Hunting for the pancreas

Type I diabetes mellitus

Svetlana Bozrova, Pavel Volchkov, "Biomolecule"

Sugar disease – sounds mysterious and as if it is not serious. What lies behind this name? Unfortunately, sugar disease (diabetes mellitus) – absolutely "not sugar": against the background of large-scale fluid loss, patients are exhausted by constant thirst, and Among the complications of uncontrolled diabetes mellitus, lesions of the eyes, kidneys, nervous and cardiovascular systems are not uncommon, and therefore this disease is attributed to one of the most serious problems of our society.

Ancient Indian, ancient Egyptian and ancient Greek doctors wrote about the "disease of unquenchable thirst and loss of fluid". Its specific name is διαβαινω (which in Greek means "I cross, I cross") – appeared in the third century BC, most likely in the writings of Apollo from Memphis. It reflected the ideas of those times about this disease: the patient, forced to constantly withdraw and take liquid, reminded others of a kind of siphon through which water constantly "passes". The first detailed description of what we now call diabetes mellitus, that is, diabetes mellitus, was given by Aretei from Cappadocia.

Today, approximately 8.5% of the world's population suffers from diabetes mellitus of the first and second types, that is, every twelfth of its inhabitants. Most often, type 2 diabetes affects residents of developed countries, but the incidence rate is now higher in less prosperous regions. Statistical data collected in the USA also indicate racial and ethnic heterogeneity in the predisposition to sugar disease: for example, diabetes is found in almost every sixth Indian or Alaskan Eskimo and only in every thirteenth "white" with non-Spanish roots. At such a scale of spread, the disease acquires, in addition to medical, also social significance. Just imagine what will happen if the states run out of money for the production of insulin or for the training of diabetes specialists! Therefore, developed countries pay special attention to this disease, creating adaptation centers for those who are ill and allocating money to scientists for research on diabetes mellitus.

The first recipe for a medicine for the treatment of sugar disease (more precisely, its leading symptom – polyuria, or rapid urination) was found in the source of the 16th century BC – the Ebers papyrus (Fig. 1). Probably, in the area of the sixth century BC, the Indian physician Sushruta invented a method for diagnosing diabetes, the essence of which remains unchanged and according to this day. Of course, the "equipment" has changed: In ancient India, the disease was determined by the sweet taste of the patient's urine. Around the same time, other symptoms were described: tendency to obesity, increased thirst, diabetic gangrene. The most brilliant doctors of different centuries tried to cope with this disease, however, despite the solid "age" of a detailed description of diabetes, they did not achieve great success.

   Drawing 1. The Ebers papyrus. website wikiwand.com

What does insulin promise us?

What breaks down in our body so finely and elegantly arranged that it begins to hurt so badly? Diabetes mellitus can bring a patient to coma and death, which means that jokes are bad with him, and it is necessary to figure out where everything comes from.

Everyone has heard of a certain substance – insulin – but not everyone knows what it is. Insulin is a peptide [1], or more precisely– a peptide hormone. It is secreted into the human blood by the cells of the islets of Langerhans of the pancreas. These islands were discovered in 1869 by a 22-year-old medical student Langerhans, who later became a famous German histologist and anatomist (Fig. 2a). Examining sections of the pancreas with a microscope, he discovered unusual islands of cells (Fig. 2b), which, as it turned out later, secrete substances important for digestion. The islets of Langerhans consist of three types of cells:

• There are few MARK cells (about 20%), they secrete the hormone glucagon, an insulin antagonist

• beta cells are the majority, they secrete insulin - the main hormone of sugar processing in the human body

• There are very few δ cells (about 3%), they secrete the hormone somatostatin, which inhibits the secretion of many glands.

Islets of Langerhans (cell islets) in the pancreas.

The immediate task of insulin is to help the sugars consumed get into the cell that needs them.

Insulin binds to two monomers of the insulin receptor located in the cell membrane, connecting them into a dimer. Intracellular domains of the insulin receptor are tyrosine kinases (that is, enzymes that attach a phosphate residue to the amino acid tyrosine) that trigger an intracellular phosphorylation cascade. Phosphorylation, in turn, causes the penetration of glucose into the cell, as glucose channel proteins move from the intracellular space to the membrane (Fig. 3) [2]. By the way, tyrosine kinases related to the insulin receptor are an extensive family of sensors that respond to growth factors, hormones and even alkaline pH (!) [3].

