Insulin is a hormone produced by the beta cells of the islets of Langerhans in the pancreas. The name insulin comes from the Latin insula - island. Effects of insulin
Although insulin causes many effects in various tissues of the human body, its main effect is to stimulate the movement of glucose from the blood into cells, which leads to a decrease in blood glucose concentrations.
Other effects of insulin are stimulating the synthesis of glycogen from glucose in the liver and muscles, increasing the creation of fats and proteins, and suppressing the activity of enzymes that break down fats and proteins. Thus, insulin has an anabolic effect because it enhances the formation of fats and proteins while slowing down their breakdown.
The main effect of insulin is to enhance the transport of glucose across the cell membrane into the cell. There are no other hormones that lower blood glucose levels in the human body. The main effects of insulin occur in muscle and adipose tissue, which is why these tissues are called insulin-dependent. Blood glucose levels decrease when exposed to insulin and increase when exposed to the so-called. hyperglycemic hormones (glucagon, growth hormone, glucocorticoids).
Additional effects of insulin are an increase in the intensity of glycogen formation, a decrease in the formation of glucose in the liver, and an increase in the absorption by cells of amino acids necessary for protein synthesis. At the same time, insulin reduces the destruction of proteins and fats. Thus, the overall effect of insulin is anabolic - aimed at the formation of fat and muscle tissue.
Hormonal activity of the islets of Langerhans
The small size of islet accumulations, as well as the small area they occupy in the pancreas, is an indisputable fact. However, the importance of this structure for the entire organism as a whole is very great, because it is in it that hormones are formed that take part in the metabolic process. This includes not only insulin, but also somatostatin, glucagon, and pancreatic polypeptide. Let's consider their main purpose.
- Insulin is necessary to regulate carbohydrate balance, maintain adequate blood glucose levels, transport potassium, fats, glucose and amino acids into cells. In addition, this hormone is involved in the formation of glycogen, it affects the synthesis of fats and proteins, and also increases the permeability of the plasma membrane.
- The hormone glucagon has a whole list of functions, which:
- Promotes the breakdown of glycogen, due to which glucose is released;
- Triggers the breakdown of lipids: when the level of lipase increases in fat cells, lipid breakdown products begin to enter the blood, acting as sources of energy;
- Provides rapid removal of sodium from the body, thereby improving the functioning of blood vessels and the heart;
- Increases calcium concentration inside cells;
- Improves blood flow to the kidneys;
- Activates the formation of glucose from substances that are not components of the carbohydrate group;
- Increases blood pressure;
- Promotes the restoration of liver cells;
- It has an antispasmodic effect at particularly high concentrations.
- The delta cell hormone somatostatin controls the production of digestive enzymes as well as other hormones. Due to its effect, there is a decrease in the production of insulin and glucagon.
- Pancreatic polypeptide - it is produced by PP cells, and despite the fact that there are very few of them in islet accumulations, the significance of this substance is very important: the polypeptide takes an active part in controlling the secretion of the stomach and liver. It is known that with insufficient amounts of this hormone, various pathological processes develop.
How are islands arranged and what is their purpose?
The main task of the islets of Langerhans is to maintain carbohydrate balance, as well as to control the activity of all endocrine organs. These clusters are very well supplied with blood, and their innervation occurs due to the vagus and sympathetic nerves.
The structure of the islands is quite complex; their cells are arranged in a chaotic order, like a mosaic. Each of the clusters is an independent perfect formation, consisting of lobules surrounded by connective tissues and having blood capillaries passing through the cells. Beta cells are located in the center of the clusters, alpha and delta cells make up the periphery. By interacting with each other, cells trigger a feedback mechanism, characterized by the influence of some cells on others located nearby:
- Alpha cells produce glucagon, which in turn has a specific effect on d cells;
- Somatostatin, produced by d-cells, inhibits the activity of alpha and beta cells;
- It suppresses alpha cells and insulin, but at the same time, it activates beta cells.
When any disruption occurs in the functioning of the immune system, special immune bodies arise, leading to dysfunction of beta cells, resulting in the development of a pathology such as diabetes mellitus (DM).
A little anatomy
The pancreatic tissue contains not only acini, but also islets of Langerhans. The cells of these formations do not produce enzymes. Their main function is to produce hormones.
These endocrine cells were first discovered in the 19th century. The scientist after whom these formations are named was still a student at that time.
There are not so many islands in the iron itself. Among the entire mass of the organ, Langerhans' zones account for 1-2%. However, their role is great. The cells of the endocrine part of the gland produce 5 types of hormones that regulate digestion, carbohydrate metabolism, and stress response. With the pathology of these active zones, one of the common diseases of the 21st century develops - diabetes mellitus. In addition, the pathology of these cells causes Zollinger-Ellison syndrome, insulinoma, glucoganoma and other rare diseases.
Today it is known that pancreatic islets have 5 types of cells. Let's talk more about their function below.
Alpha cells
These cells make up 15-20% of the total islet cells. It is known that humans have more alpha cells than animals. These zones secrete hormones responsible for the fight and flight response. Glucagon, which is formed here, sharply increases glucose levels, enhances the work of skeletal muscles, and speeds up the heart. Glucagon also stimulates the production of adrenaline.
Glucagon is designed for a short duration of action. It is quickly destroyed in the blood. The second significant function of this substance is insulin antagonism. Glucagon is released when there is a sharp decrease in blood glucose. Such hormones are administered in hospitals to patients with hypoglycemic conditions and coma.
Beta cells
These areas of parenchymal tissue secrete insulin. They are the most numerous (about 80% of cells). They can be found not only in the islets; there are single zones of insulin secretion in the acini and ducts.
The function of insulin is to lower glucose concentrations. Hormones make cell membranes permeable. Thanks to this, the sugar molecule quickly gets inside. Further, they activate a chain of reactions that produce energy from glucose (glycolysis) and store it in reserve (in the form of glycogen), and form fats and proteins from it. If insulin is not secreted by cells, type 1 diabetes develops. If the hormone does not act on the tissue, type 2 diabetes mellitus is formed.
Insulin production is a complex process. Its level can be increased by carbohydrates from food and amino acids (especially leucine and arginine). Insulin increases with an increase in calcium, potassium and some hormonally active substances (ACTH, estrogen and others).
C-peptide is also formed in the beta zones. What it is? This word refers to one of the metabolites that is formed during the synthesis of insulin
Recently, this molecule has acquired important clinical significance. When an insulin molecule is formed, one molecule of C-peptide is formed
But the latter has a longer decay life in the body (insulin lasts no more than 4 minutes, and C-peptide about 20). C-peptide decreases in type 1 diabetes mellitus (little insulin is initially produced), and increases in type 2 diabetes (there is a lot of insulin, but the tissues do not respond to it), insulinoma.
Delta cells
These are zones of pancreatic tissue of Langerhans cells that secrete somatostatin. The hormone inhibits the activity of enzyme secretion. The substance also slows down other organs of the endocrine system (hypothalamus and pituitary gland). The clinic uses a synthetic analogue or Sandostatin. The drug is actively administered during attacks of pancreatitis and pancreas operations.
Type 1 diabetes mellitus (T1DM) is a chronic disease that affects genetically predisposed individuals in whom the insulin-secreting β-cells of the islets of Langerhans (IL) of the pancreas (P) are selectively and irreversibly destroyed as a result of an autoimmune attack of the body [1–4]. According to the International Diabetes Federation, more than 36 million people suffer from T1DM worldwide, and 1.4 million people in the USA [5, 6]. Dynamics of 2013-2016 The prevalence of diabetes continues to increase. In the Russian Federation, as of December 31, 2016, the prevalence of T1DM was 164.19 cases per 100 thousand population, or 6% of the total number of patients (255 thousand out of 4348 million) [7]. Although the introduction of insulin therapy has led to a significant increase in the life expectancy of patients with T1DM, chronic complications such as vision loss and renal failure continue to reduce the quality of life of patients and require multi-billion dollar annual expenditures in the healthcare system [8, 9].
