Mannose therapy at a diabetes mellitus

From the received own data on biochemical impairment of the carbohydrate metabolism in patients with diabetes mellitus and features of functioning of a genetic control system the organism and literary data it is possible to offer the following scheme of restoration the metabolism of carbohydrates.

1. To normalize structure of carbohydrates in nutrition of patients up to norm according to the theory of the balanced foodstuffs, which is up to parity: 4 parts of carbohydrates, 1,5-2 parts of fats and 1 part proteins.

2. Foods should be safe, should not contain pathogenic microorganisms and not promoting occurrence of allergic reactions(peanut, egg, milk, gluten, tree nuts, soya, fish, crustacea, sesame).

3. To enter in nutrition of the patients with diabetes mellitus of the food with the contents of mannose, fucose or hemicellulose on their basis up to 50 - 100 g into day.

4. To enter in nutrition of the patients with insulin-dependent diabetes mellitus peroral 2 time in day 150 mg D-mannose through 30-40 min from reception of foods.

5. For normalisation of biochemical processes in intestinal tract be necessary entered the bifidobacteria 1-2 time in week for 30 min before reception of foods.

6. For normalization of metabolic processes to support such level of carbohydrates in nutrition during a long period before the following genetic transition. During the next genetic transition necessitate to supervise the contents of mannose in blood of the patient with diabetes mellitus and fucose in structure mucopolysaccharides of the saliva.

The purpose of my researches is the determination of a potential role the minor monosugars in various biological functions in human organism, management of insulin secretion, glycoprotein synthesis and immune function.

There are in blood of the healthy person, except of glucose, also others monosugars (D-mannose, L-fucose, D-ribose, D-galactose and others) in sum 10 - 15mg%. It is necessary to find out their role in biochemical processes of the healthy person, and also in patients with diabetes mellitus.

For synthesis of various glycoproteins, functioning in human body, it is necessary that in human organism alongside with proteins there were also carbohydrates. For synthesis the oligosaccharide structures of the glycoprotein is necessary the researches on a determination the role those or other sugars in human organism. In human body cells for synthesis of glycoproteins and nucleoproteins are necessary the following sugar and sugar-conformable substances - glucose, galactose, mannose, xylose, fucose, ribose, 2-deoxy-D-ribose, ribulose, sialic acid, N-acetyl-D-glucosamine, N-acetyl-D-galactosamine, arabinose and others. Some sugars enter intro cells from the blood, other sugars are synthesized themselves in cells.

General need of human organism in the mannose and fucose compound only for synthesis of immunoglobulins 80,5 mg/day. Besides of the mannose and the fucose are necessary also for synthesis of proteoglycans, keratansulphate, many of hormones, mucopolysaccharides, receptors of cells and many others glycoproteins.

The decrease of a level of the contents in blood of various monosugars results in impairment of secretion of the insulin and synthesis many of glycoproteins, nucleoproteins.

Hypotheses of this research are:

1. The role of mannose in management of insulin secretion out of basophile cells in a pancreas at the patients with diabetes mellitus.

2. The role of mannose & fucose in the synthesis of glycoproteins at the patients with diabetes mellitus.

However researches in this area practically are not conducted, as many researchers are engaged only in study of a protein part of the glycoproteins.

The carbohydrate part of glycoproteins basically is determined on reaction with lectins, or concanavalin A or P-selectin [2,3,4,5,6 ].

In the present research will be determined the potential role only mannose and fucose in biochemical processes of human organism which support a main role in management of insulin secretion out of basophile cells of the pancreas and in synthesis of the glycoproteins at the patients with diabetes mellitus.

Global hypotheses of the given research are following:

The decrease of a level of the contents in blood of various monosugar results in impairment of insulin secretion and synthesis some the glycoproteins, nucleoproteins.

