29 November 2013

Insulin resistance: from a protective reaction to illness

Different faces of insulin resistance

P. M. Schwarzburd, Doctor of Biological Sciences, Institute of Theoretical and Experimental Biophysics of the Russian Academy of Sciences, Pushchino
"Chemistry and Life" No. 7, 2013
Published on the website "Elements"

DiabetesIn recent years, many developed countries have faced an epidemic increase in type 2 diabetes mellitus (hereinafter simply "diabetes").

According to the data given in the review by Professor of the University of California Jerold Olefsky (The Origins and Drivers of Insulin Resistance), more than 300 million people worldwide suffer from this form of diabetes, 55 million of them in India, 25 million in the USA and 80 million in China, and the number of patients doubles every 10-15 years. Type 2 diabetes develops when some of the patient's tissues are insensitive to the action of insulin, that is, they acquire insulin resistance. This ailment should not be confused with the rarer type 1 diabetes (juvenile diabetes) - a disease in which immune cells, for an unknown reason, attack specialized beta cells of the pancreas that produce the hormone insulin and destroy them.

As a result, the pancreas is unable to synthesize enough insulin, and patients are forced to inject it regularly. Any diabetes is dangerous with the most severe complications: blindness, disorders of blood clotting, blood supply to the extremities, the work of the nervous and cardiovascular systems.

Trying to fight type 2 diabetes, doctors and researchers pay special attention to its formidable harbinger – insulin resistance. The main physiological function of insulin is to ensure the supply of glucose from peripheral blood to cells (primarily muscle and adipose tissue) and to suppress excess glucose production in liver cells. It performs this task by stimulating the expression of special transporter proteins that drag glucose from the peripheral blood through the cell membrane into the cell (Fig. 1). As a result of the action of insulin, the number of transporter proteins on the membrane increases 5-10 times, and their content inside the cell decreases by 50-60%.

Fig. 1. Insulin regulates the flow of glucose into cells with insulin receptors.
Special carrier proteins are involved in this processThe sensitivity of cells to insulin depends primarily on the number of insulin receptors and their activity.

So, fat cells and hepatocytes (liver cells) contain 200-300 thousand receptors, and monocytes and erythrocytes – an order of magnitude less. The number of receptors and their affinity (affinity) to insulin are unstable: in healthy people they are higher in the evening and at night, and lower in the morning; they increase with physical exertion, decrease in the elderly. Normally, insulin also causes relaxation of the smooth muscle wall of blood vessels due to the release of nitric oxide, however, this ability is also impaired in patients with insulin resistance and obesity.

If the susceptibility of peripheral tissues to the action of insulin is reduced for some reason, a person develops compensatory hyperinsulinemia - his pancreas synthesizes and releases an increased amount of insulin into the blood. As long as beta cells can work in an emergency mode and maintain a hormone level in the blood plasma sufficient to overcome insulin resistance, patients maintain a normal concentration of sugar in the blood. However, the reserves of the pancreas are not limitless, beta cells "exhale", and then the sugar level begins to rise.

The situation is aggravated by the fact that the liver does not work properly with insulin resistance. Usually, this organ maintains the necessary sugar concentration by breaking down glycogen or synthesizing glucose from substances of a non-carbon nature. When insulin levels increase, a healthy liver reduces glucose production. And with insulin resistance, the liver, as if nothing had happened, continues to throw it into the blood, which causes hyperglycemia in a hungry patient.

In other words, when beta cells lose the ability to constantly increase hormone production, insulin resistance flows into type 2 diabetes mellitus, which is characterized by a chronic lack of insulin and, as a consequence, increased blood glucose. However, the blood sugar level is only an indicator of the problem, the essence of which is that glucose cannot get into the cells, they starve and perform their functions poorly.

The question of the causes of insulin resistance remains open. It has been found that it develops more often with overweight and obesity, in people over 45 years of age, with insufficient physical activity, stress and high blood pressure. How does obesity contribute to the development of insulin resistance?

Obesity and inflammationSpecialists of the National Diabetes Institute of the USA have been studying the Pima Indians living in Arizona and Mexico for more than 30 years.

They found that half of all adult Indians inhabiting reservations in Arizona have diabetes and 95% of them suffer from obesity, and Mexican pimas have this disease rarely, and obesity is not peculiar to them, because they eat low-calorie foods with a high content of dietary fiber and are physically much more active than their foreign counterparts fellow tribesmen. The researchers concluded that the main risk factor in the development of type 2 diabetes is obesity. Moreover, the risk of obesity can be reduced even with a hereditary predisposition to it, if you lead the right lifestyle.