Drawing 3. The mechanism of action of insulin. Binding of insulin triggers a cascade of phosphorylation of intracellular proteins, which leads to the assembly of a glucose transporter on the membrane and the penetration of glucose molecules into the cell. [4], the drawing is adapted.

Sugar is a vital substance for the body. It is thanks to sugar – glucose – that our complex and intelligent brain functions: when glucose is broken down, it receives energy for its work [5]. Cells of other organs also need glucose very much – this is the most universal source of their vital energy. Our liver stores sugar in the form of glycogen – a polymer of glucose – and for a rainy day it can be processed and stored as fat deposits. However, in order to penetrate into the cells of some tissues, glucose needs insulin. Such tissues are called insulin-dependent. First of all, these include liver, muscle and adipose tissue. There are also insulin–dependent tissues – nervous, for example - but this is a completely different story.

In the case of insulin–dependent tissues, glucose cannot penetrate the cells on its own - it necessarily needs a conductor, which is just insulin. Glucose and insulin independently penetrate to the cells of organs through the "doors" of the bloodstream. Then insulin interacts with its receptor on the cell surface and opens the passage for glucose.

The main signal for the entry of insulin into the blood is an increase in glucose levels in it. But there are other stimuli: for example, insulin secretion is enhanced not only by carbohydrates, but also by some other substances coming from food – amino acids and free fatty acids. The nervous system also contributes: when receiving certain signals, it can give the command to increase or decrease the level of insulin in the blood.

There are many of you, but I am alone

It would seem that the lack of such an important hormone as insulin is already a considerable disaster for patients and doctors. But no, the problem of diabetes is much deeper. The fact is that there are two types of it, differing in the reasons for the insufficient effectiveness of insulin.

To be quite precise, it's not even two, but more, they're just not so common. For example, LADA (latent autoimmune diabetes in adults) is a latent autoimmune diabetes of adults, or type 1.5 diabetes [6]. In terms of symptoms, it is similar to type 2 diabetes, but the mechanism of its development is completely different: antibodies to beta cells of the pancreas and the enzyme glutamate decarboxylase appear in the body. Another type of diabetes mellitus is MODY (maturity onset diabetes of the young), mature type diabetes in young people [7]. The name of this monogenic, inherited by autosomal dominant type, disease is due to the fact that it begins at a young age, but proceeds gently, like "adult" type 2 diabetes, while reducing insulin sensitivity may not occur.

Type 2 diabetes (also called insulin-resistant) is much more common than all other forms of the disease: it is diagnosed in about 80% of diabetics. Its main feature is that the sensitivity of cells to the action of insulin is significantly reduced, that is, insulin practically loses the ability to launch glucose into tissues. At the same time, the pancreas receives a signal that there is not enough insulin, and begins to produce it with increased intensity. Due to the constant overload, beta cells are depleted over time, and a person has to do insulin injections. But those with the second type of diabetes have the opportunity to minimize its manifestations: with sufficient physical activity, diet and weight loss, the amount of glucose in the blood decreases, carbohydrate metabolism normalizes.

Type 1 diabetes is detected in 5-10% of diabetics, but this diagnosis promises less rosy prospects for the patient. This is an autoimmune disease, that is, the body attacks itself for some reason, as a result of which the insulin content in the blood tends to zero. Beta cells of pancreatic Langerhans islets are under attack (Fig. 2b).

Although the symptoms of the two diabetics are similar, their biological essence is different. Type 1 diabetes is a disease of the immune system, the root cause of type 2 diabetes lies in metabolic disorders. They also differ in the "type" of patients: the first type of diabetes most often affects young people under 30, and the second – middle-aged and older people.

There are no survivors. Mechanism of development of autoimmune diabetes

The main mechanisms of destruction of normal tissues of the body by their own immune cells have already been considered in the first article of our special project on autoimmune diseases ("Immunity: the fight against alien and.. their own" [8]). In order to study without difficulty what happens to the body during diabetes mellitus, we highly recommend reading it.