Maintaining blood glucose levels within certain limits is considered the most effective approach to prevent the manifestation and slow down the progression of chronic complications of T1DM [10]. Currently, this problem can be solved by intensified therapy with multiple injections of insulin, requiring accurate monitoring of blood glucose levels [11]. However, in terms of its effectiveness, subcutaneous insulin administration can never approach its wave-like secretion by normally functioning β-cells and rarely provides normal blood glucose levels without the risk of episodes of severe hypoglycemia [12]. In addition, intensive insulin therapy is only suitable for a certain group of patients [13].
Pancreas transplantation is an alternative treatment that can prevent the development of complications of diabetes without increasing the risk of hypoglycemic episodes [14]. Transplantation of P.Zh. started in the 70s. and was quickly introduced into clinical practice. Over the past 40 years, the technique has been constantly improved, leading to favorable outcomes [15]. The rate of reduction in insulin dependence during simultaneous kidney and pancreas transplantation increased from 77% in the period from 1987 to 1993 to 91.3% in 2010–2014. [16].
Although this technique provides a higher rate of reduction in insulin dependence, it nevertheless has a more complicated course of the postoperative period and requires a more stringent regimen of immunosuppressive therapy (IST) [17]. In addition, when a pancreas transplant is rejected, immediate removal of the transplanted tissue is required, which leads to immediate and complete loss of graft function. Unfortunately, this operation, usually performed simultaneously with a kidney transplant, is accompanied by a high incidence of both complications and mortality [18]. Despite the significant improvement in the quality of life of patients, pancreas transplantation, as a rule, is indicated only for a narrow circle of patients [19].
In this regard, organ transplantation represents an alternative solution to the problem, normalizing glucose metabolism without the risk of severe hypoglycemia and eliminating potentially life-threatening complications after single organ pancreas transplantation [20]. It may be too limited to evaluate the results of these two surgeries in terms of reducing insulin dependence because each has many different features. Of course, prospective randomized controlled trials comparing both methods are needed to enrich the evidence base [21].
Brief history and main stages in the development of islet transplantation of Langerhans
F. Banting and C. Best [22] were the first to use insulin therapy in 1922 and radically changed the treatment of patients with SD. The technique has extended the lives of millions of patients. However, insulin therapy treats but does not cure patients. Unfortunately, it does not prevent the development of secondary complications associated with the long course of the disease. The need for more durable remission has inspired researchers to look for other options.
In 1967, R. Lacy and M. Kostianovsky [23] reported that it was possible to obtain viable pancreatic islet cells from donor rats. Their experiments proved that administration of OL through the portal vein to recipient rats with diabetes helps to achieve stable normoglycemia. This experience formed the basis for creating a method for isolating OB and identifying an organ for transplantation. Subsequent advances in enzymatic digestion and purification of pancreatic tissue have increased the rate of successful collection of OB from humans [24]. Intraductal injection of collagenase has become an effective way to obtain islets in large animals and humans. The first clinical islet cell transplantation was performed at the University of Minnesota, USA [25]. In Russia, allotransplantation of OB cell cultures was first carried out in 1979 at the Research Institute of Transplantology and Artificial Organs (NIITiIO). The life span of 16–22-week human fetuses was chosen as a source of OL [26].
Due to the difficulty of obtaining sufficient numbers of human OB cells, first transplants were rarely successful. This continued until S. Ricordi [27] presented a new method for isolating OB cells in humans. This method allowed researchers to systematically obtain large quantities of purified and viable islets for transplantation. Attempts to transplant OB cells into patients suffering from diabetes ended in failure, with the exception of cases described in the early 90s. in Pittsburgh, USA. This was the first successful series of allotransplantations. She proved the concept; worldwide, only 8% of all recipients suffering from diabetes were able to manage without the administration of exogenous insulin [28].
Indications
OB cell transplantation can be performed on its own or after a kidney transplant [29, 30]. The main indications for isolated OB cell transplantation are T1DM, complicated by insensitivity to the development of hypoglycemia, severe hypoglycemic attacks and/or glycemic lability, despite attempts to relieve it with intensive insulin therapy with appropriate monitoring [31]. In children, it is important to avoid the risks of IST and take into account the criteria of T1DM duration of more than 5 years and age over 18 years [32].
However, if there is a threat to the patient's life or possible irreversible brain damage due to severe uncontrolled hypoglycemic attacks that cannot be prevented by other methods, expanding the indications for transplantation is considered [33]. OB cell transplantation should not be performed in patients with insulin resistance or requiring very high doses of insulin, and especially in patients with a body mass index (BMI) of more than 30 kg/m2 and/or a body weight of more than 90 kg, and/or on daily insulin doses exceeding 1 unit/kg [34].
The selection criteria for OB cell transplantation after kidney transplantation are more lenient than for isolated OB cell transplantation, since in the first case, patients already receive permanent IST after kidney transplantation [35]. However, before selecting patients, the function of the transplanted kidney should be assessed [36]. Patients should not be carriers of polyomaviruses (BKV), this will eliminate additional risks, since as a result of IST with T-lymphocyte suppression, the risk of developing BK virus-associated nephropathy increases. This virus is an opportunistic infection that worsens in the setting of IST, causing BK viral nephropathy and kidney transplant rejection [37].
It is important to have a negative cross histocompatibility test for the long-term function of the transplanted OB cells [38]. The risk of general sensitization to the major histocompatibility complex exists after blood transfusions or previous kidney transplantation [39, 40].
Obtaining cells of the islets of Langerhans and transplantation
To successfully obtain OB cells and long-term functioning of the graft, it is important to select a suitable donor [41]. Ideally, it should be suitable for transplantation of both the pancreas and its cells [33]. However, unlike organ transplantation, where a high risk of complications is associated with high donor BMI, in cell transplantation people with a high BMI can be donors [42]. Moreover, a higher BMI correlates with successful collection of OB cells, provided the donor is aged between 20 and 50 years and has normal blood glucose levels at the time of cell culture isolation. Obtaining cells from donors under 50 years of age with a BMI >27 kg/m2 is in fact possible and is a key factor for achieving a good outcome [43]. When considering donors with a BMI >30 kg/m2, those with glycated hemoglobin (HbA1c) levels greater than 6.5% should not be selected for reasons of risk of latent T2DM and associated undiagnosed disorders of insulin secretion [44].
Recovery of the pancreas during transplantation of OB cells is similar to that during organ transplantation [45]. However, when harvesting the graft, it is not necessary to preserve the blood vessels because surgical reconstructions will not be necessary. In order to obtain functionally complete and sufficient donor islets, manipulations with the pancreas should be carried out as carefully and carefully as possible so as not to damage the capsule, minimize procedure time and maximize oxygenated blood flow in the pancreas before cross-clamping the aorta [46]. After clamping the aorta and harvesting the remaining organs for transplantation, the pancreas should be removed en bloc with the portion of the duodenum adjacent to its head and placed in a triple bag with a chilled preservative solution (University of Wisconsin or an alternative solution) at a temperature of 4 ° C for transportation under sterile conditions to the laboratory where OB cells are obtained [47, 48].