In recent decades, there has been an epidemic increase in the number of overweight people. So, in the USA about 65% of adults are overweight and about 32% suffer from obesity. As we remember, obesity is often combined with insulin resistance. If a person's weight exceeds the ideal by 35-40%, then insulin sensitivity decreases by more than 40%. The increased release of fatty acids from adipocytes (adipose tissue cells) into the blood also contributes to the development of insulin resistance. Clinical studies have shown that pharmacological lipolysis inhibitors (drugs that slow down the breakdown of fats and thereby reduce the level of fatty acids in the blood) are able to quickly restore insulin sensitivity to obese patients. Weight loss also reduces the flow of fatty acids and improves insulin sensitivity.

There are two main ways of energy supply in the body: "day" and "night". With the "daytime" method of energy supply, the main source of energy is glucose and, to a lesser extent, fat. With "night", on the contrary, the body draws energy mainly from fatty acids that enter the blood during the breakdown of fat deposits. According to Leningrad medical professor Vladimir Mikhailovich Dilman, with obesity, the mechanism of daily switching of energy homeostasis is disrupted, and the body switches mainly to the fat supply pathway. But why is this happening?

It is known that in the adult body the number of fat cells is constant. The accumulation of fat increases the volume of the adipocyte, which leads to a decrease in the density of insulin receptors on its enlarged surface, and the sensitivity of adipose tissue to the action of insulin decreases. However, if a person still overeats, the cells are forced to continue synthesizing fats from those excess glucose that cannot be "spent" in other organs. The pancreas responds to this with an additional, compensatory increase in insulin production.

And yet the "pumping" of adipocytes with fat cannot be endless. When the adipose tissue is overloaded, hypoxia increases in it and part of the adipocytes dies, causing inflammation. Macrophages rush from the bone marrow to the focus of inflammation. Normally, adipose tissue contains no more than 5% of macrophages, but with obesity their proportion increases to 50%. At the same time, macrophages are activated and secrete inflammatory cytokines – small peptide molecules that ensure the mobilization of an inflammatory response – in particular, tumor necrosis factor TNF-alfa (remember this abbreviation, we will need it later) and interleukin-6. These cytokines, in turn, support insulin resistance both in adipocytes and in liver and muscle cells (Fig. 2).

Fig. 2. Obesity leads to the development of chronic inflammation and reduces sensitivity to the action of insulin
not only in the adipose tissue itself, but also in the muscles and liverAs established by American researchers led by Professor Stephen Grinspoon, director of the clinic at Harvard Medical School (Boston, USA), neutralization of pro-inflammatory TNF-alfa improves insulin sensitivity in obesity (TNF-alfa Antagonism with Etanercept Decreases Glucose and Increases the Proportion of High Molecular Weight Adiponectin in These Subjects with Features of the Metabolic Syndrome).

This discovery suggested that in obesity, adipose tissue becomes a source of chronic activation of inflammation capable of maintaining insulin resistance (Fig. 2, 3). The mechanisms of such activation of local and systemic inflammation are intensively studied.

However, inflammation is not a disease, but a normal reaction of the body, in particular, to a bacterial infection. The purpose of inflammation is to destroy bacteria with the help of a cytotoxic reaction of a "respiratory" or "oxygen explosion". It got this name because phagocyte cells that have captured bacteria or their decay products dramatically (explosively) increase the consumption of oxygen and glucose, which are involved in the formation of highly active radicals with antibacterial activity. The reaction reaches a maximum in 50-120 seconds after the onset of phagocytosis. To carry out the "respiratory explosion" reaction, it is necessary to quickly deliver a large amount of glucose to activated phagocytes. It can be assumed that such a directed flow of glucose is provided by the physiological mechanism of insulin resistance, which temporarily restricts the flow of glucose into muscles and fat cells, directing it mainly to neutrophils and macrophages (Fig. 3).

Fig. 3. Cancer, obesity and phagocyte response to bacterial infection are accompanied by inflammation,
and inflammation supports insulin resistance

It turned out that insulin resistance regulates glucose flows in other adaptive situations, during pregnancy, for example.

Pregnancy and tumor growthGlucose is the main source of energy for the mother and fetus.

As the fetus grows, it needs more and more glucose, and its consumption in the second half of pregnancy outstrips its availability. Therefore, the normal level of glucose in the fetal blood is about 10-20 mg / 100 ml (0.6-1.1 mmol/l) lower than the mother's. (The physiological norm for a pregnant woman is 3.3–6.6 mmol/l.) Attention is drawn to the fact that during the period of maximum fetal growth, all pregnant women develop physiological insulin resistance, with the help of which, probably, glucose flows are redirected from the mother's organs to the growing fetus. This effect is regulated by the placenta – the main source of TNF-alfa secretion during pregnancy, especially in its second half. Approximately 94% of placental TNF-alfa is released into the maternal bloodstream, and only 6% is released into the fetal bloodstream. Thus, a high level of TNF-alfa ensures insulin resistance of maternal tissues.