What should happen for the body to start attacking the cells of its own pancreas? This is most often due to the fact that T helper immune cells break through the blood-brain barrier - a barrier between blood vessels and the brain that prevents certain substances and immune cells from interacting with neurons. When this barrier suffers, and these two types of cells meet, the body's protective cells are immunized. According to a similar mechanism, another disease develops – multiple sclerosis (MS), however, with MS, other antigens of nerve cells are immunized. With the help of their T-cell receptor and an additional CD4 receptor, T-helpers interact with the MHC-II–peptide complex on the surface of antigen-presenting brain cells and gain the ability to recognize antigens that are located in nerve cells. Such T-helpers already know what "weapons" they will need if they encounter the same "enemies-antigens" as in brain cells, and they are already fully ready to fight them. Unfortunately, the MHC complex in some people "too" effectively presents antigens of beta cells of the pancreas, very similar to those that exist in nerve cells, and this causes a strong immune response.

The most important of the neural antigens that is expressed on the surface of β-cells is the N–CAM adhesion molecule. Nerve cells need this molecule for growth and interaction with each other. In the pancreas, N-CAM performs an adhesive function and plays an important role in the structural organization of the organ [9], [10].

T-helpers soon recognize beta-cell antigens, begin to attack them and, alas, most often win. Therefore, with type 1 diabetes, insulin in patients stops being produced at all, because all cells that were able to produce it are destroyed by immunocytes. The only thing that can be advised to such patients is to inject insulin into the blood artificially, in the form of injections. If this is not done, then diabetes quickly leads to large-scale "destruction" in the body.

Insulin for these purposes is obtained by genetic engineering. The first step is to cultivate a bacterial strain-producer of a hybrid protein containing human proinsulin – Escherichia coli BL21/pPINS07(BL07) or Escherichia coli JM109/pPINS07. Then the bacterial cells destroy and separate the inclusion bodies containing the hybrid protein. Next, the bodies are pre-washed, the protein is simultaneously dissolved and disulfide bonds are restored in it, it is renaturated and the hybrid protein is purified by ion exchange chromatography. Cleavage of proinsulin is carried out by joint hydrolysis with trypsin and carboxypeptidase B. Purification of the final product – insulin – is carried out by hydrophobic chromatography or reverse-phase high-performance liquid chromatography followed by gel filtration. The pure product is isolated by crystallization in the presence of zinc salts [11]. 

Diabetes mellitus affects most organs. The resulting hyperglycemia (excess sugar in the blood) entails glucosuria (the appearance of sugar in the urine), polyuria (increased urination), polydipsia (intense thirst), increased appetite and at the same time a significant decrease in body weight, and in addition, causes increased fatigue and weakness. Vessels (microangiopathy) and kidneys (nephropathy), the nervous system (neuropathy) and connective tissues are also affected, diabetic foot syndrome may develop.NOTE

Since those tissues that need insulin most for glucose assimilation (liver, muscle and fat) stop using this sugar, its level in the blood increases rapidly: hyperglycemia begins. This condition gives rise to other problems, including activation of the breakdown of proteins and fats in muscle and adipose tissues, respectively, and consequently, the release of fatty acids and amino acids into the bloodstream and increased formation of ketone bodies. These bodies, the brain and some other tissues in conditions of starvation (carbohydrate deficiency) are forced to use to extract energy. Fluid is actively excreted from the body, since glucose in the blood "pulls" water from the tissues and causes it to turn into urine. The consequences of all these processes are very unpleasant: the body is dehydrated, deprived of most of the necessary minerals and the main source of energy, muscle and adipose tissue begin to break down in it.

The formation of ketone bodies due to the destruction of adipose tissue causes the so-called ketoacidosis. This condition is dangerous because ketone bodies (in particular, acetone) in high concentrations are very toxic, and if it is not stopped in time, a diabetic coma may develop.

Since the destruction of nerves and blood vessels begins with diabetes, the patient is threatened with complications such as diabetic neuropathy and encephalopathy, often leading to paresis, paralysis, mental disorders.

One of the most famous and frightening symptoms – visual impairment, or diabetic ophthalmopathy – develops as a result of the destruction of the retina of the eye. In addition, the work of the kidneys is significantly disrupted, the joints begin to ache and crackle, as a result of which the mobility of the patient suffers.

These manifestations and complications of the disease are really terrible, but scientific achievements are still able to correct the situation. Scientists and doctors already know a lot about this disease and are able to manage its course. However, to find the key to curing or preventing diabetes, it is necessary to know its causes.

You can't list all the reasons...