Since the pancreas is very sensitive to trauma and nonspecific activation of endogenous proteolytic enzymes, it is better to isolate it first, before harvesting the remaining abdominal organs, in order to minimize ischemia time and possible tissue damage. The full cycle of obtaining and purifying OB cells consists of 4-6 hours of multi-stage extraction of hundreds of thousands of cell clusters, constituting only 1-2% of the total mass of organ tissue. Exposure to proteolytic enzymes in combination with mild mechanical separation, purification and placement in culture are included in the established procedure for preparing OB cells for transplantation in the form of granules less than 5 cm3 in size for intraportal administration [49].
The process of isolating OB cells has undergone changes over the past forty years. However, the automated Ricordi technique [50] remains a key technology adopted in many countries around the world. Its main stages include processing of the pancreas in a closed loop using an enzymatic process following the intraductal introduction of enzymes (collagenase types I and II), and mechanical separation with purification by centrifugation [51, 52].
Standardized instructions and a consolidated serial production protocol describe in detail each stage of the procedure: from donor selection, cell culture preparation and purification to pre-transplant in vitro
, quality control and release criteria for the finished product for transplantation (determining the identity, viability, potency and sterility of the finished product of OB cells). All these indicators are subject to registration. Currently, the most efficient clinical cell retrieval laboratories can prepare more than 50% of processed organs for subsequent transplantation, with a maximum efficiency of 89.5%. For a satisfactory metabolic effect after transplantation, the minimum recommended number of β-cells should exceed 5000. However, when receiving a culture from a single donor, insulin independence when administered into the portal vein system is achieved in the presence of more than 7000 IEQ/kg (OL equivalent units per 1 kg of body weight).
After obtaining OB cells, they are placed in a nutrient medium and incubated for 24–72 hours to carry out the necessary quality control, as well as to begin IST for the patient before transplantation. This procedure depends on the specific medical institution; in some transplant centers they prefer to perform the transplant immediately. A number of researchers [53] believe that the cultivation period leads to better purification of the drug; the number of dead or apoptotic cells becomes minimal. In addition, byproducts and cytokines can trigger and increase inflammation after transplantation [54, 55].
The prepared cell mass is placed in the transplantation medium and transferred to a sterile infusion system with heparin at the rate of 70 U/kg of recipient body weight. The solution is infused under the influence of gravity or by insertion into a percutaneously installed catheter into the portal vein system. Access to the portal vein is created under ultrasound and X-ray control, which makes transplantation of OB cells one of the safest transplant procedures [56]. In experienced hands, the risk of bleeding is virtually eliminated despite heparin anticoagulation aimed at preventing portal vein thrombosis. After infusion, the liver catheter is removed and topical hemostatic agents (DSTAT or Avitene) are used to prevent bleeding [57]. The use of these pastes on an area of at least 4 cm significantly reduces the risk of bleeding after intraportal administration of OL in combination with heparin. After the procedure, systemic heparin therapy is continued at a rate of 3 units/kg/hour until the activated partial thromboplastin time is 60-80 seconds. As a rule, heparin administration is continued for 48 hours in order to reduce the activation of the immediate release of pro-inflammatory cytokines: with heparin (enoxaparin 30 mg subcutaneously 2 times a day, for 7 days) and then switched to oral aspirin 81 mg for 14 days.
HbA1c levels and liver function are closely monitored after transplantation. In the future, the condition of the portal vein must be assessed using the ultrasound method in the manner that is customary in a particular clinic. Usually, ultrasound is performed the next day after transplantation and then on the 3rd and 5th days over time. If percutaneous access is not possible, a mini-laparotomy is made for intravenous injection of cells after probing the branches of the portal vein (epiploic or mesenteric veins).
Although experts in clinical OB cell transplantation consider the portal vein to be the best or most appropriate site for transplantation, significant early loss of viable cells occurs in the perigraft period due to low partial pressure of oxygen, release of inflammatory mediators and proinflammatory cytokines [58]. At the current level of development of clinical transplantation of OB cells, the liver may not necessarily be considered the best place for their transplantation [59]. Firstly, the organ is not accessible for safe biopsy of the transplanted tissue and its removal is impossible [60]. Secondly, the liver does not have optimal conditions for graft engraftment due to the high level of inflammatory mediators in the portal circulation and the effect of the immediate release of proinflammatory cytokines [61].
However, so far an alternative injection site for OB cell transplantation that has superior characteristics to the liver has not been found. The outcome of a transplant depends primarily on the number of viable and functional cells, so researchers are focused on finding additional organs that may be suitable for transplantation. In addition to the portal vein, cells were experimentally transplanted under the kidney capsule, into the spleen, pancreas, peritoneum, omentum, intestinal wall, testicles, thymus, bone marrow, anterior chamber of the eye and intermuscular spaces [62-65]. Despite certain successes in such studies, transplantation into the portal vein system is clinically justified. Because the success of OB cell transplantation primarily depends on the number of viable and functional cells that are retained during the perigraft period, researchers are working to identify alternative sites suitable for transplantation. Cells transplanted into the omentum gave rise to well-vascularized insulin-producing islets. Compared with the portal vein, islets transplanted into the omentum showed delayed engraftment, ultimately achieving similar levels of C-peptide production. Not long ago, a minimally invasive laparoscopic approach for introducing OB cells into the omental bursa with immobilization with coagulated serum was successfully performed in one patient. A group of researchers used a section of bone marrow for transplantation [66]. An external, oxygenating infusion device has also shown promising results in a single patient, and a subcutaneously implanted version of the device is being tested [67]. The intermuscular location is also considered attractive due to easy access and a well-oxygenated environment. When transplanting endoscopically in pigs, the submucosal layer of the stomach wall was used, and the technique is now undergoing clinical trials in the UCSF group [68]. The submucosal layer of the intestinal wall is attractive because of its ease of access and the presence of desired portal discharge, but it does not provide sufficient space to accommodate cells for transplantation in humans [69]. These preliminary results from alternative sites are encouraging, but large clinical studies are needed to confirm safety and efficacy.
Immune therapy for islet cell transplantation of Langerhans
IST during OB cell transplantation is complex. Like any organ transplantation, IST, according to modern protocols, prevents rejection of the transplanted tissue in the recipient, but at the same time has toxic side effects on other organs and increases the risk of infections and malignancies [70]. According to the Edmonton Protocol, induction with daclizumab, an anti-IL-2 monoclonal antibody, allows for the establishment of a less diabetogenic treatment regimen without the use of corticosteroids and with a combination of sirolimus with low doses of tacrolimus as immunosuppressive support [71, 72].
Daclizumab is well tolerated by patients and produces minimal side effects, but is not a potent drug. The use of thymoglobulin with primary inhibition of T-lymphocytes has a pronounced positive effect on long-term insulin independence without taking into account the choice of immunosuppressive support [73]. Good results with T-lymphocyte suppression with alemtuzumab (anti-CD-52 antibodies) were obtained in the recipient group in terms of potency, tolerability, durability of effect and cost. Alemtuzumab in combination with etanercept induction was reported to be well tolerated by patients. Much higher five-year rates of insulin independence were obtained after OB cell transplantation compared to therapy with high doses of sirolimus, tacrolimus and monoclonal antibodies to IL-2 used in the first groups of patients treated according to the Edmonton protocol [31]. The effect of alemtuzumab on suppression of the immune system in recipients after TB cell transplantation should be determined by further studies in patients with newly diagnosed T1DM. A team of researchers at the University of Minnesota is currently testing the effect of Orthoclone OKT-3, a humanized anti-CD3-specific antibody, as an induction agent supported by sirolimus and tacrolimus. Anti-CD3 antibody therapy suppresses effector T lymphocytes and switches the immune response to type 2 T helper cells. Administration of anti-CD3 antibodies has been reported to induce tolerance in non-autoimmune allotransplantation models and also to slow progression of newly diagnosed DM in humans.
