetes at age 35 or 40, instead of 65 or 70." [15]


Variation in the NAT2 gene is associated with insulin resistance by affecting insulin sensitivity. Specifically, it is believed that the rs1208 loci near the NAT2 gene plays a role in insulin resistance. One study showed that when the expression of the NAT1 gene, the mouse equivalent of NAT2, is reduced there was a decrease in insulin stimulated glucose uptake and therefore decreases insulin sensitivity. Further research has shown that loci near the GCKR and IGFI genes are linked to insulin resistance. Several other loci have also been determined to be associated with insulin insensitivity. These loci however, are estimated to only account for 25-44% of the genetic component of insulin resistance. [53]


One of insulin's functions is to regulate delivery of glucose into cells to provide them with energy. [54] Insulin resistant cells cannot take in glucose, amino acids and fatty acids. Thus, glucose, fatty acids and amino acids 'leak' out of the cells. A decrease in insulin/glucagon ratio inhibits glycolysis which in turn decreases energy production. The resulting increase in blood glucose may raise levels outside the normal range and cause adverse health effects, depending on dietary conditions. [55] 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. [56]

Insulin resistance in muscle and fat cells reduces glucose uptake (and also local storage of glucose as glycogen and triglycerides, respectively), whereas insulin resistance in liver cells results in reduced glycogen synthesis and storage and also a failure to suppress glucose production and release into the blood. Insulin resistance normally refers to reduced glucose-lowering effects of insulin. However, other functions of insulin can also be affected. For example, insulin resistance in fat cells reduces the normal effects of insulin on lipids and results in reduced uptake of circulating lipids and increased hydrolysis of stored triglycerides. Increased mobilization of stored lipids in these cells elevates free fatty acids in the blood plasma. Elevated blood fatty-acid concentrations (associated with insulin resistance and diabetes mellitus Type 2), reduced muscle glucose uptake, and increased liver glucose production all contribute to elevated blood glucose levels. High plasma levels of insulin and glucose due to insulin resistance are a major component of the metabolic syndrome. If insulin resistance exists, more insulin needs to be secreted by the pancreas. If this compensatory increase does not occur, blood glucose concentrations increase and type 2 diabetes or latent autoimmune diabetes of adults occurs. [55] [57]

Any food or drink containing glucose (or the digestible carbohydrates that contain it, such as sucrose, starch, etc.) causes blood glucose levels to increase. In normal metabolism, the elevated blood glucose level instructs beta (β) cells in the Islets of Langerhans, located in the pancreas, to release insulin into the blood. The insulin, in turn, makes insulin-sensitive tissues in the body (primarily skeletal muscle cells, adipose tissue, and liver) absorb glucose, and thereby lower the blood glucose level. The beta cells reduce insulin output as the blood glucose level falls, allowing blood glucose to settle at a constant of approximately 5 mmol/L (mM) (90 mg/dL). In an insulin-resistant person, normal levels of insulin do not have the same effect in controlling blood glucose levels. During the compensated phase on insulin resistance, insulin levels are higher, and blood glucose levels are still maintained. If compensatory insulin secretion fails, then either fasting (impaired fasting glucose) or postprandial (impaired glucose tolerance) glucose concentrations increase. Eventually, type 2 diabetes or latent autoimmune diabetes occurs when glucose levels become higher throughout the day as the resistance increases and compensatory insulin secretion fails. The elevated insulin levels also have additional effects (see insulin) that cause further abnormal biological effects throughout the body.[ citation needed ]

The most common type of insulin resistance is associated with overweight and obesity in a condition known as the metabolic syndrome. Insulin resistance often progresses to full Type 2 diabetes mellitus (T2DM) or latent autoimmune diabetes of adults. [58] [59] This often is seen when hyperglycemia develops after a meal, when pancreatic β-cells are unable to produce sufficient insulin to maintain normal blood sugar levels (euglycemia) in the face of insulin resistance. The inability of the β-cells to produce sufficient insulin in a condition of hyperglycemia is what characterizes the transition from insulin resistance to T2DM. [60]

Various disease states make body tissues more resistant to the actions of insulin. Examples include infection (mediated by the cytokine TNFα) and acidosis. Recent research is investigating the roles of adipokines (the cytokines produced by adipose tissue) in insulin resistance. TNF-α has been found in increased amounts in obese patients. Due to its effects on adipocytes it is possible that excessive TNF-α is one of several factors that leads to insulin resistance. TNF-α can inhibit lipogenesis, promote lipolysis, disrupt insulin signaling, and reduce the expression of GLUT4. [61] Animal studies have tested the theory by reducing the expression of TNF-α and its receptor in obese animals.Beneficial results were found in some studies, supporting the idea that TNF-α plays a role in insulin resistance. [62]

Certain drugs also may be associated with insulin resistance (e.g., glucocorticoids).[ citation needed ]

The presence of insulin leads to a kind of insulin resistance; every time a cell is exposed to insulin, the production of GLUT4 (Glucose transporter type 4) on the membrane of the cell decreases somewhat. [63] 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, [64] but if it is left unchecked, it may contribute to insulin resistance.