There are many reasons and reasons for the development of such a complex disease as diabetes mellitus. It is impossible for all patients to identify any one, universal root cause that could be eliminated and thereby finally rid them of the sugar disease.

Until the beginning of the twentieth century, doctors did not even imagine what could cause diabetes. However, by that time they had accumulated a huge statistical base, so it was possible to draw some conclusions. After a long analysis of information about sick people, it became clear that there is a genetic predisposition to diabetes [12], [13]. This does not mean at all that if you have certain gene variants, you will definitely get sick. But the risk is definitely increasing. Only those who do not have any genetic features that contribute to the development of diabetes can breathe easy.

Predisposition to type 1 diabetes is associated primarily with the genes of the main human histocompatibility complex of the second type (HLA II) – a molecular complex that plays a crucial role in the immune response. This is not surprising, because it is the interaction of HLA with the T-cell receptor that determines the strength of the immune response. HLA genes have many allelic variants (different forms of the gene). Alleles of the HLA-DQ receptor gene with the names DQ2, DQ2/DQ8 and DQ8 are considered to be among the most predisposing to the disease, and the least is the DQ6 allele [14].

Analysis of the genome of 1792 European patients showed that the relative risk of disease for monogaplotypes DQ2 or DQ8 and heterogaplotype DQ2/DQ8 is 4.5% and 12.9%, respectively. The relative risk for people who do not carry any of these variants of the HLA locus is 1.8% [15].

Although the genes of the main histocompatibility complex account for 50% of all "predictor genes" [14], they are not the only ones that determine the degree of human resistance to the development of diabetes. Despite extensive searches, recently scientists have managed to discover only a few interesting genes of predisposition to diabetes mellitus:

– genetic variations of the CTLA4 molecule, normally responsible for inhibiting the activity of T cells, also affect the development of this disease. With some point mutations of the CTLA4 gene, the risk of getting sick increases [16], because the worse the system that reduces the strength of the immune response works, the higher the probability of an autoimmune response, alas

– a mutation in the MTTL1 gene, which encodes the mitochondrial transport RNA carrying the amino acid leucine during protein synthesis in mitochondria, causes "diabetes and deafness syndrome" and is transmitted through the maternal line [17]

– mutations in the GCK gene encoding glucokinase (an enzyme that stimulates the addition of phosphorus to glucose), and in the genes of hepatocyte nuclear factors HNF-1a or HNF-4a (transcription factors synthesized mainly in liver cells) – the most frequent changes leading to diabetes MODY.

As we can see, there can be quite a lot of genetic causes of diabetes. But if we know which genes are responsible for the disease, it will be possible to diagnose it faster and select the most effective treatment.

However, in addition to genetic factors for the development of type 1 diabetes, there are other external factors. The most interesting contribution of viruses. It would seem that diabetes does not belong to viral diseases in the usual sense for us. But studies show that some enteroviruses make a significant contribution to the pathogenesis of this disease [18]. If you think about it, it's not so surprising. When viruses (for example, coxsackievirus B1) infect the beta cells of the pancreas, an innate immune response develops - inflammation and the production of interferon–α, which normally serve to protect the body from infection. But they can also play against it: such an attack of the pathogen by the body creates all the conditions for the development of an autoimmune response (Fig. 4).

Drawing 4. The development of an immune response during the reproduction of coxsackievirus B1 in beta cells of the pancreas.1 – The body reacts to the invasion of the virus by producing antibodies.
The virus infects leukocytes and β-cells, resulting in the production of interferon-α, which can stimulate autoimmune processes.2 – Genetic variability affects the likelihood of type 1 diabetes mellitus.
Variants of the OAS1 gene increase the risk of disease, and polymorphism of the IFIH1 gene reduces it. 3 – Enterovirus causes the production of interferon-α and interferon-β, induces apoptosis and expression of MHC class I antigens, and also stimulates the production of chemokines that attract T cells that produce pro-inflammatory cytokines.
 4 – Enterovirus infection simultaneously stimulates acquired immunity: antibodies are produced and T-killers that infect β-cells are attracted, which leads to the release of their antigens. 5 – Simultaneous activation of inflammation and presentation of β-cell antigen cause increased stimulation of acquired immunity.
All these processes lead to the emergence of autoreactive T cells that infect beta cells ([18], figure adapted).