After childbirth, its concentration decreases sharply and rapidly, and in parallel, insulin sensitivity is restored. However, in overweight pregnant women, the TNF-alfa content is significantly higher than in normal-weight pregnant women. In overweight women, pregnancy often proceeds with complications, and after childbirth, insulin sensitivity not only does not recover, but also the risk of developing diabetes increases. However, with the correct course of pregnancy, adaptive insulin resistance helps the normal growth of the fetus.

Embryonic tissues are similar to tumor tissues in terms of isoenzyme and antigenic compositions, as well as the type of cellular metabolism (activation of glycolysis). The question arises: does insulin resistance develop during tumor growth and, if so, what consequences does it lead to?

Cancer cells absorb glucose 10-30 times more actively than normal ones. Consuming glucose at a rate greater than the rate of its intake, a cancerous tumor acts as a powerful pump pumping glucose out of the host's body. Researchers from the University of Southern California Ethan Orgel and Steven Mittelman have shown that most malignant tumors cause insulin resistance in the muscles, liver and adipose tissue of the patient in parallel with an increase in the level of pro-inflammatory TNF-alfa (The Links Between Insulin Resistance, Diabetes, and Cancer). This creates more favorable conditions for tumor growth to the detriment of the normal functioning of healthy organs and tissues.

Contrary to popular belief that cancer patients die from metastases to vital organs, many of them die from a complex of diseases known as "paraneoplastic syndrome". These are secondary nonspecific disorders of the functions of various organs and systems that are not directly related to the localization of the primary tumor. Paraneoplastic syndrome occurs in 60% of cancer patients. It is caused by the increasing synthesis of TNF-alfa, which in high concentration turns into endotoxin, causing systemic inflammation and prolonged restriction of glucose intake into muscles, liver and adipose tissue. As a result, the mass of muscle and adipose tissue decreases, and the patient noticeably loses weight – the so-called cancerous cachexia (Fig. 3). Therefore, in oncological diseases, it is advisable to use drugs that reduce systemic inflammation and increase the sensitivity of liver cells, muscles and adipose tissue to the action of insulin. They can not only slow down the growth of the tumor, but also prevent the development of cachexia. It has long been noticed that antidiabetic drugs (biguanides) that restore insulin resistance increase the effectiveness of treatment of cancer patients, but they were not used to prevent the development of cachexia, probably due to insufficient attention to the effect of insulin resistance in tumor growth.

And insulin resistance can also lead to the development of polycystic ovary syndrome (the mechanism of development is not established). In women with this disease, the menstrual cycle is disrupted and infertility develops. A six-month treatment with the most famous biguanide metformin restores a regular ovulation cycle.

Is insulin resistance a protective reaction or a disease?To choose the right answer, a detailed analysis of the situation in which insulin resistance has arisen is necessary, although this often becomes a separate difficult task.

With uncomplicated pregnancy or with the development of a short-term "respiratory explosion" reaction aimed at eliminating bacterial infection, insulin resistance is an adaptive, physiologically justified response. After giving birth or defeating the infection, it passes by itself and does not require treatment. However, according to professor-biologist Ya. A. Alexandrovsky, a chronic increase in blood sugar levels by itself, without infection, can cause a "prolonged respiratory explosion" in neutrophils, which, accumulating near the walls of blood vessels, can damage them. Therefore, diabetes increases the risk of vascular complications. In other words, the physiological inflammatory reaction, as its duration increases, acquires pathological features, and then its action is directed not so much against bacteria as against blood vessels.

Insulin resistance is considered as a precursor to the clinical manifestation of type 2 diabetes mellitus, but it can also indicate the latent development of the tumor process. In such situations, a more detailed diagnosis is necessary, and during the examination, a person should avoid risk factors: excessive and improper nutrition, low physical activity, emotional stress. After the examination, it is advisable to adjust insulin resistance with the help of biguanides, salicylates and other anti-inflammatory drugs.

It is impossible not to mention the amazing discoveries of recent years made in several foreign laboratories. According to Harvard Medical School Professor Richard Hodin, taking intestinal alkaline phosphatase mitigates the negative effects of excessive consumption of fatty foods (Intestinal alkaline phosphatase prevents metabolic syndrome in mice). It turns out that some representatives of the intestinal microflora can support or suppress the development of cancer and diabetes in the host body. Moreover, the microflora that contributes to the development of diabetes is sometimes transmitted from a diabetic pregnant woman to the fetus and thus increases the risk of developing this pathology in a child. The influence of microflora on the development of diabetes is now being intensively investigated, the future will show how fair the assumptions of scientists are and whether it is possible to use them in practice.

The phenomenon of insulin resistance has many faces. Nature economically uses the same mechanism to achieve different goals: it provides both an antibacterial protective reaction of the "respiratory explosion" and the normal development of the fetus. Alas, an incorrect lifestyle provokes a pathological course of the process, and then insulin resistance contributes to the emergence of obesity, cancer or diabetes.

Portal "Eternal youth" http://vechnayamolodost.ru29.11.2013

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