Maintaining immunosuppression after transplantation remains a challenge in OL cell transplantation. The calcineurin inhibitor, CNI (cyclosporine or tacrolimus), used as one of the drugs to suppress the immune response, is a highly effective inhibitor of rejection and relapse of the autoimmune process [74]. However, the drug impairs kidney function, causes headaches, and is toxic to β-cells. Sirolimus works by blocking the response of T and B lymphocytes to the release of cytokines that are involved in the stimulation, activation and expansion of T and B lymphocytes.
Prior to use in humans, the validity of sirolimus as an effective immunosuppressive drug was confirmed in experiments in dogs and subsequently in pigs. Sirolimus was a key drug in the original Edmonton protocol and the CIT consortium studies. A number of clinics have obtained promising results regarding the tolerability of side effects in protocols with mTOR inhibitors. It is obvious that an immunosuppressive regimen without the use of a CNI such as tacrolimus can provide an immunoprotective effect with less negative effects, which would be highly effective in OB cell replacement therapy.
It is known that a nonspecific inflammatory reaction occurs in the perigraft period at the microlevel in the environment of the transplanted OB tissue, which leads to early loss of the graft and reduces its function. Transplanted OB cells soon after the procedure find themselves in the portal venules in a “trap” and are subject to immune attack. Anti-inflammatory blocking of TNF-α release with etanercept in combination with an IL-1 receptor antagonist such as anakinra for islet engraftment has been shown to have a likely beneficial effect in several clinical trials.
The mentioned modern anti-inflammatory drugs, which can effectively inhibit non-specific inflammation immediately after transplantation, should be the subject of further research to improve the results of OB cell transplantation.
Blockade of immunoregulatory pathways, Treg induction, dendritic cell targeting, and anti-inflammatory drugs may be potential options to provide immunosuppression. Behind these directions lies the improvement of the suppression of the immune response during allogeneic transplantation of OB cells in the future.
Achieving ongoing recipient tolerance to the OB allograft remains the most important challenge facing researchers, who hope to find a way to completely eliminate the need to suppress the recipient's immune system. Cell encapsulation is one of the new methods of blocking the immune system and saving the transplanted tissue from destruction by creating a membrane around the OB [75].
The membrane surrounding the OB contains pores large enough to allow the passage of nutrients and insulin for exchange between the host and the transplanted tissue, but at the same time does not allow cells of the immune system to pass through and protects the OB from their influence [76]. Similar devices have undergone phase 1 and 2 clinical trials. However, with existing methods of maintaining the viability and function of the OB, the latter are still damaged and do not eliminate insensitivity to the development of hypoglycemia, severe hypoglycemic attacks or insulin dependence in patients.
Complications of transplantation of islets of Langerhans
The risk of mortality after OB cell transplantation is extremely low. The documented case fatality rate of the Collaborative Islet Transplantation Registry (CITR) is 2.9%. Most cases are associated with long-term visceral complications of T1DM, and only 3 of 25 deaths were confirmed to be related to transplantation or rejection surgery [77].
The use of standard ultrasound guidance and percutaneous transhepatic access to the portal vein provides this method with a low transplant risk. However, complications are possible; portal vein thrombosis and bleeding are the main complications after intrahepatic transplantation of OB cells [78]. Their frequency can be reduced by following anticoagulant therapy protocols and local use of a paste that obliterates the wound channel from the catheter.
Temporary discomfort and pain of varying intensity at the site of catheter placement can be observed in 50% of patients, but can be relieved within 24-48 hours with the help of traditional analgesics. It is also possible in 50% of cases to increase the level of liver enzymes (ALT, AST), which returns to normal within 30 days without targeted treatment [79].
Bacterial contamination of purified transplant-prepared cell mass has been reported, as has inadvertent administration of a contaminated graft, but no clinically proven systemic events have been observed. If O.L. were received from several donors, sensitization of the recipient by the major histocompatibility complex is possible. These risks are minimized by refusing several donors and conducting therapy to suppress the induction of T-lymphocytes. Chronic immunosuppression can lead to malignancy. 17 (2%) of 874 patients developed treatable skin cancer.
Results of islet cell transplantation of Langerhans
The technique of clinical transplantation of OB has been constantly improved over the past 30 years, clear advances have been noted in the field of their production and clinical outcomes with restoration of insulin secretion and relief of glycemic instability in patients with T1DM [80]. In 2000, the Edmonton group reported a series of 7 consecutive patients who achieved insulin independence after multiple donor OB transplantation and received sirolimus without the use of steroids [72]. This was a major milestone in clinical OB allotransplantation. Unlike previous samples, patients without uremia, with labile diabetes, were selected as recipients, each of whom was administered a minimum of 10,000 IEQ/kg. By May 2003, 51 allogeneic O.L. transplants had been performed at the University of Alberta in Edmonton. Cumulative survival rate was 100%. Insulin independence 1 and 3 years after transplantation was 79 and 50%, respectively. In 88% of patients, the functioning of the transplanted tissue was noted 3 years after transplantation. When comparing the results of transplantation of the entire liver and pancreas, it was revealed that HbA1c levels remained in the normal range in the majority of patients over the next 3 years.
In 2006, A. Shapiro et al. [81] presented the results of a multicenter prospective study conducted in collaboration with the National Institutes of Health and the Immune Tolerance Network at 6 North American and 3 European sites to examine the feasibility of the Edmonton Protocol. One of the objectives was to establish centers of excellence for future immunotolerance research.
The protocol standardized the selection of pancreatic samples, the process of obtaining pancreatic cells, the criteria for the finished product, the selection of recipients and their management after transplantation. A total of 77 OB transplants were performed in 36 patients in 9 clinics. The primary endpoint of insulin independence was achieved by 44% of patients: HbA1c less than 6.5%, evening glucose level up to 140 mg/dL more than 3 times a week, 2-hour postprandial glucose level up to 180 mg/dL more than 4 times in Week. Two years after transplant, 76% of patients became insulin dependent. C-peptide was detected in 70%; all patients with residual OB function were freed from severe hypoglycemia and hyperglycemia.
The investigators noted that prior experience in each case significantly impacted achievement of the primary endpoint, and regionalization of transplant centers has the potential to reduce costs and improve outcomes.
The study demonstrated that OB transplantation performed according to the Edmonton protocol can restore long-term endogenous insulin secretion and glycemic stability. Although insulin independence was not achieved, persistent islet function relieved recipients of severe hypoglycemia and improved HbA1c values. A. Gangemi et al. [82] reported that, in addition to the Edmonton Protocol, combination therapy with etanercept and exenatide improves graft function and makes it easier to achieve insulin independence with the administration of fewer islets.
Subsequently, the Edmonton group reported a long-term study of the efficacy and safety of islet transplantation in 7 patients with T1DM in the United States. In these patients, constant OB function was confirmed, which was registered in the multicenter international Edmonton protocol [83]. Patients were followed for 12 years with serial testing for prolonged allograft function assessed by C-peptide levels. All 7 individuals demonstrated prolonged OB function for more than 10 years from the time of initial transplantation. All patients showed a progressive decrease in the C-peptide/glucose ratio. None of them had severe hypoglycemia, opportunistic infection, or lymphoma.
Thus, despite the short duration of insulin independence, the Edmonton protocol has been proven to be safe in long-term follow-up. Currently, the technique is indicated primarily for patients with a history of life-threatening conditions - severe hypoglycemia and insensitivity to the development of hypoglycemia. For them, transplantation of OB cells would be extremely effective in the short and long term. According to the latest CITR presentation, 1055 allogeneic transplants were performed in 50 transplant centers in North America, Europe, Australia and South Korea (IPITA, IXA, CTS Joint Conference in Melbourne, 2015) [80].