Elevated blood levels of glucose—regardless of cause—lead to increased glycation of proteins with changes, only a few of which are understood in any detail, in protein function throughout the body. [65] [66]

Insulin resistance often is 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 may cause insulin resistance. Second, visceral adiposity is related to an accumulation of fat in the liver, a condition known as non-alcoholic fatty liver disease (NAFLD). The result of NAFLD is an excessive release of free fatty acids into the bloodstream (due to increased lipolysis), and an increase in hepatic glycogenolysis and hepatic glucose production, both of which have the effect of exacerbating peripheral insulin resistance and increasing the likelihood of Type 2 diabetes mellitus.[ citation needed ]

Also, insulin resistance often is associated with a hypercoagulable state (impaired fibrinolysis) and increased inflammatory cytokine levels. [67]

Another factor that may promote insulin resistance is Leptin, a hormone produced from the ob gene and adipocytes. [68] Its physiological role is to regulate hunger by alerting the body when it is full. [69] From an adaptation perspective, it is possible that leptin resistance was favorable for survival during periods when food was scarce. [69] Today however studies show that lack of leptin causes severe obesity and is strongly linked with insulin resistance. [70] Leptin replacement in mice with obesity and diabetes has been found to quickly decrease glucose and insulin levels and can affect insulin sensitivity. [71] Further research into the molecular mechanisms of these effects would be beneficial for increased understanding. [71]


Fasting insulin levels

A fasting serum insulin level greater than 25 mU/L or 174 pmol/L is considered insulin resistance. The same levels apply three hours after the last meal. [72]

Glucose tolerance testing

During a glucose tolerance test (GTT), which may be used to diagnose diabetes mellitus, a fasting patient takes a 75 gram oral dose of glucose. Then blood glucose levels are measured over the following two hours.

Interpretation is based on WHO guidelines. After two hours a glycemia less than 7.8 mmol/L (140 mg/dL) is considered normal, a glycemia of between 7.8 and 11.0 mmol/L (140 to 197 mg/dL) is considered as impaired glucose tolerance (IGT), and a glycemia of greater than or equal to 11.1 mmol/L (200 mg/dL) is considered diabetes mellitus.

An oral glucose tolerance test (OGTT) may 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 peak (after the meal) in insulin production. Extension of the testing (for several more hours) may reveal a hypoglycemic "dip," that is a result of an overshoot in insulin production after the failure of the physiologic postprandial insulin response.[ citation needed ]

Measuring insulin resistance

Hyperinsulinemic euglycemic clamp

The gold standard for investigating and quantifying insulin resistance is the "hyperinsulinemic euglycemic clamp," so-called because it measures the amount of glucose necessary to compensate for an increased insulin level without causing hypoglycemia. [73] 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 commonly is referred to in diabetes literature as the GINF value. [74]

The procedure takes about two 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 five to ten minutes. [74]

The rate of glucose infusion during the last thirty 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. [74]

This basic technique may be enhanced significantly by the use of glucose tracers. Glucose may 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). [74]

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. [74]

Patients initially receive 25 μg of octreotide (Sandostatin) in 5 mL of normal saline over 3 to 5 minutes via intravenous infusion (IV) as an initial bolus, and then, are infused continuously with an intravenous infusion of somatostatin (0.27 μg/m2/min) to suppress endogenous insulin and glucose secretion. Next, insulin and 20% glucose are infused at rates of 32 and 267 mg/m2/min, respectively. Blood glucose is checked at zero, 30, 60, 90, and 120 minutes, and thereafter, every 10 minutes for the last half-hour of the test. These last four 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. [74]


Given the complicated nature of the "clamp" technique (and the potential dangers of hypoglycemia in some patients), alternatives have been sought to simplify the measurement of insulin resistance. The first was the Homeostatic Model Assessment (HOMA), and a more recent method is the Quantitative insulin sensitivity check index (QUICKI). Both employ fasting insulin and glucose levels to calculate insulin resistance, and both correlate reasonably with the results of clamping studies. Wallace et al. point out that QUICKI is the logarithm of the value from one of the HOMA equations. [75]


The primary treatment for insulin resistance is exercise and weight loss. Research shows that a low-carbohydrate diet may help. [76] Both metformin and thiazolidinediones improve insulin resistance, but are approved therapies only for type 2 diabetes, not for insulin resistance. By contrast, growth hormone replacement therapy may be associated with increased insulin resistance. [77]

Metformin has become one of the more commonly prescribed medications for insulin resistance. [78] Unfortunately, Metformin also masks Vitamin B12 deficiency, so accompanying sub-lingual Vitamin B12 tablets are recommended.

Insulin resistance is often associated with abnormalities in lipids particularly high blood triglycerides and low high density lipoprotein. [26] [27]

The Diabetes Prevention Program (DPP) showed that exercise and diet were nearly twice as effective as metformin at reducing the risk of progressing to type 2 diabetes. [79] However, the participants in the DPP trial regained about 40% of the weight that they had lost at the end of 2.8 years, resulting in a similar incidence of diabetes development in both the lifestyle intervention and the control arms of the trial. [80] One 2009 study found that carbohydrate deficit after exercise, but not energy deficit, contributed to insulin sensitivity increase. [81]

Resistant starch from high-amylose corn, amylomaize, has been shown to reduce insulin resistance in healthy individuals, in individuals with insulin resistance, and in individuals with type 2 diabetes. [82] Animal studies demonstrate that it cannot reverse damage already done by high glucose levels, but that it reduces insulin resistance and reduces the development of further damage. [83] [84] [85]

Some types of polyunsaturated fatty acids (omega-3) may moderate the progression of insulin resistance into type 2 diabetes, [86] [87] [88] 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. [89]

Caffeine intake limits insulin action, but not enough to increase blood-sugar levels in healthy persons. People who already have type 2 diabetes may see a small increase in levels if they take 2 or 2-1/2 cups of coffee per day. [90]


The concept that insulin resistance may be the underlying cause of diabetes mellitus type 2 was first advanced by Professor Wilhelm Falta and published in Vienna in 1931, [91] and confirmed as contributory by Sir Harold Percival Himsworth of the University College Hospital Medical Centre in London in 1936, [92] however, type 2 diabetes does not occur unless there is concurrent failure of compensatory insulin secretion. [93]

Adaptive explanations

There is some prevailing thought that insulin resistance can be an evolutionary adaptation. In 1962, James Nee l proposed his thrifty gene hypothesis.