The level of glucose in human blood is adjusted by insulin, which is synthesized in a pancreas beta - cells. After a man consume of carbohydrate-contain food in 30 minutes is increased in human organism the level of glucose in blood. For decrease of the level of glucose in human blood is entered the insulin which penetrating in cells of a liver and skeletal muscles participates in synthesis of glycogen from the glucose. The increased contents of glucose thus are reduced and hereinafter are supported at a stable level.

For regulation of a deducing the insulin from a beta - cell is necessary a mediator. However hitherto is not installed, what substances promote the deducing of insulin from the beta - cell at increase of the level glucose in human blood. It is known, that some hormones (glucagon, secretin, cholecystokinin, somatotropin, prostaglandin A1, and also L-arginine and L-leucine increase secretion of insulin. However what substances directly participate in regulation of the deducing of insulin out of beta-cell are not known yet.

The glucose itself can not be mediator, as it the levels in blood healthy and diabetic patients practically do not differ, but secretion of insulin is different. A amino acids and the fatty acids no should accept participant in regulation of the glucose, so at the increase of glucose in blood the synthesis of these groups of substances through glyconeogenesis is durable and also multilevel. Therefore most effective and reliable can be management through monosugar, which can be synthesized from glucose by the shortest metabolic pathway. And such pathway is present. It is synthesis of mannose. The metabolic pathways synthesis of mannose and fucose from glucose is indicated on figure 1.

Figure 1. Metabolic pathway synthesis of D-Mannose and L-Fucose from glucose in the human organism

At the increase of concentration the glucose in blood are intensify many metabolic processes of utilization of the glucose, including this pathway. The increase of concentration mannose in the beginning in blood, and behind that in the cell is resulted in creation of vesicles in a Golgi apparatus by a beta - cell. For synthesis of glycoprotein vesicle environment is necessary also of mannose. In vesicle is introduced of proinsulin and on pathway of the deducing from the cell in the vesicle result the sharing of proinsulin on C3- peptide and insulin [1].

In blood flow are introduced two components - insulin and C3-peptide. So is execute the regulation of insulin from a beta - cell at the healthy people (See figure 2). The base level of mannose in blood is supported for the account of the nutrition, and the regulating level of mannose is synthesized in the liver for the deducing of insulin. The more level of glucose in blood, the more is synthesized of mannose and the more is deduced the insulin. The closer level of glucose in blood to norm, the less is synthesized of mannose and the less is deduced the insulin from a beta - cell.

Partially this theoretical model of regulation is represented in [ 1 ]. However this theoretical model should be tested in a practice. Previously, we took for a research of influence the mannose on synthesis of insulin 25 insulin-dependent diabetes mellitus which were ill by diabetes within 3-5 years. Their age made 16-18 years, and the dozes introduced long and short insulin made 26- 36 units per day.

Figure 2. The general circuit of processes insulin secretion in pancreatic B-cell

1-rough endoplasmic reticulum ; 2- Golgi apparatus; 3-vesicle with insulin ; 4-vesicle; 5-insulin + C-peptide.

To the first group from 10 persons we gave the mannose for 2 hours prior to meal during 1 month. To the second group of the patients from 15 persons we gave of mannose in 30 minutes after reception of meal. In the first group of the patients the level introduced exogenous insulin practically was not changed. In the second group of the patients the necessity in exogenous insulin through 2 - 3 days after has decreased on 15-25 %, and at the end of the month it was stabilized at this level.

Thus, the introduction of mannose at the insulin-dependent diabetes mellitus in 30 minutes after nutrition is optimum and allows partially to compensate of natural regulation the insulin and to include in process of insulin's synthesis a part a reserve beta - cell.

The level of mannose in the blood of healthy person is 20 - 50 mkmol/L [9] that cannot be supplied by intracellular or metabolic processes. Therefore, for the synthesis of glycoproteins mannose should be supplied with the diet. For the synthesis of carbohydrate portion of immunoglobulins in human organism should be on our accounts 80 mg mannose and fucose (see table 1).

