Инсулинге төзімділік: себептері, факторлары және түзету жолдары

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 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 weight reduction, exercise, and dietary changes.

Some medications are associated with insulin resistance including corticosteroids, protease inhibitors (type of HIV medication), and atypical antipsychotics.

Being exposed to light during sleep has been shown to cause insulin resistance and increase heart rate.

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.

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.

Multiple studies involving different methodology suggest that impaired function of mitochondria might play a pivotal role in the pathogenesis of insulin resistance. Mitochondrial dysfunction may result from the formation of reactive oxygen species, genetic factors, aging, and reduced mitochondrial biogenesis. Important questions remain unsolved to date, however. If confirmed by rigorous studies, a link between mitochondrial disorders and reduced insulin sensitivity might pave the way to new therapeutic approaches.

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.

Several genetic loci have been identified as associated with insulin insensitivity. These include variations in loci near the NAT2, GCKR, and IGFI genes, which are linked to insulin resistance. Further research has indicated that loci near these genes are correlated with insulin resistance. However, it is estimated that these loci only account for 25–44% of the genetic component of insulin resistance.

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. 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.

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, entails significant metabolic changes, during which the mother must decrease the insulin sensitivity of her muscles to conserve more glucose for both the maternal and fetal brains. This adaptation can occur by elevating the response threshold, thereby delaying the onset of sensitivity. This is achieved through the secretion of placental growth factor, which interferes with the interaction between insulin receptor substrate (IRS) and PI3K. This concept forms the basis of the adjustable threshold hypothesis of insulin resistance.

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.

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.

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 referred to in diabetes literature as the GINF value. 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. and more recent methods include the Quantitative insulin sensitivity check index (QUICKI) and SPINA GR, a measure for insulin sensitivity. All of these calculated markers employ fasting insulin and glucose levels to calculate insulin resistance, and all correlate reasonably with the results of clamping studies.

Maintaining a healthy body weight and engaging in regular physical activity can help mitigate the risk of developing insulin resistance. Both metformin and thiazolidinediones improve insulin sensitivity. Metformin is approved for prediabetes and type 2 diabetes and has become one of the more commonly prescribed medications for insulin resistance. 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. 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. In epidemiological studies, higher levels of physical activity (more than 90 minutes per day) reduce the risk of diabetes by 28%. Furthermore, physical training has also generally been seen to be an effective antagonist of insulin resistance in obese or overweight children and adolescents (under the age of 19). The authors caution against demeaning the importance of resistance and combined exercise, as this type of training is generally less researched than aerobic training. Some types of polyunsaturated fatty acids (omega 3) may 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.

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, and confirmed as contributory 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.

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." Other prevailing thoughts that insulin resistance can be an evolutionary adaptation include the 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. Yet, there has been an increase in mean insulin resistance in both the normoglycemic population as well as the diabetic population. J. V. Neel posits that in ancient human ancestors, during periods of heightened famine, genes facilitating increased glucose storage would have conferred an advantage. However, in today's modern environment, this is no longer the case. Modern hypotheses propose that insulin metabolism serves as a socio ecological adaptation, with insulin serving as the mechanism for allocating energy to different body components and insulin sensitivity being an adaptation to regulate this energy allocation. The Behavioral Switch Hypothesis suggests that insulin resistance leads to two methods of altering reproductive and behavioral strategies. These strategies are termed "r to K" and "soldier to diplomat." The "r to K" strategy involves directing insulin through the placenta to the fetus, resulting in weight gain in the fetus but not the mother, indicating an increase in parental investment (K strategy). In the "soldier to diplomat" strategy, the insensitivity of skeletal muscle to insulin could redirect glucose to the brain, which does not require insulin receptors. This has been shown to enhance cognitive development across various studies.