This hypothesis raises the point that if there is a genetic component to insulin resistance and Type 2 Diabetes, these phenotypes should be selected against. [94] Yet, there has been an increase in mean insulin resistance in both the normoglycemic population as well as the diabetic population. [95]

Neel Postulates that originally in times of increased famine in ancient humans ancestors, that genes conferring a mechanism for increased glucose storage would be advantageous. In the modern environment today however this is not the case. [94]

Evidence is contradictory to Neel in studies of the Pima Indians, which indicate that the people with higher insulin sensitives tended to weigh the most and conversely people with insulin resistance tended to weigh less on average in this demographic. [96]

Modern hypotheses suggest that insulin metabolism is a socio-ecological adaptation with insulin being the means for differentiating energy allocation to various components of the body and insulin sensitivity an adaptation to manipulate where the energy is diverted to. The Behavioral Switch Hypothesis posits that insulin resistance results in two methods to alter reproductive strategies and behavioral methods. The two strategies are coined as “r to K” and “soldier to diplomat.” The r to K strategy involves diverting insulin via placenta to the fetus. This has demonstrated weight gain in the fetus, but not the mother indicating a method of increased parental investment (K strategy). In the “soldier to diplomat” the insensitivity of skeletal muscle to insulin could divert the glucose to the brain, which doesn’t require insulin receptors. This has shown increased in cognitive development across various studies. [97]

See also

Related Research Articles

Fat one of the three main macronutrients, along with carbohydrate and protein. Fats, also known as triglycerides, are esters of three fatty acid chains and the alcohol glycerol

Fat is one of the three main macronutrients, along with carbohydrate and protein. Fats molecules consist of primarily carbon and hydrogen atoms, thus they are all hydrocarbon molecules. Examples include cholesterol, phospholipids and triglycerides.

Metabolic syndrome clustering of medical conditions (giving a total of 16 possible combinations giving the syndrome)

Metabolic syndrome, sometimes known by other names, is a clustering of at least three of the five following medical conditions: central obesity, high blood pressure, high blood sugar, high serum triglycerides, and low serum high-density lipoprotein (HDL).

Abdominal obesity excessive abdominal fat around the stomach and abdomen

Abdominal obesity, also known as central obesity, occurs when excessive abdominal fat around the stomach and abdomen has built up to the extent that it is likely to have a negative impact on health. Central obesity has been strongly linked to cardiovascular disease, Alzheimer's disease, and other metabolic and vascular diseases.

Type 2 diabetes type of diabetes mellitus with high blood sugar and insulin resistance

Type 2 diabetes (T2D), also known as adult-onset diabetes, is a form of diabetes that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent urination, and unexplained weight loss. Symptoms may also include increased hunger, feeling tired, and sores that do not heal. Often symptoms come on slowly. Long-term complications from high blood sugar include heart disease, strokes, diabetic retinopathy which can result in blindness, kidney failure, and poor blood flow in the limbs which may lead to amputations. The sudden onset of hyperosmolar hyperglycemic state may occur; however, ketoacidosis is uncommon.

Adiponectin protein-coding gene in the species Homo sapiens

Adiponectin is a protein hormone which is involved in regulating glucose levels as well as fatty acid breakdown. In humans it is encoded by the ADIPOQ gene and it is produced in adipose tissue.

Lipogenesis is the metabolic process through which acetyl-CoA is converted to triglyceride for storage in fat. The triglycerides in fat are packaged within cytoplasmic lipid droplets. The process begins with acetyl-CoA, which is an organic compound used to transfer energy from metabolism of carbohydrates, fatty acids, and ethanol. Through the citric acid cycle, acetyl-CoA is broken down to produce ATP, which is then an energy source for many metabolic processes, including protein synthesis and muscle contraction.

Starvation response in animals is a set of adaptive biochemical and physiological changes that reduce metabolism in response to a lack of food.

Equine metabolic syndrome

Equine metabolic syndrome (EMS), is an endocrinopathy affecting horses and ponies. It is of primary concern due to its link to obesity, insulin resistance, and subsequent laminitis. There are some similarities in clinical signs between EMS and pituitary pars intermedia dysfunction, also known as PPID or Cushing's disease, and some equines may develop both, but they are not the same condition, having different causes and different treatment.

The Randle cycle, also known as the glucose fatty-acid cycle, is a metabolic process involving the competition of glucose and fatty acids for substrates. It is theorized to play a role in explaining type 2 diabetes and insulin resistance.

Prediabetes is the precursor stage before diabetes mellitus in which not all of the symptoms required to diagnose diabetes are present, but blood sugar is abnormally high. This stage is often referred to as the "grey area". It is not a disease; the American Diabetes Association says, "Prediabetes should not be viewed as a clinical entity in its own right but rather as an increased risk for diabetes and cardiovascular disease (CVD). Prediabetes is associated with obesity, dyslipidemia with high triglycerides and/or low HDL cholesterol, and hypertension." It is thus a metabolic diathesis or syndrome, and it usually involves no symptoms and only high blood sugar as the sole sign.

Adiposopathy is defined as pathologic adipocyte and adipose tissue anatomic & functional disturbances, promoted by positive caloric balance, in genetically and environmentally susceptible individuals. The ensuing pathogenic endocrine and immune responses may directly promote cardiovascular disease, and may also cause or worsen among the most common metabolic disease encountered in developed countries. Because many of these metabolic diseases are major cardiovascular disease risk factors, adiposopathy also indirectly increases CVD risk, and is an important contributor to the metabolic syndrome.

The portal-visceral hypothesis describes a possible mechanism for some of the health effects of obesity, particularly the metabolic syndrome. It says that obesity results in increased circulation of free fatty acids and thus, via Randle's effect, in insulin resistance.


Glyceroneogenesis is a metabolic pathway which synthesizes glycerol 3-phosphate or triglyceride from precursors other than glucose. Usually glycerol 3-phosphate is generated from glucose by glycolysis, but when glucose concentration drops in the cytosol, it is generated by another pathway called glyceroneogenesis. Glyceroneogenesis uses pyruvate, alanine, glutamine or any substances from the TCA cycle as precursors for glycerol 3-phosphate. Phosphoenolpyruvate carboxykinase (PEPC-K), which is an enzyme that catalyzes the decarboxylation of oxaloacetate to phosphoenolpyruvate is the main regulator for this pathway. Glyceroneogenesis can be observed in adipose tissue and also liver. It is a significant biochemical pathway which regulates cytosolic lipid levels. Intense suppression of glyceroneogenesis may lead to metabolic disorder such as type 2 diabetes.

