Glycation

A reaction in two stages

The condensation of Maillard and the rearrangement of Amadori lead to the products of glycation known as early and which characterize short or intermediate proteins of half-life, hemoglobin being regarded in this case as pertaining to this category. But if one considers the continuation of the reaction of Maillard, one obtains such called products of Maillard final product of glycation (PTG), characterizing structural proteins of prolonged lifespan. The rate of formation of these compounds is, contrary to the precedents, independent of the sugar concentration but depends only on the duration on the hyperglycemia and time on the proteinic renewal ( turn-over proteinic).

The key point is that if the first 2 stages are stabilized with a plate and have a potential reversibility according to the glycemia, 3rd progresses as from the moment when there is presence of sugars with which to react, and the Old ones (Advanced Glycation End-products or PTG) thus formed, being very reactive, are responsible for many complications. The concentration of Old is thus proportional to the glycemia over long periods of time. Moreover, the Old ones cannot be destroyed nor released from the cells in which they were formed, contrary to the early products. Indeed, the cells are equipped with a small organoid called protéasome which is charged to destroy proteins while cutting them in many rather small peptides (from 9 to 12 amino-acids) to be inoffensive. If it can thus make inoffensive the early products, the protéasome does not have any effect on the Old ones and those pile up in the cell without they being able to get rid some. Gradually, these glyquées proteins clog the cell, resulting in a dysfunction of its metabolism and finally its death.

The glycation: a negative effect on the level of the blood-vessels. The consequences of the glycation of proteins are multiple because they lose some their properties. We initially will expose some examples which lead all to vascular problems, but initially, let us study a healthy blood-vessel.

Constitution of a blood-vessel

A blood-vessel consists of three thicknesses playing a precise part (of the center towards outside): intima, media and the adventitious one. We will limit ourselves to the intima because it is on this level that the essence of the glycation is carried out and played a big role, because sugars, as well as many proteins and the Old ones, travel in the center of the vessel called light, and thus react to it. The intima consists of a endothélio-mésenchymateux complex, formed of very flattened epithelial cells, constituting the epithelium, impermeable and maintaining the medium internal of the vessel constant and liquid, and cells mésenchymateuses, undifferentiated and which consequently are the renovating cells of the vessel. The exchanges between plasma and the external medium are carried out through intercellular spaces for the smallest molecules (diameter  25 Å = 25 X 10-10 m) or via blisters adequate which make them pass through the cells by a phenomenon of pinocytosis for largest. Lastly, the intima is surrounded by a basal blade which plays the part of philter and prevents the molecules whose diameter is  60 Å to pass. The extracellular matrix consists of fibrous proteins, in particular collagen fibrins. Lastly, the Protéoglycane S are proteins whose role consists in controlling the intermolecular traffic, and thus, in this case, control the exchanges between blood circulating in the capillaries and the cells.

Vascular problems having for origin the glycation

the glycation deteriorates the enzymatic activity in several ways:

on the level of the enzyme, a residue of amino-acid glyqué in the vicinity of the active site can obstruct association site credit-substrate and thus obstruct the chemical reaction (1).
of the modifications of the conformation of the enzyme for example because of the formation of connections between the atoms, which is a phenomenon of reticulation, can cause a modification of the active site and consequently remove the actions of the enzyme (2).
the glycation of certain proteins of the vascular walls their fact of losing part of their mechanical properties and make them thus resistant to the enzymes (3).

For example, resistance to the enzymes necessary to the replanning of the walls contributes to the irreversibility of the thickening of the arterial wall at the origin of vasoconstriction (reduction of the diameter of the blood-vessels) and of thrombosis (formation of clots in the vessels), which decreases fluidity inside the vessels (I).

the phenomena of reticulation touches also other proteins, which leads to the formation of aggregates:

for example, chemical reaction between Old the very reactive ones and certain proteins has miles, which explains the deposits of these proteins in the arterial walls, thickener and more or less blocking intercellular spaces, but also those on the level of the basal membrane, which prevents the intercellular exchanges (II).

the structural modifications on the level of the basal membrane can mask the sites of recognition of the protéoglycanes which control the permeability of the basal blades. Thus, the glycation puts out of order the control of the exchanges between the vessels and the cells (III).
the assembly plurimoléculaire of the basal membrane is disturbed by the glycation, which weakens the latter and thus involves vascular escapes (IV).
the glycation reduces the susceptibility of the hydrolysis of proteins, for example that of collagen constitutive of the basal membranes, which contributes to the irreversible thickening of the basal membranes and thus of intermolecular problems of exchanges (V).
following the connection the Old ones on specific receivers of the macrophages called RAGE (Receptor off Advanced Glycation Endproducts), those secrete chemical messengers, the cytokines, and growth factors, which involves the proliferation of the cells endothéliales and the increased destruction of the protéoglycanes, inducing on the one hand vasoconstriction and thromboses, and on the other hand a vascular hyperpermeability (VI).