Table 1

Necessity human organism in mannose and fucose for synthesis of immunoglobulins

1 Principles of biochemistry/Abraham White et al.//McGraw-Hill, Inc. 1978

2 Sum of the mannose and fucose from sum of all sugars immunoglobulin were calculated by a formula in [7]

General necessity human organism in the mannose and fucose only for synthesis of immunoglobulins is 80,5 mg/day.

Besides of these mannose and fucose are necessary also for synthesis of proteoglycans, keratansulphate, many of hormones, mucopolysaccharides, receptors of cells and many others glycoproteins.

Huge role of glycoproteins and various sugars, included in them, consist during process of synthesis and secretion of insulin, interaction it with receptors of various cells. The olygosaccharires of the glycoproteins pertain the important role in construction of cell membranes of the basic substance of a connecting fabric, of proteoglycans and collagen�s of a connective tissue. In cartilage tissue of collagen on 10 % consists of the carbohydrates. The collagen of a skin, bones, sinews, skin of embryo, the walls of blood vessels are formed also from tissue containing of the carbohydrates.

Just the carbohydrates determine acquired information or individual features of many molecules, into structure that they include. An intercellular recognition depends from of a carbohydrate part of the cells' receptors. Glycolipids and glycoproteins are receptors many hormones, mediators, viruses, toxins.

One from the factors that conduce to development of complications with diabetes mellitus is hyperlipidemia, what it is possible to associate with insufficiency of synthesis lipoproteinlipase as, and the glucose, mannose and fructose activate this enzyme.

Thus is necessary in detail to investigate all these various and very important functions the minor sugars in the human organism. Also is necessary determine influence the minor monosugars on functioning of sick organism, participation them in biochemical processes and in management of cells.

However researches on the monosugars role in biochemical processes of the human organism be not actually carried out, so all scientific schools is engaged only in protein exchange, sequencing of proteins part of the molecules, role of genes in synthesis of protein molecules.

But you see the role of carbohydrates is more essential in a control system and regulation by biochemical processes in human organism and consequently researches in this area should be do in two - three times more, than in the field of biochemistry of proteins or fats.

This research are devoted to finding of the role of minor sugars in management, regulation and control of biochemical processes in organism of the healthy person and patient with diabetes mellitus.

With the help of gas-liquid chromatography we established for the first time that, in blood of patients with diabetes mellitus, fucose is absent and the level of mannose is lower than in healthy people [ 13,14 ]. The concentration of pyruvic acid, an intermediate of the metabolic pathway of transformation of glucose into fatty acids and amino acids, is very high (by a large quantity what at the healthy people) [ 15 ].

We received a patent on a method to correct the impairment of carbohydrates metabolism in patients with the diabetes mellitus with the help of minor sugars [ 16].

We received the patent on a method of diagnostic the diabetes mellitus [ 17 ].

This method allows to distinguish juvenile diabetes from adult insulin-dependent diabetes on difference of metabolic pathways proceeding in their organisms.

Previously we studied 50 patients with diabetes mellitus, including 30 - insulin-dependent diabetes and 20 - insulin-independent diabetes. From 30 patients with insulin-dependent diabetes in a stage of indemnification (the first group) was studied 11 patients, and 19 - in a stage of decompensation (the second group). Compensated of insulin-independent diabetes was marked at 8 patients (the third group), and decompensated - at 12 patients (4th group).

By the reason of decompensation of the disease diabetes mellitus were such factors, as errors in diet therapy and high-proteins nutrition, wrong application of peroral hypoglycemic agents and insulin therapy, for the first time revealed diabetes, of intercurrent disease, trauma and surgical illnesses. For elimination of decompensation to patients with insulin-dependent diabetes have carried out of insulin therapy, and with insulin-independent diabetes - diet therapy under the existing circuit and treatment of peroral hypoglycemic agents. Besides it, with decompensation of disease if necessary have carried out pathogenetic and symptomatic therapy directed on decrease (reduction) hyperglycemia, hypercoagulation and hypoxia, and also correction of acid-alkaline balance, water-electrolytic balance and other decompensation of diabetes mellitus. The clinic-laboratory parameters of these patients are submitted in table 2. The control group consisted of 10 healthy persons of different age and sex.