The insulin transduction pathway is a biochemical pathway by which insulin increases the uptake of glucose into fat and muscle cells and reduces the synthesis of glucose in the liver and hence is involved in maintaining glucose homeostasis. This pathway is also influenced by fed versus fasting states, stress levels, and a variety of other hormones.

Lipotoxicity is a metabolic syndrome that results from the accumulation of lipid intermediates in non-adipose tissue, leading to cellular dysfunction and death. The tissues normally affected include the kidneys, liver, heart and skeletal muscle. Lipotoxicity is believed to have a role in heart failure, obesity, and diabetes, and is estimated to affect approximately 25% of the adult American population.

A number of lifestyle factors are known to be important to the development of type 2 diabetes including: obesity, physical activity, diet, stress, and urbanization. Excess body fat underlies 64% of cases of diabetes in men and 77% of cases in women. A number of dietary factors such as sugar sweetened drinks and the type of fat in the diet appear to play a role.

Intramyocellular lipids are fats stored in droplets in muscle cells. They provide an important energy source for working muscle. During exercise, a large amount of circulating free fatty acids are directed into muscle cells for energy; during rest, incoming fatty acids are instead stored in the muscle cell as triglycerides for later burning. However, an increase in muscle insulin resistance, caused by obesity, diabetes mellitus type 2, and metabolic syndrome, will result in an excess accumulation of intramyocellular lipids.

Diabetes mellitus (DM) is a type of metabolic disease characterized by hyperglycemia. It is caused by either defected insulin secretion or damaged biological function, or both. The high-level blood glucose for a long time will lead to dysfunction of a variety of tissues.