Of course, we must not forget about the more familiar external factors affecting the development of the disease. The most important of them are stress and a sedentary lifestyle. Obesity, which occurs due to low physical activity and poor nutrition, plays an important role in the development of type 2 diabetes, however, in the case of type 1, it also contributes. People whose body receives an excessive amount of sugars are at risk, since an increase in blood glucose levels with low insulin levels can stimulate autoimmune processes. Sugar lovers have a hard time, because temptations are everywhere. At such a scale of the spread of diabetes mellitus, it is necessary to approach the problem of "overconsumption" of sugar comprehensively. First of all, scientists advise removing glucose from the list of safe substances. At the same time, it is worth teaching people to determine the carbohydrate composition of foods and to ensure that they do not exceed the permissible sugar consumption rates [19].

Scientists have found out that there is a connection between type 1 diabetes mellitus and the composition of the intestinal microbiota [20], [21]. An experiment in which rats predisposed to the disease were studied showed that healthy animals have fewer representatives of the Bacteroidetes type in their intestines. A thorough examination of children with type 1 diabetes revealed a significant difference in the composition of their intestinal microbiota relative to healthy children. Moreover, the ratio of Bacteroidetes/Firmicutes was increased in diabetics, and the bacteria that utilize lactic acid prevailed. Healthy children had more butyric acid producers in their intestines [22].

In the third study, scientists "turned off" the interaction of microbiota with host cells by removing the MyD88 gene from experimental animals – one of the main signal transmitter genes. It turned out that a violation of the communication of intestinal microbes with the host quite quickly leads to the development of type 1 diabetes mellitus in mice [23]. This dependence is not surprising, because it is our bacteria that primarily "train" the immune system.

The source of many human troubles – stress – also makes a significant contribution to the development of diabetes mellitus. It increases inflammatory processes in the body, which, as already described, increases the likelihood of developing type 1 diabetes. In addition, at the moment it is reliably known that due to stress, the blood-brain barrier can "break through", which leads to many, many troubles.

What to do? What should we do? Therapy of type 1 diabetes mellitus

It would seem that the answer to the question "what to do?" it lies on the surface. If there is not enough insulin, then you need to add it. And so it happens. Insulin is administered intramuscularly to patients throughout their lives. From the moment a person is diagnosed with diabetes mellitus of the first type, his life changes dramatically. After all, even if insulin enters the body, the metabolism is already disrupted anyway, and the patient has to monitor his every step so that the fragile system, assembled with such difficulty, does not collapse.

Now, with the development of modern technologies, scientists are trying to make it as easy as possible for patients to take care of themselves. In 2016, Google employees developed a lens with sensors that measure the concentration of glucose in the tear fluid. When the threshold sugar level is reached, miniature LEDs light up in the lens, thereby notifying its owner of the changes that have occurred and of the need to make another injection.

In order to be able to automatically inject insulin into the blood as needed, scientists from Switzerland have come up with a special device – an insulin pump with a set of functions that significantly facilitate the patient's life (Fig. 5) [24], [25]. So far, such devices are used for chemotherapy of oncological diseases, but perhaps soon many diabetics will be able to get a similar medical machine. More comfortable devices are also being created: for example, sensors have already been developed that register the concentration of glucose in sweat, and on their basis a special patch has been created that determines and even regulates blood sugar levels [26]. To do this, they built a system of microneedles that inject medicine if the concentration of sugar in sweat is high. So far, this system has been tested only on laboratory mice.

Drawing 5. Implantable pump for people suffering from diabetes.

While a variety of devices are in development, doctors give their patients old recommendations. However, nothing supernatural is required from the patient: it is usually recommended to follow a low-carb diet, do light sports and carefully monitor their general condition. From the outside, it may seem that this is quite simple. But one has only to imagine oneself in the place of a sick person, as there is a very unpleasant feeling that now all your life you will have to limit yourself in many ways and adhere to a strict regime in all spheres of life – otherwise the consequences will be severe. No one wants to live with such serious responsibility for their health. Therefore, doctors and scientists continue to look for other ways of treating diabetes mellitus, with the help of which it will be possible to either completely cure the sick, or at least significantly facilitate their lives.