Among the reported cases, isolated OB cell transplantation (ITA) was the most common procedure ( n
=858), followed by OB cell transplantation after kidney transplantation (IAK) and simultaneous OB and kidney transplantation (SIK) (
n
=197).
CITR data identified factors influencing successful outcome and achievement of insulin independence when the recipient is over 35 years of age and administered a total of more than 0.5 million units. TB equivalent (IEQ), glucose stimulation index more than 1.5, induction therapy with T-cell and TNF-α inhibition, CNI and mTOR support. The combination of these factors led to stable insulin independence after 5 years in 60% of 60 patients. Recipient age, IEQ, and CNI support were also predictive of good C-peptide (≥0.3 ng/mL; n
=308) and HbA1c (<6.5% or 2% or more reduction;
n
=530) levels. Age and IEQ determined the absence of episodes of severe hypoglycemia (less than 90% of patients within 5 years). Another indicator of the improvement of the technique was a significant reduction in the number of adverse events over the past 5 years in 80% of patients.
Later, the results of a phase 3 clinical trial of a multicenter, noncomparative study were presented [77]. The work was carried out in 8 clinics in North America. We enrolled 48 adults with T1DM of more than 5 years' duration, with absent C-peptide after stimulation, with documented sudden onsets of hypoglycemia and severe hypoglycemic episodes despite close monitoring. Each received immunosuppressive therapy and underwent one or more transplants, performed in accordance with the principles of good practice and monitoring methods. The primary endpoint was successfully achieved in 87.5% of patients at 1 year and in 71% of patients at 2 years.
The mean HbA1c level was 5.6% (38 mmol/mol) at 1 and 2 years. Sensitivity to the development of hypoglycemia was restored with pronounced positive dynamics on the Clarke and HYPO scales ( p
<0.0001). There were no deaths or cases of disability recorded in the study. 5 (10.4%) participants experienced bleeding requiring transfusion (corresponding to 5 of 75 procedures), and 2 (4.1%) experienced infections associated with immunosuppression. The glomerular filtration rate decreased markedly against the background of suppression of the immune system; the production of donor-specific antibodies was noted in 2 patients.
This study concluded that transplantation of donor OB provides glycemic control, restoration of sensitivity to its development, and protects patients from severe hypoglycemic attacks. Reported safety events related to handling technique and IST included bleeding and decreased renal function.
Therefore, OB cell transplantation should be considered for those patients with T1DM and hypoglycemia refractoriness in whom less aggressive treatments remain ineffective in preventing severe hypoglycemia.
Thus, the results of recent studies confirm the importance of OB cell transplantation in order to prevent severe episodes of hypoglycemia and insensitivity to the development of hypoglycemia, as well as for stable glycemic control in the majority of patients with T1DM without taking into account insulin dependence. It is likely that further improvement of methods for obtaining and transplanting OB cells will lead to more favorable outcomes of the disease. The accumulated experience in OB cell transplantation is a good basis for clinical searches for alternative sources of β-cell transplantation.
The authors declare no conflict of interest.
Islets of Langerhans of the pancreas
Groups of such cells were discovered back in 1869 by the scientist Paul Langerhans, after whom they were named. Islet cells are concentrated predominantly in the tail of the pancreas and account for 2% of the organ's mass. In total, there are about 1 million islets in the parenchyma.
It was revealed that in newborns the islets occupy 6% of the total mass of the organ. As the body ages, the proportion of structures with endocrine activity decreases. By the age of 50, only 1-2% remain. During the day, the islets of Langerhans secrete 2 mg of insulin.
What cells are islets made of?
The islets of Langerhans contain different, morphologically and functionally, cells.
The endocrine segment of the pancreas includes:
- Alpha cells - produce glucagon, which is an insulin antagonist and ensures an increase in plasma glucose levels. They occupy 20% of the mass of the remaining cells.
- Beta cells - synthesize insulin and ameline. They make up 80% of the island's mass.
- Delta cells - provide the production of somatostatin, which can inhibit the secretion of other glands. These cells make up from 3 to 10% of the total mass.
- PP cells – produce pancreatic polypeptide. It is responsible for increasing gastric secretion and suppressing pancreatic function.
- Epsilon cells secrete ghrelin, which is responsible for the feeling of hunger.
Why are islands needed and how are they arranged?
The islets of Langerhans are responsible for maintaining the balance of carbohydrates in the body and the functioning of other endocrine organs. They have an abundant blood supply and are innervated by the vagus and sympathetic nerves. Among the islets are neuroinsular complexes. Ontogenetically, islet cells are formed from epithelial tissue.
The islet has a complex structure and each of them is a full-fledged functionally active formation.
Its structure promotes the exchange of biologically active substances between other glands for the simultaneous secretion of insulin. The cells of the islets are arranged in the form of a mosaic, that is, they are mixed together.
The exocrine structure of the pancreas can be represented by clusters of several cells and large islets.
It is known that a mature islet in the parenchyma has an ordered organization. It is surrounded by connective tissue, has lobules, and blood capillaries run inside. The center of the lobule is filled with beta cells, and alpha and delta cells are located on the periphery. We can say that the structure of the island is directly related to its size.
What is the endocrine function of islets and why are antibodies formed against them? When islet cells interact, a feedback mechanism is formed. Cells influence nearby:
- Insulin has an activating effect on beta cells and inhibits alpha cells.
- Glucagon activates alpha cells, which in turn influence delta cells.
- Somatostatin inhibits the functioning of alpha and beta cells.
When immune mechanisms against beta cells are disrupted, antibodies are formed that destroy them and lead to the development of diabetes mellitus.
Why is islets transplanted?
Islet transplantation serves as a worthy alternative to pancreas transplantation or installation of an artificial organ. This intervention gives patients with diabetes a chance to restore the structure of beta cells.
Clinical studies were conducted in which islet cells from donors were transplanted into patients with type 1 diabetes. As a result of the tests, it was revealed that such an intervention leads to the restoration of regulation of carbohydrate levels.
Patients with diabetes undergo powerful immunosuppressive therapy to prevent rejection of donor tissue.
An alternative source of material for islet repair is stem cells. They may be relevant since donor cell reserves are limited.
Regenerative medicine is developing rapidly, offering new treatments in many areas
It is important to restore the immune system's tolerance, since the new transplanted cells will also be destroyed after a certain period of time.
Xenotransplantation—transplantation of a pancreas from a pig—has promise. Before the discovery of insulin, extracts from pork pancreas were used to treat diabetes.
It is known that human and pork insulin differ in only one amino acid.
The study of the structure and function of the islets of Langerhans has great prospects, since diabetes mellitus develops due to damage to their structure.
Author : Nikulina Natalya Viktorovna, especially for the site Moizhivot.ru
about the pancreas
Source:
Determination of antibodies to the islets of Langerhans
If for some reason a malfunction occurs in the body, and the active production of antibodies against its own tissues begins, this leads to tragic consequences. When beta cells are exposed to antibodies, type 1 diabetes mellitus develops due to insufficient insulin production. Each type of antibody produced acts against a specific type of protein. In the case of the islets of Langerhans, these are beta cell structures responsible for the synthesis of insulin. The process proceeds progressively, the cells die completely, carbohydrate metabolism is disrupted, and with normal nutrition the patient may die of starvation due to irreversible changes in the organs.