  1. 1 2 3 4 Wang G (December 2014). "Raison d'être of insulin resistance: the adjustable threshold hypothesis". Journal of the Royal Society, Interface. 11 (101): 20140892. doi:10.1098/rsif.2014.0892. PMC   4223910 . PMID   25320065.
  2. Diagnosis and Mellitus. (2013). Diabetes Care, 37(Supplement_1), S81–90.
  3. 1 2 Basciano H, Federico L, Adeli K (February 2005). "Fructose, insulin resistance, and metabolic dyslipidemia". Nutrition & Metabolism. 2 (1): 5. doi:10.1186/1743-7075-2-5. PMC   552336 . PMID   15723702.
  4. Frank Hu Associate Professor of Nutrition and Epidemiology Harvard School of Public Health (20 February 2008). Obesity Epidemiology. Oxford University Press. pp. 283–285. ISBN   978-0-19-971847-4 . Retrieved 20 April 2013.
  5. Travis A. Smith (November 2010). Taxing Caloric Sweetened Beverages: Potential Effects on Beverage Consumption, Calorie Intake, and Obesity. DIANE Publishing. pp. 13–14. ISBN   978-1-4379-3593-6 . Retrieved 20 April 2013.
  6. Gallagher, James (24 February 2017). "Fasting diet 'regenerates diabetic pancreas'" (Health and science reporter, BBC News website). BBC. Retrieved 6 August 2018.
  7. Sakzewski, Emily (27 Feb 2017). "Fasting diet could regenerate pancreas and reverse diabetes, researchers say". ABC. Retrieved 6 August 2018.
  8. Chiu HK, Tsai EC, Juneja R, Stoever J, Brooks-Worrell B, Goel A, Palmer JP (August 2007). "Equivalent insulin resistance in latent autoimmune diabetes in adults (LADA) and type 2 diabetic patients". Diabetes Research and Clinical Practice. 77 (2): 237–44. doi:10.1016/j.diabres.2006.12.013. PMID   17234296.
  9. Thorell, Anders; Nygren, Jonas; Ljungqvist, Olle (January 1999). "Insulin resistance: A marker of surgical stress". Current Opinion in Clinical Nutrition and Metabolic Care. 2 (1): 69. doi:10.1097/00075197-199901000-00012.
  10. Thorell A, Efendic S, Gutniak M, Häggmark T, Ljungqvist O (January 1994). "Insulin resistance after abdominal surgery". The British Journal of Surgery. 81 (1): 59–63. doi:10.1002/bjs.1800810120. PMID   8313123.
  11. Cao H, Hegele RA (January 2000). "Nuclear lamin A/C R482Q mutation in canadian kindreds with Dunnigan-type familial partial lipodystrophy". Human Molecular Genetics. 9 (1): 109–12. doi:10.1093/hmg/9.1.109. PMID   10587585.
  12. Musso C, Cochran E, Moran SA, Skarulis MC, Oral EA, Taylor S, Gorden P (July 2004). "Clinical course of genetic diseases of the insulin receptor (type A and Rabson-Mendenhall syndromes): a 30-year prospective". Medicine. 83 (4): 209–22. doi:10.1097/ PMID   15232309.
  13. 1 2 3 4 5 6 7 8 9 10 Mayfield J (October 1998). "Diagnosis and classification of diabetes mellitus: new criteria". American Family Physician. 58 (6): 1355–62, 1369–70. PMID   9803200.
  14. 1 2 3 4 5 6 7 8 "Type 2 diabetes: Risk factors". Mayo Clinic. Retrieved 21 December 2011.
  15. 1 2 3 4 Milner KL, van der Poorten D, Trenell M, Jenkins AB, Xu A, Smythe G, Dore GJ, Zekry A, Weltman M, Fragomeli V, George J, Chisholm DJ (March 2010). "Chronic hepatitis C is associated with peripheral rather than hepatic insulin resistance". Gastroenterology. 138 (3): 932–41.e1–3. doi:10.1053/j.gastro.2009.11.050. PMID   19962985. Lay summary Science Daily (March 10, 2010).
  16. Yasuda K, Hines E, Kitabchi AE (November 1982). "Hypercortisolism and insulin resistance: comparative effects of prednisone, hydrocortisone, and dexamethasone on insulin binding of human erythrocytes". The Journal of Clinical Endocrinology and Metabolism. 55 (5): 910–5. doi:10.1210/jcem-55-5-910. PMID   6749880.
  17. 1 2 Wang G (December 2010). "Singularity analysis of the AKT signaling pathway reveals connections between cancer and metabolic diseases". Physical Biology. 7 (4): 046015. Bibcode:2010PhBio...7d6015W. doi:10.1088/1478-3975/7/4/046015. PMID   21178243.
  18. Wang G (October 2012). "Optimal homeostasis necessitates bistable control". Journal of the Royal Society, Interface. 9 (75): 2723–34. doi:10.1098/rsif.2012.0244. PMC   3427521 . PMID   22535698.
  19. Lucidi P, Rossetti P, Porcellati F, Pampanelli S, Candeloro P, Andreoli AM, Perriello G, Bolli GB, Fanelli CG (June 2010). "Mechanisms of insulin resistance after insulin-induced hypoglycemia in humans: the role of lipolysis". Diabetes. 59 (6): 1349–57. doi:10.2337/db09-0745. PMC   2874695 . PMID   20299466.
  20. Wang G, Zhang M (February 2016). "Tunable ultrasensitivity: functional decoupling and biological insights". Scientific Reports. 6: 20345. Bibcode:2016NatSR...620345W. doi:10.1038/srep20345. PMC   4742884 . PMID   26847155.
  21. Stryer, Lubert (1995). Biochemistry (Fourth ed.). New York: W.H. Freeman and Company. pp. 773–774. ISBN   0 7167 2009 4.
  22. 1 2 Isganaitis E, Lustig RH (December 2005). "Fast food, central nervous system insulin resistance, and obesity". Arteriosclerosis, Thrombosis, and Vascular Biology. 25 (12): 2451–62. doi:10.1161/01.ATV.0000186208.06964.91. PMID   16166564.
  23. Kahn SE, Hull RL, Utzschneider KM (December 2006). "Mechanisms linking obesity to insulin resistance and type 2 diabetes". Nature. 444 (7121): 840–6. doi:10.1038/nature05482. PMID   17167471.
  24. Unger RH, Scherer PE (June 2010). "Gluttony, sloth and the metabolic syndrome: a roadmap to lipotoxicity". Trends in Endocrinology and Metabolism. 21 (6): 345–52. doi:10.1016/j.tem.2010.01.009. PMC   2880185 . PMID   20223680.
  25. Chiu KC, Chu A, Go VL, Saad MF (May 2004). "Hypovitaminosis D is associated with insulin resistance and beta cell dysfunction". The American Journal of Clinical Nutrition. 79 (5): 820–5. doi:10.1093/ajcn/79.5.820. PMID   15113720.