The analysis of the data of table 2 allows revealing the following differences in these groups. In the first group of patients with insulin-dependent diabetes mellitus were patients on the average in the age of 12,5 years, in the second group - per 20 years. In the third group of the patients with insulin-independent diabetes were presented on the average in the age of 41,5 years, in the fourth group - per 42 years.

At compensated of the patients with diabetes mellitus in the second group the level of glycosylation hemoglobin was increased up to 12,5 %, and in the fourth group - up to 10,1 %. It was specified, that decompensation of the glucose at decompensated insulin-dependent diabetes resulted in large accumulation of glycosylation hemoglobin, than at the patients with insulin-independent diabetes. This parameter also was specified on infringements in carbohydrate structure at synthesis of the glycoproteins in organism of the patients.

Table 2

The note: IRI - immunoreactive insulin; GC - general cholesterol; LPVLD - lipoproteins of very low-density; LPHD - lipoproteins of high density; TG - triglycerides; CA - coefficient of aterogenety.

In group of the compensated diabetes mellitus a cholesterol level in blood becomes lower, than at decompensating of the patients, also is lower in blood at the compensated patients the lipoproteins of very low density. Others the parameters at patients practically do not change depending on a type of diabetes mellitus and degree of its indemnification.

All patients are receiving a standard set of foods, including carbohydrate containing. Previously were carried out researches on structure of sugars and polysaccharides of carbohydrate containing of foods used by the patients. The received results are given in table 3. From lab findings the tables follows, that fucose practically is not contained in foods, that offered the patient with diabetes mellitus. The mannose is present only at groats and bread. Thus the greatest contents of mannose is in rye bread, what and is recommended to the patient with diabetes mellitus and promotes normalization in some measure of carbohydrate metabolism in the patients.

The many hemicelluloses are contained in the structure in small quantities of mannose. Therefore these hemicellulose-containing products introduce in the nutrition of the patients with diabetes and obesity for are normalizing of the carbohydrates metabolism.

Table 3 Structure of sugars and polysaccharides carbohydrate-containing of foods in the surveyed group of the patients with diabetes mellitus

The note: - absence of a parameter.

However such of carbohydrate-containing products, as milk, kefir, sour cream, cottage cheese contain mainly only lactose, which with hydrolysis in small intestine enzyme of lactase gives only glucose and galactose. As these products of a nutrition are used by the patients in plenty, it are result at a lack in the organism such sugars as mannose, fucose.

Necessary was study, how nutrition by carbohydrate- containing foods are influenced on metabolic processes in organism of the patient with diabetes mellitus. Therefore further we have carried out researches by definition of a blood structure with the help of gas-liquid chromatography and was determined whole spectrum of sugars, but not just one glucose. The researches of the blood structure have carried out on an empty stomach, and also through 2 hours after was reception of food and the received results are given in tables 4, 5.

Table 4 Contents of monosugars in whey blood of healthy person and patients with diabetes mellitus (M + m)

The note: X - not identified peaks of sugars and acids. P - reliability of distinctions of parameters in control group and in group of the patients with diabetes mellitus.

Before than were researched a blood sugars structure in the patients with diabetes mellitus and healthy persons with the purpose of reliable identification of peaks previously were analyzed a various sugar mixes, including glucose, galactose, fructose, mannose and fucose.

As seen from given the tables, fucose was presented as traces at the healthy person, and also at the patients with insulin-independent diabetes mellitus. In the patients with insulin-dependent diabetes mellitus the fucose was not displayed even as traces. In this patients was not determined the mannose. The peak �5 by gas-chromatographic parameters was identified presumably as sialic acid. Sialic acid are contained in blood at the patients with diabetes mellitus in tens times bigger, than in the healthy person.

Thus, we see that on the empty stomach in blood of the patients with diabetes mellitus are absented necessary the minor sugars.