One of the most interesting and seemingly working approaches turned out to be diabetes immunotherapy [27]. To reduce the destructive effect of T-helpers, T-killers and B-cells, the so-called DNA vaccine is injected into the body [28]. It sounds mysterious, but in fact, the DNA vaccine is a small circular DNA molecule containing the proinsulin gene (in the case of type 1 diabetes) or another protein that is needed to prevent a particular disease. In addition to the protein gene, such a vaccine contains all the genetic elements necessary for the production of this protein in the cells of the body. Moreover, the DNA vaccine has been learned to be designed in such a way that when it interacts with the immune cells of innate immunity, their reactions weaken rather than strengthen. This effect was achieved by replacing the native CpG motifs in the proinsulin DNA with GpG motifs that suppress the antigen-specific immune response.

Another potential treatment option for type 1 diabetes is the blockade of receptor molecules on T cells attacking the pancreas. Next to the T-cell receptor is a functionally complementary, that is, a coreceptor, protein complex. It is called CD3 (from the English cell differentiation – cell differentiation). Despite the fact that this molecular complex is not an independent receptor, it is very important, because without it, the T-cell receptor will not fully recognize and transmit signals from the outside into the cell. Without CD3, the T-cell receptor can even detach from the cell membrane, since the coreceptor helps it stay on it. Scientists quickly realized that if CD3 was blocked, the T cells would not work very well. Although for a healthy body, the immunity weakened in this way will not bring any joy, in autoimmune diseases it can serve a good service [29].

More radical approaches even involve replacing the "failed" pancreas with a new one. In 2013, a group of Japanese scientists reported on the development of technology for growing human organs in pigs. In order to obtain a foreign pancreas, it is necessary to "turn off" the genes responsible for the formation and development of its own organ in a pig embryo, and then introduce a human stem cell into this embryo, from which the desired pancreas will develop [30]. The idea is excellent, but the establishment of mass production of organs in this way raises many questions, including ethical ones. But an option without the use of animals is also possible: pre-manufactured synthetic frames can be populated with cells of the necessary organs, which will subsequently "corrode" these frames. Technologies for constructing some organs based on natural skeletons obtained from other animals have also been developed [31]. And of course, we must not forget about the very rapidly spreading method of 3D printing. In this case, the printer uses the appropriate cells instead of paint, building the organ layer by layer. However, this technology has not yet entered clinical practice [32], and besides, a patient with a similar pancreas will still have to suppress the immune system in order to avoid attacks by immune cells on a new organ.

Warned – almost saved

But still, few people will disagree that it is better to prevent the disease than to treat it later. Or at least know in advance what to prepare for. And then genetic testing comes to the aid of humanity. There are a lot of genes that can be used to judge predisposition to sugar disease. As already mentioned, the genes of the main human histocompatibility complex are now considered the most promising in this regard [33]. If such tests are carried out at a very early age or even before the birth of a child, it will be possible to estimate in advance how likely it is to ever encounter diabetes, and in the future avoid those factors that can cause the disease to develop.

Diabetics all over the world – unite!

Although type 1 diabetes is no longer considered a deadly disease, patients face a lot of trouble. Of course, the sick really need support – both from their loved ones and from society as a whole. For such purposes, communities of diabetics are created: thanks to them, people communicate with other patients, learn about the peculiarities of their disease and learn a new way of life. One of the best organizations of this kind is the American Diabetes Society. The society's portal is filled with articles about different types of diabetes, and there is also a forum and information about possible problems for "beginners" is provided. There are similar communities in many developed countries, including England. Russia also has such a society, and this is great, because without it, it would be much more difficult for Russian diabetics to adapt to the current situation.

* * *

It's nice to dream that diabetes can disappear from the face of the Earth. Like smallpox, for example. For the sake of realizing such a dream, you can come up with a lot of things. It is possible, for example, to transplant Langerhans islets to patients with all the necessary cells. However, there are still a lot of questions about this method: it is not yet known how they will take root, whether they will adequately perceive hormonal signals from a new host, and so on.

And it is even better to create an artificial pancreas. Just imagine: in addition to the fact that patients do not have to constantly inject themselves with insulin, it will also be possible to adjust its level at the touch of a button in the mobile application. However, for now it all remains in dreams. But it is likely that someday the diagnosis of "type 1 diabetes mellitus" will disappear from the list of lifelong serious diseases, and people with a predisposition to it will be able to breathe easy!

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Portal "Eternal youth" http://vechnayamolodost.ru  12.05.2017