  26. 1 2 3 Storlien LH, Jenkins AB, Chisholm DJ, Pascoe WS, Khouri S, Kraegen EW (February 1991). "Influence of dietary fat composition on development of insulin resistance in rats. Relationship to muscle triglyceride and omega-3 fatty acids in muscle phospholipid". Diabetes. 40 (2): 280–9. doi:10.2337/diabetes.40.2.280. PMID   1991575.
  27. 1 2 3 Schinner S, Scherbaum WA, Bornstein SR, Barthel A (June 2005). "Molecular mechanisms of insulin resistance". Diabetic Medicine. 22 (6): 674–82. doi:10.1111/j.1464-5491.2005.01566.x. PMID   15910615.
  28. Koyama K, Chen G, Lee Y, Unger RH (October 1997). "Tissue triglycerides, insulin resistance, and insulin production: implications for hyperinsulinemia of obesity". The American Journal of Physiology. 273 (4 Pt 1): E708–13. PMID   9357799.
  29. Roden M, Price TB, Perseghin G, Petersen KF, Rothman DL, Cline GW, Shulman GI (June 1996). "Mechanism of free fatty acid-induced insulin resistance in humans". The Journal of Clinical Investigation. 97 (12): 2859–65. doi:10.1172/JCI118742. PMC   507380 . PMID   8675698.
  30. Kraegen EW, Clark PW, Jenkins AB, Daley EA, Chisholm DJ, Storlien LH (November 1991). "Development of muscle insulin resistance after liver insulin resistance in high-fat-fed rats". Diabetes. 40 (11): 1397–403. doi:10.2337/diabetes.40.11.1397. PMID   1936601.
  31. Ivy JL (November 1997). "Role of exercise training in the prevention and treatment of insulin resistance and non-insulin-dependent diabetes mellitus". Sports Medicine. Auckland, NZ. 24 (5): 321–36. doi:10.2165/00007256-199724050-00004. PMID   9368278.
  32. Mayer-Davis EJ, D'Agostino R, Karter AJ, Haffner SM, Rewers MJ, Saad M, Bergman RN (March 1998). "Intensity and amount of physical activity in relation to insulin sensitivity: the Insulin Resistance Atherosclerosis Study". JAMA. 279 (9): 669–74. doi:10.1001/jama.279.9.669. PMID   9496984.
  33. Helmrich SP, Ragland DR, Leung RW, Paffenbarger RS (July 1991). "Physical activity and reduced occurrence of non-insulin-dependent diabetes mellitus". The New England Journal of Medicine. 325 (3): 147–52. doi:10.1056/NEJM199107183250302. PMID   2052059.
  34. Manson JE, Rimm EB, Stampfer MJ, Colditz GA, Willett WC, Krolewski AS, Rosner B, Hennekens CH, Speizer FE (September 1991). "Physical activity and incidence of non-insulin-dependent diabetes mellitus in women". Lancet. 338 (8770): 774–8. doi:10.1016/0140-6736(91)90664-B. PMID   1681160.
  35. Fantry, Lori E (2003-03-24). "Protease Inhibitor-Associated Diabetes Mellitus: A Potential Cause of Morbidity and Mortality". Journal of Acquired Immune Deficiency Syndromes. 32 (3){{inconsistent citations}}.
  36. Haag M, Dippenaar NG (December 2005). "Dietary fats, fatty acids and insulin resistance: short review of a multifaceted connection" (PDF). Medical Science Monitor. 11 (12): RA359–67. PMID   16319806. Archived from the original (PDF) on 2011-10-08.
  37. Morino K, Petersen KF, Shulman GI (December 2006). "Molecular mechanisms of insulin resistance in humans and their potential links with mitochondrial dysfunction". Diabetes. 55 Suppl 2 (Suppl 2): S9–S15. doi:10.2337/db06-S002. PMC   2995546 . PMID   17130651.
  38. Bachmann OP, Dahl DB, Brechtel K, Machann J, Haap M, Maier T, Loviscach M, Stumvoll M, Claussen CD, Schick F, Häring HU, Jacob S (November 2001). "Effects of intravenous and dietary lipid challenge on intramyocellular lipid content and the relation with insulin sensitivity in humans". Diabetes. 50 (11): 2579–84. doi:10.2337/diabetes.50.11.2579. PMID   11679437.
  39. Sato F, Tamura Y, Watada H, Kumashiro N, Igarashi Y, Uchino H, Maehara T, Kyogoku S, Sunayama S, Sato H, Hirose T, Tanaka Y, Kawamori R (August 2007). "Effects of diet-induced moderate weight reduction on intrahepatic and intramyocellular triglycerides and glucose metabolism in obese subjects". The Journal of Clinical Endocrinology and Metabolism. 92 (8): 3326–9. doi:10.1210/jc.2006-2384. PMID   17519317.
  40. Tamura Y, Tanaka Y, Sato F, Choi JB, Watada H, Niwa M, Kinoshita J, Ooka A, Kumashiro N, Igarashi Y, Kyogoku S, Maehara T, Kawasumi M, Hirose T, Kawamori R (June 2005). "Effects of diet and exercise on muscle and liver intracellular lipid contents and insulin sensitivity in type 2 diabetic patients". The Journal of Clinical Endocrinology and Metabolism. 90 (6): 3191–6. doi:10.1210/jc.2004-1959. PMID   15769987.
  41. Haugaard SB, Madsbad S, Høy CE, Vaag A (February 2006). "Dietary intervention increases n-3 long-chain polyunsaturated fatty acids in skeletal muscle membrane phospholipids of obese subjects. Implications for insulin sensitivity". Clinical Endocrinology. 64 (2): 169–78. doi:10.1111/j.1365-2265.2006.02444.x. PMID   16430716.
  42. Russo GL (March 2009). "Dietary n-6 and n-3 polyunsaturated fatty acids: from biochemistry to clinical implications in cardiovascular prevention". Biochemical Pharmacology. 77 (6): 937–46. doi:10.1016/j.bcp.2008.10.020. PMID   19022225.
  43. 1 2 Brown, Dave D (2003). USMLE Step 1 Secrets. p. 63.
  44. King, Michael W (2005). Lange Q&A USMLE Step 1 (6th ed.). New York: McGraw-Hill Medical. p. 82. ISBN   978-0-07-144578-8.
  45. Piroli GG, Grillo CA, Reznikov LR, Adams S, McEwen BS, Charron MJ, Reagan LP (2007). "Corticosterone impairs insulin-stimulated translocation of GLUT4 in the rat hippocampus". Neuroendocrinology. 85 (2): 71–80. doi:10.1159/000101694. PMID   17426391.
  46. Solinas G, Vilcu C, Neels JG, Bandyopadhyay GK, Luo JL, Naugler W, Grivennikov S, Wynshaw-Boris A, Scadeng M, Olefsky JM, Karin M (November 2007). "JNK1 in hematopoietically derived cells contributes to diet-induced inflammation and insulin resistance without affecting obesity". Cell Metabolism. 6 (5): 386–97. doi:10.1016/j.cmet.2007.09.011. PMID   17983584.
  47. "UCSD researchers discover inflammation, not obesity, cause of insulin resistance". D life. Archived from the original on 2007-11-21. Retrieved 2008-01-12.
