insulin resistance insulin resistance insulin resistance (ir) is a pathological condition in which cells either fail to respond normally to the hormone insulin or downregulate insulin receptors in response to hyperinsulinemia. insulin resistancespecialtyendocrinology insulin is a hormone that facilitates the transport of glucose from blood into cells, thereby reducing blood glucose (blood sugar). insulin is released by the pancreas in response to carbohydrates consumed in the diet. in states of insulin resistance, the same amount of insulin does not have the same effect on glucose transport and blood sugar levels. there are many causes of insulin resistance and the underlying process is still not completely understood. risk factors for insulin resistance include obesity, sedentary lifestyle, family history of diabetes, various health conditions, and certain medications. insulin resistance is considered a component of the metabolic syndrome. there are multiple ways to measure insulin resistance such as fasting insulin levels or glucose tolerance tests, but these are not often used in clinical practice. insulin resistance can be improved or reversed with lifestyle approaches, such as exercise and dietary changes. cause risk factors there are a number of risk factors for insulin resistance, including being overweight or obese or having a sedentary lifestyle. various genetic factors can increase risk, such as a family history of diabetes, and there are some specific medical conditions associated with insulin resistance, such as polycystic ovary syndrome. the national institute of diabetes and digestive and kidney diseases states that specific risks that may predispose an individual to insulin resistance can include: being aged 45 or older having african american, alaska native, american indian, asian american, hispanic/latino, native hawaiian, or pacific islander american ethnicity having health conditions such as high blood pressure and abnormal cholesterol levels having a history of gestational diabetes having a history of heart disease or stroke. in addition some medications and other health conditions can raise the risk. lifestyle factors dietary factors likely contribute to insulin resistance, however, causative foods are difficult to determine given the limitations of nutrition research. foods that have independently been linked to insulin resistance include those high in sugar with high glycemic indices, low in omega-3 and fiber, and which are hyper-palatable which increases risk of overeating. overconsumption of fat- and sugar-rich meals and beverages have been proposed as a fundamental factor behind the metabolic syndrome epidemic. diet also has the potential to change the ratio of polyunsaturated to saturated phospholipids in cell membranes. the percentage of polyunsaturated fatty acids (pufas) is inversely correlated with insulin resistance. it is hypothesized that increasing cell membrane fluidity by increasing pufa concentration might result in an enhanced number of insulin receptors, an increased affinity of insulin to its receptors, and reduced insulin resistance. vitamin d deficiency has also been associated with insulin resistance. sedentary lifestyle increases the likelihood of development of insulin resistance. in epidemiological studies, higher levels of physical activity (more than 90 minutes per day) reduce the risk of diabetes by 28%. studies have consistently shown that there is a link between insulin resistance and circadian rhythm, with insulin sensitivity being higher in the morning and lower in the evening. a mismatch between the circadian rhythm and the meals schedule, such as in circadian rhythm disorders, may increase insulin resistance. medications some medications are associated with insulin resistance including corticosteroids, protease inhibitors (type of hiv medication), and atypical antipsychotics. hormones many hormones can induce insulin resistance including cortisol, growth hormone, and human placental lactogen. cortisol counteracts insulin and can lead to increased hepatic gluconeogenesis, reduced peripheral utilization of glucose, and increased insulin resistance. it does this by decreasing the translocation of glucose transporters (especially glut4) to the cell membrane. based on the significant improvement in insulin sensitivity in humans after bariatric surgery and rats with surgical removal of the duodenum, it has been proposed 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. leptin is a hormone produced from the ob gene and adipocytes. its physiological role is to regulate hunger by alerting the body when it is full. studies show that lack of leptin causes severe obesity and is strongly linked with insulin resistance. diseases polycystic ovary syndrome and non-alcoholic fatty liver disease (nafld) are associated with insulin resistance. hepatitis c also makes people three to four times more likely to develop type 2 diabetes and insulin resistance. inflammation acute or chronic inflammation, such as in infections, can cause insulin resistance. tnf-α is a cytokine that may promote insulin resistance by promoting lipolysis, disrupting insulin signaling, and reducing the expression of glut4. genetics several genetic loci have been determined to be associated with insulin insensitivity. this includes variation in loci near the nat2, gckr, and igfi genes associated with insulin resistance. further research has shown that loci near the genes are linked to insulin resistance. however, these loci are estimated to only account for 25-44% of the genetic component of insulin resistance. pathophysiology in normal metabolism, the elevated blood glucose instructs beta (β) cells in the islets of langerhans, located in the pancreas, to release insulin into the blood. the insulin makes insulin-sensitive tissues in the body (primarily skeletal muscle cells, adipose tissue, and liver) absorb glucose which provides energy as well as lowers blood glucose. 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 (90 mg/dl). in an insulin-resistant person, normal levels of insulin do not have the same effect in controlling blood glucose levels. when the body produces insulin under conditions of insulin resistance, the cells are unable to absorb or use it as effectively and it stays in the bloodstream. certain cell types such as fat and muscle cells require insulin to absorb glucose and when these cells fail to respond adequately to circulating insulin, blood glucose levels rise. the liver normally helps regulate glucose levels by reducing its secretion of glucose in the presence of insulin. however, in insulin resistance, this normal reduction in the liver's glucose production may not occur, further contributing to elevated blood glucose. insulin resistance in fat cells results in reduced uptake of circulating lipids and increased hydrolysis of stored triglycerides. this leads to elevated free fatty acids in the blood plasma and can further worsen insulin resistance. 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, insulin resistance stimulates the formation of new fatty tissue and accelerates weight gain. in states of insulin resistance, beta cells in the pancreas increase their production of insulin. this causes high blood insulin (hyperinsulinemia) to compensate for the high blood glucose. during this compensated phase of insulin resistance, beta cell function is upregulated, 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 as the resistance increases and compensatory insulin secretion fails. 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. insulin resistance is strongly associated with intestinal-derived apob-48 production rate in insulin-resistant subjects and type 2 diabetics. insulin resistance often is found in people with visceral adiposity, hypertension, hyperglycemia, and dyslipidemia involving elevated triglycerides, small dense low-density lipoprotein (sdldl) particles, and decreased high-density lipoprotein (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 breakdown of glycogen stores into glucose (glycogenolysis), both of which have the effect of exacerbating peripheral insulin resistance and increasing the likelihood of type 2 diabetes mellitus. the excessive expansion of adipose tissue that tends to occur under sustainedly positive energy balance (as in overeating) has been postulated by vidal-puig to induce lipotoxic and inflammatory effects that may contribute to causing insulin resistance and its accompanying disease states. also, insulin resistance often is associated with a hypercoagulable state (impaired fibrinolysis) and increased inflammatory cytokine levels. molecular mechanism at the molecular level, a cell senses insulin through insulin receptors, with the signal propagating through a signaling cascade collectively known as pi3k/akt/mtor signaling pathway. 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. the pathway's sensitivity to insulin may be blunted by many factors such as lipolysis of free fatty acids, 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. 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. 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. diagnosis fasting insulin levels a fasting serum insulin level greater than 29 microiu/ml or 174 pmol/l indicates insulin resistance. the same levels apply three hours after the last meal. 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. 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. 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