For revealing influence of foods on the recommended diet on the level of minor sugars in blood of the patients with diabetes mellitus are determined the structure sugars in human blood through two hours after reception of foods, and the received results are submitted in table 5.

Table 5 Structure and contents of sugars in blood (in mg%) at the patients with diabetes mellitus I and II types in 2 hours after reception of food

The note: X - not identified fractions of sugars; SI - stage of indemnification of disease; SS - stage of subindemnification; SD - stage of decompensation. In brackets - duration of disease. Dash - the sugar is not determined.

From the received data follows, that through two hours after reception of food recommended dietitians, in blood of the patients with diabetes mellitus are not contained such monosugars, as mannose and fucose, but the level of glucose in blood can raise up to 400 mg%, both at compensated, and at decompensated of the patients. Thus, the recommended diets for the patients with diabetes mellitus do not result by increase in blood of the level of fucose and mannose, and it promotes impairment of carbohydrate metabolism and development of hyperglycemia.

The impairment of the carbohydrate metabolism at the patient with diabetes mellitus are displayed not only in blood, but also in others secretors liquids (saliva, mucus of gastrointestinal tract, spinocerebral, respiratory ways).

In urine are concentrated many of metabolic substances of the human organism and consequently practically always with impairment of metabolic processes necessary are research an urine compound at the patients. At normal levels the metabolic processes of the glucose in the human organism in the urine are present in traces quantities only pyruvic, wine and citric acid. It is natural metabolic components of glycogenesis.

At impairment of carbohydrate metabolism in urine are appeared various other substances, on which it is possible to judge possible impairments of biochemical processes proceeding in human organism. So in the urine the concentration of metabolic substances in tens time is higher, than in blood. At impairment of processes exchange at the person in the urine is significant informative than those in blood. So, in urine are concentrated the products of metabolic processes not only by synthesis of new cells, but also old cells which were synthesised earlier. Thus, in urine concentrate not only "abnormal" substances circulating in blood the person nowadays, but also substances participating in metabolic processes little earlier. Therefore on presence of those or other substances in urine is possible in any measure to judge and impairments of biochemical processes, proceeded earlier.

From products of carbohydrate metabolism are determined in human organism nowadays in urine only glucose and oxalic acid. Us were developed new techniques of research various substances of the carbohydrate metabolism in urine at the patients with diabetes mellitus [ 15 ]. Simultaneously in the urine, with the help of gas-liquid chromatography, us are determined as sugar, as various organic acids. In table 6 are given the received results.

Table 6 Contents of sugars and them of metabolite in the urine at healthy and patients with diabetes mellitus

At the healthy person, from receive dates of the table, completely are absent the sugars in the urine, and pyruvic, citric and wine acid are presented practically in traces quantities.

In group of the compensated patient insulin-dependent diabetes mellitus the contents of pyruvic acid in the urine were equally to sum a wine and a citric acids. It is specifies metabolic pathway for these patients (cycle of tricarbonic acids of the carbohydrate metabolism). The increased contents of the pyruvic acid in urine the patients are specified on the metabolic ways of translation of proteins and fats into glucose. This pathway has name a glyconeogenesis. That is way synthesis of sugars from replaceable amino acids and fatty acids.

At decompensation insulin-dependent diabetes in urine of the patients were discovered only of glucose and fructose. Simultaneously level of pyruvic acid is reduced twice, but wine and citric acid were no discovered.

It specifies probably, that the increased contents in blood of glucose it is results the eduction of its part in urine. Simultaneously are reduced metabolism of glucose, and some stopping other the carbohydrate metabolic processes.