  48. |Kant S, Barrett T, Vertii A, Noh YH, Jung DY, Kim JK, Davis RJ (August 2013). "Role of the mixed-lineage protein kinase pathway in the metabolic stress response to obesity". Cell Reports. 4 (4): 681–8. doi:10.1016/j.celrep.2013.07.019. PMC   3769115 . PMID   23954791.
  49. Hoehn KL, Salmon AB, Hohnen-Behrens C, Turner N, Hoy AJ, Maghzal GJ, Stocker R, Van Remmen H, Kraegen EW, Cooney GJ, Richardson AR, James DE (October 2009). "Insulin resistance is a cellular antioxidant defense mechanism". Proceedings of the National Academy of Sciences of the United States of America. 106 (42): 17787–92. Bibcode:2009PNAS..10617787H. doi:10.1073/pnas.0902380106. PMC   2764908 . PMID   19805130.
  50. Garrido-Sanchez L, Murri M, Rivas-Becerra J, Ocaña-Wilhelmi L, Cohen RV, Garcia-Fuentes E, Tinahones FJ (2012). "Bypass of the duodenum improves insulin resistance much more rapidly than sleeve gastrectomy". Surgery for Obesity and Related Diseases. 8 (2): 145–50. doi:10.1016/j.soard.2011.03.010. PMID   21570362.
  51. Goodman, Alice (June 1, 2016). "Duodenal resurfacing achieves metabolic benefits in type 2 diabetes". Family Practice News. Retrieved 12 March 2017.
  52. Nafiye Y, Sevtap K, Muammer D, Emre O, Senol K, Leyla M (April 2010). "The effect of serum and intrafollicular insulin resistance parameters and homocysteine levels of nonobese, nonhyperandrogenemic polycystic ovary syndrome patients on in vitro fertilization outcome". Fertility and Sterility. 93 (6): 1864–9. doi:10.1016/j.fertnstert.2008.12.024. PMID   19171332.
  53. Brown AE, Walker M (August 2016). "Genetics of Insulin Resistance and the Metabolic Syndrome". Current Cardiology Reports. 18 (8): 75. doi:10.1007/s11886-016-0755-4. PMC   4911377 . PMID   27312935.
  54. "A heavy burden". The Economist. December 15, 2012. Retrieved 10 January 2013.
  55. 1 2 "Insulin resistance". Medicine net.
  56. "Science daily". Jun 2009.
  57. Insulin Resistance Leads to LADA (Report). Diabetes Health. Retrieved Feb 21, 2015.
  58. Behme MT, Dupre J, Harris SB, Hramiak IM, Mahon JL (November 2003). "Insulin resistance in latent autoimmune diabetes of adulthood". Annals of the New York Academy of Sciences. 1005 (1): 374–7. Bibcode:2003NYASA1005..374B. doi:10.1196/annals.1288.062. PMID   14679095.
  59. "Latent Autoimmune Diabetes: A Little Known Type of Diabetes". Pharmacy Times. Retrieved May 30, 2014.
  60. McGarry JD (January 2002). "Banting lecture 2001: dysregulation of fatty acid metabolism in the etiology of type 2 diabetes". Diabetes. 51 (1): 7–18. doi:10.2337/diabetes.51.1.7. PMID   11756317.
  61. Peraldi P, Spiegelman B (May 1998). "TNF-alpha and insulin resistance: summary and future prospects". Molecular and Cellular Biochemistry. 182 (1–2): 169–75. doi:10.1023/A:1006865715292. PMID   9609126.
  62. Hotamisligil GS (June 1999). "The role of TNFalpha and TNF receptors in obesity and insulin resistance". Journal of Internal Medicine. 245 (6): 621–5. doi:10.1046/j.1365-2796.1999.00490.x. PMID   10395191.
  63. Flores-Riveros JR, McLenithan JC, Ezaki O, Lane MD (January 1993). "Insulin down-regulates expression of the insulin-responsive glucose transporter (GLUT4) gene: effects on transcription and mRNA turnover". Proceedings of the National Academy of Sciences of the United States of America. 90 (2): 512–6. Bibcode:1993PNAS...90..512F. doi:10.1073/pnas.90.2.512. PMC   45693 . PMID   8421683.
  64. MacLean PS, Zheng D, Jones JP, Olson AL, Dohm GL (March 2002). "Exercise-induced transcription of the muscle glucose transporter (GLUT 4) gene". Biochemical and Biophysical Research Communications. 292 (2): 409–14. doi:10.1006/bbrc.2002.6654. PMID   11906177.
  65. Koga M, Kasayama S (2010). "Clinical impact of glycated albumin as another glycemic control marker". Endocrine Journal. 57 (9): 751–62. doi:10.1507/endocrj.K10E-138. PMID   20724796.
  66. Puddu A, Viviani GL (June 2011). "Advanced glycation endproducts and diabetes. Beyond vascular complications". Endocrine, Metabolic & Immune Disorders Drug Targets. 11 (2): 132–40. doi:10.2174/187153011795564115. PMID   21476962.
  67. Nagaev I, Bokarewa M, Tarkowski A, Smith U (December 2006). Valcarcel J (ed.). "Human resistin is a systemic immune-derived proinflammatory cytokine targeting both leukocytes and adipocytes". PLOS One. 1 (1): e31. Bibcode:2006PLoSO...1...31N. doi:10.1371/journal.pone.0000031. PMC   1762367 . PMID   17183659.
  68. Friedman JM (April 2000). "Obesity in the new millennium". Nature. 404 (6778): 632–4. doi:10.1038/35007504. PMID   10766249.
  69. 1 2 Flier JS (May 1998). "Clinical review 94: What's in a name? In search of leptin's physiologic role". The Journal of Clinical Endocrinology and Metabolism. 83 (5): 1407–13. doi:10.1210/jcem.83.5.4779. PMID   9589630.
  70. Elmquist JK, Maratos-Flier E, Saper CB, Flier JS (October 1998). "Unraveling the central nervous system pathways underlying responses to leptin". Nature Neuroscience. 1 (6): 445–50. doi:10.1038/2164. PMID   10196541.
  71. 1 2 Halaas JL, Gajiwala KS, Maffei M, Cohen SL, Chait BT, Rabinowitz D, Lallone RL, Burley SK, Friedman JM (July 1995). "Weight-reducing effects of the plasma protein encoded by the obese gene". Science. 269 (5223): 543–6. doi:10.1126/science.7624777. PMID   7624777.
  72. Insulin at eMedicine
  73. DeFronzo RA, Tobin JD, Andres R (September 1979). "Glucose clamp technique: a method for quantifying insulin secretion and resistance". The American Journal of Physiology. 237 (3): E214–23. doi:10.1152/ajpendo.1979.237.3.e214. PMID   382871.