Diagnostic methods have been developed to determine the presence of antibodies to insulin in the human body. Indications for such a study are:
- obesity based on family history,
- any pathology of the pancreas, including previous injuries,
- severe infections: mainly viral, which can trigger the development of an autoimmune process,
- severe stress, mental stress.
There are 3 types of antibodies through which type 1 diabetes is diagnosed:
- to glutamic acid decarboxylase (one of the essential amino acids in the body),
- to the insulin produced
- to OB cells.
These are unique specific markers that must be included in the examination plan for patients with existing risk factors. From the listed volume of research, the detection of antibodies to the glutamic amino acid component is an early diagnostic sign of diabetes. They appear when there are still no clinical signs of the disease. They are detected mainly at a young age and can be used to identify people with a predisposition to developing the disease.
How are islands arranged and what are they for?
The main function performed by the islets of Langerhans is to maintain the correct level of carbohydrates in the body and control other endocrine organs.
The islets are innervated by sympathetic and vagus nerves and are abundantly supplied with blood. The islets of Langerhans in the pancreas have a complex structure. In fact, each of them is an active, full-fledged functional formation. The structure of the islet ensures the exchange between biologically active substances of the parenchyma and other glands. This is necessary for the smooth secretion of insulin.
The cells of the islets are mixed among themselves, that is, they are arranged in the form of a mosaic. A mature islet in the pancreas has the correct organization. The islet consists of lobules that are surrounded by connective tissue; blood capillaries pass inside the cells.
In the center of the lobules there are beta cells, while in the peripheral part there are alpha and delta cells. Therefore, the structure of the islets of Langerhans depends entirely on their size.
Why are antibodies formed against islets? What is their endocrine function? It turns out that when islet cells interact, a feedback mechanism develops, and then these cells influence other cells located nearby.
- Insulin activates the function of beta cells and inhibits alpha cells.
- Alpha cells are activated by glucagon, which acts on delta cells.
- The work of alpha and beta cells is inhibited by somatostatin.
Important! When immune mechanisms fail, immune bodies directed against beta cells are formed. Cells are destroyed and lead to a terrible disease called diabetes mellitus.
Prevention: how to preserve the islet apparatus?
Since the function of the islets of Langerhans of the pancreas is to produce substances important for humans, lifestyle modification is necessary to maintain the health of this part of the pancreas. Key points:
- giving up alcohol and smoking,
- eliminating junk food
- physical activity,
- minimizing acute stress and neuropsychic overload.
Alcohol causes the greatest harm to the pancreas: it destroys pancreatic tissue and leads to pancreatic necrosis - the total death of all types of organ cells that cannot be restored.
Excessive consumption of fatty and fried foods leads to similar consequences, especially if this happens on an empty stomach and regularly. The load on the pancreas increases significantly, the number of enzymes that are necessary to digest large amounts of fat increases and depletes the organ. This leads to fibrosis and changes in the remaining cells of the gland.
Therefore, at the slightest sign of digestive dysfunction, it is recommended to consult a gastroenterologist or therapist in order to timely correct changes and early prevent complications.
Diseases of the cells of the islets of Langerhans
The cellular system of the islets of Langerhans in the gland can be destroyed.
This occurs during the following pathological processes: autoimmune reactions, oncology, pancreatic necrosis, acute exotoxicosis, endotoxicosis, systemic diseases.
Elderly people are also susceptible to the disease. Illnesses occur in the presence of serious growth of destruction.
This occurs when cells are susceptible to tumor-like phenomena. The neoplasms themselves are hormone-producing, and therefore are accompanied by signs of failure of the hyperfunction of the pancreatic organ.
There are several types of pathologies associated with the destruction of the gland. The critical rate is if the loss is more than 80 percent of the islets of Langerhans.
With the destruction of the pancreas, the production of insulin is impaired, and therefore the hormone is not enough to process the sugar that enters the body.
Due to this failure, the development of diabetes is observed. It is worth noting that diabetes mellitus of the first and second degree must be understood as two different pathologies.
In the second case, the increase in sugar levels will be related to the fact that the cells are not sensitive to insulin. As for the functioning of Langerhans zones, they operate as before.
The destruction of hormone-forming structures provokes the development of diabetes mellitus. This phenomenon is characterized by a number of signs of failure.
These include the appearance of dry mouth and constant thirst. In this case, there may be attacks of nausea or increased nervous excitability.
A person may experience insomnia and a sharp loss of body weight, despite eating heavily.
If the sugar level in the body increases, it is possible that an unpleasant acetone smell will appear in the mouth. Possibly impaired consciousness and a hyperglycemic state of coma.
From the above information, it is worth concluding that pancreatic cells are capable of producing a number of hormones needed by the body.
Without them, the full functioning of the body will be disrupted. These hormones carry out carbohydrate metabolism and a number of anabolic processes.
Destruction of the zones will lead to the development of complications associated with the need for hormonal therapy in the future.
To avoid the need for such events to develop, it is recommended to adhere to special recommendations from specialists.
Basically, they boil down to the fact that you should not consume alcoholic beverages in large doses, it is important to promptly treat infectious pathologies and autoimmune disorders in the body, and visit a doctor at the first signs of an illness associated with damage to the pancreas and other organs included in the gastrointestinal tract. .
Insulin preparations
Currently, the pharmaceutical industry produces a significant number of insulin preparations with various biological effects. There are human, porcine, and bovine insulins. According to the degree of purification, traditional, monopeak, and monocomponent insulins are distinguished. Based on the duration of action, insulins are divided into short- and long-acting insulins. The latter are divided into medium-, long- and extra-long-acting insulins. There are also ultra-short insulins and depot insulins, which are released slowly from the subcutaneous tissue.
Selecting an insulin therapy regimen is a complex and very responsible undertaking. The success of achieving compensation for diabetes mellitus and, as a consequence, the patient’s quality of life depends on the correct choice of the form of insulin and its dosage regimen.
What is a transplant and why is it needed?
A worthy alternative to gland parenchyma transplantation is islet transplantation. In this case, installation of an artificial organ will not be required. The transplant gives diabetics a chance to restore their beta cell structure and does not require a full pancreas transplant.
Based on clinical studies, it has been proven that in patients with type 1 diabetes mellitus who were transplanted with donor islet cells, the regulation of carbohydrate levels is completely restored. To prevent rejection of donor tissue, such patients were given powerful immunosuppressive therapy.
There is another material for restoring islets - stem cells. Since the reserves of donor cells are not unlimited, this alternative is very relevant.
It is very important for the body to restore the sensitivity of the immune system, otherwise the newly transplanted cells will be rejected or destroyed after some time. . Today, regeneration therapy is developing rapidly, offering new techniques in all areas
Xenotransplantation, the transplantation of a pig pancreas into a person, is also promising.
Today, regeneration therapy is developing rapidly, offering new techniques in all areas. Xenotransplantation, the transplantation of a pig pancreas into a person, is also promising.
Porcine parenchyma extracts were used to treat diabetes mellitus even before the discovery of insulin. It turns out that human and pork glands differ in only one amino acid.
Since diabetes mellitus develops as a result of damage to the islets of Langerhans, their study has great prospects for effective treatment of the disease.
Islet cell transplantation
Transplantation of OB cells is an alternative to transplantation of the pancreas or part thereof, as well as the installation of an artificial organ. This is due to the high sensitivity and tenderness of the pancreas tissue to any influence: it is easily injured and has difficulty restoring its functions.
Islet transplantation today makes it possible to treat type I diabetes mellitus in cases where insulin replacement therapy has reached its limits and becomes ineffective. The method was first used by Canadian specialists and consists of introducing healthy endocrine donor cells into the portal vein of the liver into the patient using a catheter. It is aimed at making the remaining own beta cells work.