In theory, insulin tends to inhibit this receiver and Tumor Necrosis Factor, or TNF, which is a protein secreted by the macrophages to kill out of the cells, tends to activate it.

Stopped channels

To insert here and in place of this page Thus, the glycation in the blood-vessels is one of the persons in charge of the deterioration of the vessels called angiopathy diabetic and vascular ageing.

Glyquée hemoglobin.

HbA1c: a particular glyquée hemoglobin. There exist many alternatives of glyquée hemoglobin, but most representative and most common is HbA1c, also will take we it for example. This term is reserved for the molecules of hemoglobin having a molecule of glucose fixed on the end of one or the two chains β of protein. Thus the alternatives of glyquée hemoglobin can correspond to the difference in nature of the ose, of its site on the chain of hemoglobin, the number of fixed oses…

The glycation of hemoglobin.

Hemoglobin, or Hb, is a protein of short half-life, thus it will undergo the condensation and the rearrangement of Amadori to form an early product of glycation: glyquée hemoglobin. These two stages being dependant on the glycemia, the rate of HbA1c will be more or less important according to the level of the diabetes and the potential reversibility of these products according to the evolution of the glycemia provides us an indicator of the evolution of the diabetes. Thus, by measuring the rate of HbA1c between two dates, one can deduce the evolution from it from the diabetes. Moreover, the lifespan in the organization of Hb glyquée lying between 1 and 2 months, there is habit to analyze the rate of HbA1c per interval from 4 to 8 weeks, thus the glyquées proteins were it during this time interval because the already modified proteins were degraded meanwhile. Thus, the rate of HbA1c constitutes a reflection of the average glycemia from the 4 to 8 weeks preceding proportioning, which constitutes the marker of balance diabetic more at the present time employed.

The role of Hba1c

Is generally used it to evaluate in a retrospective way the effectiveness of a treatment, in complement of proportionings of the instantaneous glycemia carried out daily because the results of such analyzes strongly depend on the recent context glycemic (meal, fast, efforts…) whereas the glycemia is independent of the food mode and the physical exercise, as of the state of fast (even if research showed a light increase in HbA1c with the age and seasonal variations). At the patient diabetic, the goal is to obtain a rate of HbA1c as close as possible to the figures characterizing a good balance of the glycemia. Thus, the value of reference at the healthy subjects is of 6% of Hba1c compared to the concentration of total hemoglobin (glyquées or healthy hemoglobins). In general, it is considered that balance glycemic is correct if the value of HbA1c is lower than 6,5%. However, the interpretation of the results is sometimes delicate, because of many factors can distort the results, the such alternatives of glyquées diabetes and Hb. Thus, these analyzes must be analyzed with clinical and biological factors relative to each patient.

The methods of proportionings specific of HbA1c are extremely simple because they exploit either the physicochemical characteristics of the molecule (chromatography, electrophoresis) or these immunological characteristics, which is very much used at the present time. An immunochemical proportioning consists in pouring the blood sample in a test tube with which the walls are covered with antibody (1+2) binding with part of HbA1c. By emptying the tube one does not recover as well as HbA1c, fixed at the tube via the antibodies (3). Lastly, by pouring another type of specific antibodies which will be fixed one by one on HbA1c (4+5+6) and one can evaluate the precise number by various techniques, one will be able to deduct the number of molecules from HbA1c (7).

To insert here and to replace this text the diagram on proportioning

----- specific antibody of HbA1c fixed at the test tube.

. : HbA1c.

Sample of blood 2nd specific antibody of HbA1c of which one can measure the exact number.

Example: test of a treatment against the diabetes. Let us take an individual reached of diabetes. One makes him a blood test and one gives him drugs to improve his disease. Two months later one remakes a blood test to him, three cases are possible: 1st blood test: rate of HbA1c = X. 2nd blood test:

Rate of HbA1c  X in which case the glycemia increased because HbA 1 increased C.A.: the diabetes worsened and the therapy does not have any effect: it thus should be changed.
Rate of HbA1c = X, thus the therapy goes fairly because the diabetes was stabilized but therefore did not decrease. One can then consider another therapy according to the importance of the diabetes, indeed, if the diabetes is tiny one can be satisfied to block it, whereas if it is very advanced, even while it having stabilized the risks of complications and should be considered another therapy can be large.
Taux of HbA1c <> X thus the therapy is effective and it should be continued.

Note . It should not be believed that glyquée hemoglobin does not have negative effects on the organization. Thus, it was shown that HbA1c had an affinity for oxygen more important than that of Hb what in theory supports the bad distribution of this one in the organization, but the effects remain tiny in vivo.

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