  74. 1 2 3 4 5 6 Muniyappa R, Lee S, Chen H, Quon MJ (January 2008). "Current approaches for assessing insulin sensitivity and resistance in vivo: advantages, limitations, and appropriate usage". American Journal of Physiology. Endocrinology and Metabolism. 294 (1): E15–26. doi:10.1152/ajpendo.00645.2007. PMID   17957034.
  75. Wallace TM, Levy JC, Matthews DR (June 2004). "Use and abuse of HOMA modeling". Diabetes Care. 27 (6): 1487–95. doi:10.2337/diacare.27.6.1487. PMID   15161807.
  76. Boden G, Sargrad K, Homko C, Mozzoli M, Stein TP (March 2005). "Effect of a low-carbohydrate diet on appetite, blood glucose levels, and insulin resistance in obese patients with type 2 diabetes". Annals of Internal Medicine. 142 (6): 403–11. doi:10.7326/0003-4819-142-6-200503150-00006. PMID   15767618.
  77. Bramnert M, Segerlantz M, Laurila E, Daugaard JR, Manhem P, Groop L (April 2003). "Growth hormone replacement therapy induces insulin resistance by activating the glucose-fatty acid cycle". The Journal of Clinical Endocrinology and Metabolism. 88 (4): 1455–63. doi:10.1210/jc.2002-020542. PMID   12679422.
  78. Giannarelli R, Aragona M, Coppelli A, Del Prato S (September 2003). "Reducing insulin resistance with metformin: the evidence today". Diabetes & Metabolism. 29 (4 Pt 2): 6S28–35. doi:10.1016/s1262-3636(03)72785-2. PMID   14502098.
  79. Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, Nathan DM (February 2002). "Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin". The New England Journal of Medicine. 346 (6): 393–403. doi:10.1056/NEJMoa012512. PMC   1370926 . PMID   11832527.
  80. Kahn R (January 2012). "Reducing the impact of diabetes: is prevention feasible today, or should we aim for better treatment?". Health Affairs. 31 (1): 76–83. doi:10.1377/hlthaff.2011.1075. PMID   22232097.
  81. Newsom SA, Schenk S, Thomas KM, Harber MP, Knuth ND, Goldenberg N, Horowitz JF (March 2010). "Energy deficit after exercise augments lipid mobilization but does not contribute to the exercise-induced increase in insulin sensitivity". Journal of Applied Physiology. 108 (3): 554–60. doi:10.1152/japplphysiol.01106.2009. PMC   2838634 . PMID   20044472.
  82. Keenan MJ, Zhou J, Hegsted M, Pelkman C, Durham HA, Coulon DB, Martin RJ (March 2015). "Role of resistant starch in improving gut health, adiposity, and insulin resistance". Advances in Nutrition. 6 (2): 198–205. doi:10.3945/an.114.007419. PMC   4352178 . PMID   25770258.
  83. Higgins JA, Brand Miller JC, Denyer GS (March 1996). "Development of insulin resistance in the rat is dependent on the rate of glucose absorption from the diet". The Journal of Nutrition. 126 (3): 596–602. doi:10.1093/jn/126.3.596. PMID   8598543.
  84. Byrnes SE, Miller JC, Denyer GS (June 1995). "Amylopectin starch promotes the development of insulin resistance in rats". The Journal of Nutrition. 125 (6): 1430–7. doi:10.1093/jn/125.6.1430 (inactive 2019-03-23). PMID   7782895.
  85. Wiseman CE, Higgins JA, Denyer GS, Miller JC (February 1996). "Amylopectin starch induces nonreversible insulin resistance in rats". The Journal of Nutrition. 126 (2): 410–5. doi:10.1093/jn/126.2.410. PMID   8632213.
  86. Lovejoy JC (October 2002). "The influence of dietary fat on insulin resistance". Current Diabetes Reports. 2 (5): 435–40. doi:10.1007/s11892-002-0098-y. PMID   12643169.
  87. Fukuchi S, Hamaguchi K, Seike M, Himeno K, Sakata T, Yoshimatsu H (June 2004). "Role of fatty acid composition in the development of metabolic disorders in sucrose-induced obese rats". Experimental Biology and Medicine. 229 (6): 486–93. doi:10.1177/153537020422900606. PMID   15169967.
  88. Storlien LH, Baur LA, Kriketos AD, Pan DA, Cooney GJ, Jenkins AB, Calvert GD, Campbell LV (June 1996). "Dietary fats and insulin action". Diabetologia. 39 (6): 621–31. doi:10.1007/BF00418533. PMID   8781757.
  89. Delarue J, LeFoll C, Corporeau C, Lucas D (2004). "N-3 long chain polyunsaturated fatty acids: a nutritional tool to prevent insulin resistance associated to type 2 diabetes and obesity?". Reproduction, Nutrition, Development. 44 (3): 289–99. doi:10.1051/rnd:2004033. PMID   15460168.
  90. "Does caffeine affect blood sugar?". Mayo Clinic{{inconsistent citations}}
  91. Falta, W.; Boller, R. (1931). "Insulärer und Insulinresistenter Diabetes". Klinische Wochenschrift. 10 (10): 438–43. doi:10.1007/BF01736348.
  92. Himsworth, H (1936). "Diabetes mellitus: its differentiation into insulin-sensitive and insulin insensitive types". The Lancet. 227 (5864): 127–30. doi:10.1016/S0140-6736(01)36134-2.
  93. Nolan CJ (October 2010). "Failure of islet β-cell compensation for insulin resistance causes type 2 diabetes: what causes non-alcoholic fatty liver disease and non-alcoholic steatohepatitis?". Journal of Gastroenterology and Hepatology. 25 (10): 1594–7. doi:10.1111/j.1440-1746.2010.06473.x. PMID   20880166.
  94. 1 2 Neel JV (December 1962). "Diabetes mellitus: a "thrifty" genotype rendered detrimental by "progress"?". American Journal of Human Genetics. 14 (4): 353–62. PMC   1932342 . PMID   13937884.
  95. Ioannou GN, Bryson CL, Boyko EJ (2007-11-01). "Prevalence and trends of insulin resistance, impaired fasting glucose, and diabetes". Journal of Diabetes and its Complications. 21 (6): 363–70. doi:10.1016/j.jdiacomp.2006.07.005. PMID   17967708.
  96. Swinburn BA, Nyomba BL, Saad MF, Zurlo F, Raz I, Knowler WC, Lillioja S, Bogardus C, Ravussin E (July 1991). "Insulin resistance associated with lower rates of weight gain in Pima Indians". The Journal of Clinical Investigation. 88 (1): 168–73. doi:10.1172/JCI115274. PMC   296017 . PMID   2056116.
  97. Watve MG, Yajnik CS (April 2007). "Evolutionary origins of insulin resistance: a behavioral switch hypothesis". BMC Evolutionary Biology. 7: 61. doi:10.1186/1471-2148-7-61. PMC   1868084 . PMID   17437648.

Further reading

External resources