Due to the functioning of the transplanted cells, the amount of insulin necessary to maintain normal blood glucose levels is gradually synthesized. The effect comes quickly: with a successful operation, after two weeks the patient’s condition begins to improve, replacement therapy wears off, and the pancreas begins to independently synthesize insulin.
The danger of the operation lies in the rejection of the transplanted cells. We use cadaveric materials that are carefully selected according to all parameters of tissue compatibility. Since there are about 20 such criteria, antibodies present in the body can lead to the destruction of pancreatic tissue. Therefore, proper drug treatment aimed at reducing immune reactions plays an important role. The drugs are selected in such a way as to selectively block some of them that affect the production of antibodies to the cells of the transplanted islets of Langerhans. This allows you to minimize the risk to the pancreas.
In practice, pancreatic cell transplantation for type I diabetes mellitus shows good results: there have been no recorded deaths after such an operation. A certain number of patients significantly reduced their insulin dose, and some of the operated patients no longer needed it. Other impaired functions of the organ were also restored, and health improved. A significant part has returned to a normal lifestyle, which allows us to hope for a further favorable prognosis.
As with transplantation of other organs, surgery on the pancreas, in addition to rejection, is dangerous due to other side effects due to the disruption of varying degrees of secretory activity of the pancreas. In severe cases this leads to:
- to pancreatic diarrhea,
- to nausea and vomiting,
- to severe dehydration,
- to other dyspeptic phenomena,
- to general exhaustion.
After the procedure, the patient must continuously receive immunosuppressive drugs throughout his life to prevent rejection of foreign cells. The action of these drugs is aimed at reducing immune reactions - the production of antibodies. In turn, the lack of immunity increases the risk of developing any infection, even a simple one, which can become complicated and cause serious consequences.
Research continues on pancreatic transplantation from pigs—xenotransplantation. It is known that the anatomy of the gland and pork insulin are most similar to human insulin and differ from it in one amino acid. Before the discovery of insulin, an extract from the pig pancreas was used in the treatment of severe diabetes mellitus.
Why is a transplant performed?
Damaged pancreatic tissue is not restored. In cases of complicated diabetes mellitus, when the patient is on high doses of insulin, such surgical intervention saves the patient and gives a chance to restore the structure of beta cells. In a number of clinical studies, these cells were transplanted from donors into patients. As a result, the regulation of carbohydrate metabolism was restored. But at the same time, patients have to undergo powerful immunosuppressive therapy to prevent rejection of donor tissue.
Not all patients with type 1 diabetes are candidates for cell transplantation. There are strict indications:
- lack of results from the applied conservative treatment,
- insulin resistance,
- pronounced metabolic disorders in the body,
- severe complications of the disease.
Where is the operation performed and how much does it cost?
The procedure for replacing the islets of Langerhans is widely performed in the United States - this way diabetes of any type is treated in the early stages. One of the diabetes research institutes in Miami is doing this. It is not possible to completely cure diabetes in this way, but a good therapeutic effect is achieved, and the risks of severe complications are minimized.
The cost of such an intervention is about $100 thousand. Postoperative rehabilitation and immunosuppressive therapy range from $5 to $20 thousand. The cost of this treatment after surgery depends on the body's response to the transplanted cells.
Almost immediately after the manipulation, the pancreas begins to function normally on its own, and gradually its performance improves. The recovery process takes approximately 2 months.
Pancreas
The organ belongs to the endocrine and digestive systems. It produces enzymes that break down food that enters the body. Also hormones that regulate carbohydrate and fat metabolism. The pancreas consists of lobules, each of which produces substances necessary for the body - enzymes. It is shaped like an elongated comma. Weighs from 80 to 90 g. The organ is located behind the stomach.
The gland consists of:
- heads;
- necks;
- bodies (triangular shape);
- tail (pear-shaped).
Important. The organ is equipped with blood vessels and excretory ducts
A channel passes through the entire gland, through which the produced pancreatic juice is discharged into the duodenum.
Enzymes produced by the pancreas include:
- amylase;
- lactase;
- trypsin;
- lipase;
- invertase.
Special cells, insulocytes, carry out the endocrine mission of the pancreas. They produce the following hormones:
- Gastrin.
- Insulin.
- C-peptide.
- Thiroliberin.
- Glucagon.
- Somatostatin.
Important. Hormones are involved in the body's carbohydrate metabolism.
Functional Features
The main hormone produced by the islets of Langerhans is insulin. But it should be noted that Langerhans' zones produce certain hormones with each cell.
For example, alpha cells produce glucagon, beta cells produce insulin, and delta cells produce somatostatin.
PP cells - pancreatic polypeptide, epsilon - ghrelin. All hormones affect carbohydrate metabolism, lowering or increasing blood glucose levels.
Therefore, it must be said that pancreatic cells perform the main function associated with maintaining an adequate concentration of stored and free carbohydrates in the body.
In addition, substances produced by the gland influence the formation of fat or muscle mass.
They are also responsible for the functionality of certain brain structures associated with the suppression of the secretion of the hypothalamus and pituitary gland.
From this it is worth concluding that the main functions of the islets of Langerhans will be to maintain the correct level of carbohydrates in the body and control over other organs of the endocrine system.
They are innervated by the vagus and sympathetic nerves, which are abundantly supplied with blood flow.
Types of islet cells and their functions
OB cells differ in their morphological structure, functions, and localization. Inside the islands they have a mosaic arrangement. Each island has an orderly organization. In the center are cells that secrete insulin. At the edges there are peripheral cells, the number of which depends on the size of the OB. Unlike acini, the OB does not contain its own ducts - hormones enter directly into the blood through capillaries.
There are 5 main types of OB cells. Each of them synthesizes a certain type of hormone, regulating digestion, carbohydrate and protein metabolism:
- α cells,
- β cells,
- δ cells,
- PP cells,
- epsilon cells.
Alpha cells
Alpha cells occupy a quarter of the islet area (25%) and are second in importance: they produce glucagon, an insulin antagonist. It controls the process of lipid breakdown, helps increase blood sugar levels, and is involved in reducing calcium and phosphorus levels in the blood.
Beta cells
Beta cells make up the inner (central) layer of the lobule and are the main ones (60%). They are responsible for the production of insulin and amylin, a companion of insulin in the regulation of blood glucose. Insulin performs several functions in the body, the main one being normalization of sugar levels. If its synthesis is disrupted, diabetes mellitus develops.
Delta cells
Delta cells (10%) form the outer layer in the islet. They produce somatostatin, a hormone, much of which is synthesized in the hypothalamus (a structure of the brain) and is also found in the stomach and intestines.
Functionally, it is also closely related to the pituitary gland, regulates the work of certain hormones that are produced by this department, and also suppresses the formation and release of hormonally active peptides and serotonin in the stomach, intestines, liver and pancreas itself.
PP cells
PP cells (5%) are located on the periphery, their number is approximately 1/20 of the islet. They can secrete vasoactive intestinal polypeptide (VIP), pancreatic polypeptide (PP). The maximum amount of VIP (vasointense peptide) is found in the digestive organs and the genitourinary system (in the urethra). It affects the condition of the digestive tract, performs many functions, including having antispasmodic properties against the smooth muscles of the gallbladder and sphincters of the digestive organs.
Epsilon cells
The rarest of the OB components are epsilon cells. Microscopic analysis of a preparation from a lobule of the pancreas can determine that their number in the total composition is less than 1%. Cells synthesize ghrelin. Among its many functions, the most studied is its ability to influence appetite.