At insulin-independent diabetes biochemical processes of carbohydrate metabolism differ from the same processes at insulin-dependent diabetes of patients. The level of pyruvic acid in the urine at these patients is much higher also its quantity on the average twice more, than sum of a wine and a citric acids. The increased contents of pyruvic acid in the urine at these patients specify a significant overload it of metabolic pathway. The translation high quantity of glucose not in a glycogen, but in fatty acids is characteristic for the patients this type (insulin-dependent diabetes mellitus). It results in increase deposit of adipose tissue at the patients with insulin-independent diabetes. The increased contents of pyruvic acid also confirm about translation high quantity of glucose, at these patients, in fatty acids through pyruvic acid. The overload it of metabolic pathway is results in increase of pyruvic acid in urine - intermediate component of metabolism.

Us were received the patent at the method of diagnostics of diabetes mellitus 1 and 2 types based on a various ratio pyruvic, wine and citric acids in these patients.

At decompensation insulin-independent diabetes of the patients (4 the group) also in urine was determined the increased contents of glucose, fructose. However and in this group at decompensation decreases in urine the contents of intermediate components the metabolism of sugars (pyruvic, wine and citric acid).

Simultaneously us were carried out researches at the contents of sugars and organic acids in urine of the patients with diabetes mellitus through 2 hours after reception of foods. The received results are submitted in table 7.

Table 7 Contents of sugars and organic acids in urine of the patients with diabetes mellitus through 2 hours after reception of foods

The note: X - not identified fractions of sugars; SI - stage of indemnification of disease; SS - stage of subindemnification; SD - stage of decompensation. In brackets - duration of disease. Dash - the sugar is not determined.

From receive dates in the table 7 follows, that at the patient with insulin-independent diabetes has the very high contents of pyruvic acid in urine through two hours after reception of food at the presence of small quantities of glucose. At the same time is sum of wine and citric acids does not exceed the level of these acids in urine on an empty stomach in this group of the patients. It indicates on essential overload just it metabolic pathway through 2 hours after reception of foods in this patients group. Thus, the high contents of glucose in blood of this patient through 2 hours after reception of foods results in eduction of a part of the glucose in urine, but basic part of the glucose are transformed through pyruvic acid in fatty acids.

At the patient with insulin-dependent diabetes mellitus is approximately identical the contents of the pyruvic and citric acids in urine through two hours after reception of foods. By it proves to be true, that the increased contents of glucose in blood at these patients results in inclusion not only processes of glycogenesis, but also cycle of tricarbonic acids (cycle of citric acid). The overload of these ways results in eduction in urine the intermediate metabolites of these biochemical processes (citric acid).

At decompensation the level of glucose in blood, in urine has more quantities of glucose (in 200 - 300 are more, than at the compensated patients). Thus, the nutritious substances which were entered in the human organism so were thrown out in urine and practically are not used for nourishment of cells of the organism. The patient must eat all time the foods, his weight of a body is reduced, also are decreased the reserve of glycogen.

On the basis of these received results of preliminary researches were made the following conclusions:

The mannose partakes in of regulation of the insulin in human organism.

In foods that recommended the patient with diabetes mellitus, are absent or are contained in small quantities such of minor sugars, as mannose and fucose, but prevail the glucose and the galactose;

At blood of the patients with diabetes mellitus on an empty stomach and through 2 hours after reception of foods, as against the healthy people, are not present in necessary quantity of mannose, that are resulted in impairment of the carbohydrates metabolism;

In urine of patients are present, as against the healthy people, significant quantities of pyruvic, wine and citric acids, and ratio of these acids at insulin-dependent and insulin-independent the patients variously. On this basis from ratio of organic acids in urine is offered to distinguish these two such as diabetes mellitus and was received the appropriate patent;

The very high contents in urine of the pyruvic acid specifies an overload of the metabolic way of translation of the glucose in fatty acids at the patients with insulin-dependent diabetes mellitus, that results in forming of adipose tissue;

At the decompensation of glucose are increased so in blood, so in urine contents of the various substances others of metabolic pathways.

On the basis these results the further researches also are formed in field of study of impairments of the carbohydrates metabolism at the patients with diabetes mellitus. It is necessary to offer the theoretical concept the impairments of a biochemical processes at this group of the patients, that will allow to comprehend the received results and to plan pathways of treatment of this disease.