Terms and Definitions
- Langerhans cell histiocytosis is a tumor of myeloid nature, the morphological substrate of which is pathological Langerhans cells, phenotypically similar to epidermal Langerhans cells
- Inactive disease (ID) is a disease status in which all reversible lesions have undergone reverse development
- Active disease (AD) is a disease status in which the original lesions persist or new lesions are detected
- Reactivation of the disease - the appearance of new lesions after achieving NAZ status
- Risk organs are organs (liver, spleen, bone marrow), the involvement of which in the pathological process is associated with a poor prognosis of the disease.
- Permanent complications (PC) are irreversible changes in the structure and/or function of organs as a result of lesions in LCH.
- Criteria for response to therapy
Diabetes
The beta cells in the pancreas are complex. They belong to the endocrine part of the pancreas. If they are deprived of oxygen, it stops secreting insulin. After this, diabetes begins. This is a terrible and insidious disease that completely changes a person’s life.
Type I diabetes is an autoimmune disease. Here the beta compounds are attacked by the patient's immune system. In type II diabetes, tissue resistance to the action of insulin is observed. This is why blood sugar increases. This disease shortens the patient's life by 5-8 years.
The newest method of treatment is now the transformation of pancreatic duct cells into alpha compounds, followed by transformation into beta cells. In alpha cells, the Pax4 gene is activated here. This leads to the generation of new beta cells. This procedure can be carried out 3 times.
The research team is currently working on creating pharmacological molecules that will be able to cure diabetes patients in the future.
How is the analysis carried out?
If a problem arises in the functioning of the pancreas and disruptions in its endocrine function, it is necessary to conduct a full examination. The most common cause of cell damage is an autoimmune attack. The resulting antibodies can be determined using laboratory diagnostics. They can be of three types:
- to the cellular structures of the islets of Langerhans themselves;
- the insulin they produce;
- membrane enzyme of beta cells (glutamic acid decarboxylase).
Important! Typically, damage affects not only these groups of cells, but the entire organ as a whole. Therefore, it is also necessary to do an ultrasound and check the enzymatic activity.
Notes
- ↑ Langerhans P.
Beiträge zur mikroskopischen Anatomie der Bauchspeicheldrüse: Inaugural-Dissertation, zur Erlangung der Doctorwürde in der Medicine und Chirurgie vorgelegt der Medicinischen Facultät der Friedrich-Wilhelms-Universität zu Berlin und öffentlich zu vertheidigen am 18. Februar 1869. - Berlin : Buchdruckerei von Gustav Lange, 1869. - ↑ 1234567891011
Clinical diabetology / Efimov A. S., Skrobonskaya N. A. - 1st ed. - K.: Health, 1998. - 320 p. — 3000 copies. — ISBN 5-311-00917-9. - ↑ Zhukovsky M. A.
Pediatric endocrinology. — 3rd ed. - M.: Medicine, 1995. - 656 p. — 8000 copies. — ISBN 5-225-01167-5. - ↑ (English).
- ↑ (English). October 26, 2012.
- ↑ Proshchina A. E., Savelyev S. V.
// Bulletin of Experimental Biology and Medicine. — Ed. RAMS, 2013. - T. 155, No. 6. - P. 763-767.
Historical reference
Paul Langerhans, as a medical student working with Rudolf Virchow, in 1869 described clusters of cells in the pancreas that were different from the surrounding tissue, which were later named after him. In 1881, K.P. Ulezko-Stroganova first pointed out the endocrine role of these cells. The increatory function of the pancreas was proven in Strasbourg (Germany) in the clinic of the largest diabetologist Naunin Mering and Minkowski in 1889 - pancreatic diabetes was discovered and the role of the pancreas in its pathogenesis was proven for the first time. The Russian scientist L.V. Sobolev (1876-1919) in his dissertation “On the morphology of the pancreas when ligating its duct in diabetes and some other conditions” showed that ligation of the excretory duct of the pancreas leads the acinar (exocrine) section to complete atrophy, while pancreatic islets remain intact. Based on experiments, L.V. Sobolev came to the conclusion: “the function of the pancreatic islets is the regulation of carbohydrate metabolism in the body. The death of pancreatic islets and loss of this function causes a painful condition - diabetes mellitus."
Subsequently, thanks to a number of studies conducted by physiologists and pathophysiologists in various countries (pancreatectomy, selective necrosis of pancreatic beta cells with the chemical compound alloxan), new information was obtained about the increatory function of the pancreas.
In 1907, Lane & Bersley (University of Chicago) showed the difference between two types of islet cells, which they called type A (alpha cells) and type B (beta cells).
In 1909, the Belgian researcher Jan de Meyer proposed calling the secretion product of beta cells of the islets of Langerhans insulin (from the Latin insula - islet). However, direct evidence of the production of a hormone that affects carbohydrate metabolism could not be found.
In 1921, in the laboratory of physiology of Professor J. Macleod at the University of Toronto, the young Canadian surgeon Frederick Banting and his assistant medical student Charles Best managed to isolate insulin.
In 1955, Sanger and co-authors (Cambridge) managed to determine the amino acid sequence and structure of the insulin molecule.
In 1962, Marlin et al discovered that aqueous extracts of the pancreas were capable of increasing glycemia. The substance causing hyperglycemia was called “hyperglycemic-glycogenolytic factor.” It was glucagon, one of the main physiological antagonists of insulin.
In 1967, Donathan Steiner and co-authors (University of Chicago) managed to discover the insulin precursor protein, proinsulin. They showed that the synthesis of insulin by beta cells begins with the formation of a proinsulin molecule, from which C-peptide and an insulin molecule are subsequently split off as needed.
In 1973, John Ensik (University of Washington), as well as a number of American and European scientists, carried out work on the purification and synthesis of glucagon and somatostatin.
In 1976, Gudworth & Bottaggo discovered a genetic defect in the insulin molecule, revealing two types of the hormone: normal and abnormal. the latter is an antagonist to normal insulin.
In 1979, thanks to the research of Lacy & Kemp and co-authors, it became possible to transplant individual islets and beta cells, it was possible to separate the islets from the exocrine part of the pancreas and carry out transplantation in an experiment. In 1979-1980 When transplanting beta cells, a species-specific barrier is overcome (cells from healthy laboratory animals are implanted into sick animals of a different species).
In 1990, pancreatic islet cells were transplanted for the first time into a patient with diabetes mellitus.
A little history
In 1869, the German scientist Paul Langerhans, after whom the clusters of cells in the pancreas were named, first described the heterogeneity of the structure of this organ. But it was only at the end of the 20th century that it was suggested that they play a role in the regulation of sugar metabolism. A little later, evidence of this theory was obtained and a disease such as pancreatic diabetes was discovered.
The main part of the pancreatic parenchyma is responsible for the production of juice and enzymes. With their help, complex substances supplied with food are broken down into simpler compounds that are convenient for further metabolism.
Important! The islets of Langerhans are located primarily in the tail of the pancreas; their cellular structures produce five types of hormones. The most important of them is insulin, which is involved in glucose metabolism, the rest play an auxiliary role in the general endocrine system.
If we talk about what the islets of Langerhans consist of, it should be noted that they all together represent hormonally active clusters. Their sizes can vary from one cell to large formations more than 100 microns in diameter. Each of the islands is surrounded by connective tissue fibers.
Links
| Diabetology |
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| Non-immune forms of diabetes mellitus in children |
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| Complications of treatment |
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| Complications of diabetes | Acute (diabetic coma) Ketoacidosis Lactic acidosis Hyperosmolar coma Late Microangiopathy (Diabetic retinopathy, Diabetic nephropathy) Macroangiopathy Diabetic foot Diabetic neuropathy Mauriac syndrome Nobecourt syndrome Lesions of other organs and systems |
