Diabetic Constitution

Primary Prevention of Diabetes Mellitus Type II (NIDDM)

(From the book, in advanced preparation: “*Semeiotica Biofisica. Microangiologia Clinica* “, with some modifications)

Due to the use of Biophysical Semeiotics in day-to-day practice, in order to diagnose endocrine-metabolic disorders, diabetes mellitus diagnosis has become a “clinical” one, since its really initial stages, i.e. hyperinsulinaemia-insulin resistance and, then, Impaired Glucose Tolerance (IGT), as it is described later on (1, 2, 3, and in the site: www.semeioticabiofisica.it).

Diabetes Mellitus (DM), one of the most common human diseases, particularly in highly developed countries, from the socio-economic view-point, shows a persistent and worrying annual incidence. For instance, although official data are lacking, in Italy there are 2-3 millions of diabetics, with yearly increasing of 6%, including all diabetic types, really different from both aetiopathogenetic and clinical point of view. In fact, DM represents a syndrome, metabolic in origin, very complicated in its aetiopathogenesis, surely genetically based, characterized by relative or absolute insulin-deficiency.

Due to diagnostic failure of traditional physical semeiotics, DM is very often recognized by chance, e.g., in routine blood laboratory examinations, made due to insurance, school, work, sport reasons or in the course of examinations due to numerous other diseases, i.e. events which are nowadays really frequent without any justification.

At this point, it is important to say that the assessment of glycemia of a patient on an empty stomach as well as urine examination early in the morning are frequently misleading (2, 3); certainly post-prandial glycemia provides more informations (2-3 h. after the meal). In fact, in our opinion, Glycemology, which is now a science largely spread all over the world, due particularly to economic reasons, has to be considered a part from Clinical Diabetology, less known around the world and, first of all, cause of great responsibility for doctor, but also of greatest satisfaction.

We absolutely neglect the first discipline. On the contrary, we consider exclusively the later, mainly as regards diabetic constitution, whose knowledge is essential in DM “primary” prevention.

Glycemic blood level and diabetic complications: a relation until now to be determined.

All around the world, there is not general agreement among the authors about the relation between the increase of glycemic blood-level and increase of diabetic complications, accepted mainly by the authors (4), particularly over the last decades. In fact, other authors did not observe amelioration of diabetic complications because of decreasing high glycemic blood-levels (5).

On the other hand, it is notoriously difficult to maintain in the normal ranges the value of glycemia in diabetics, since episodes of dangerous hypoglycemia occur really frequently.

In the above-mentioned research, the decrease of glycosilated hemoglobin of 1% was not followed by deads reduction of 21%, as maintain other researchers. The death-rate of diabetics intensively treated appeared to be not statistically significant, underlining the lack of positive results with the aid of this treatment.

In other words, hyperglycemia seems to be not the “actual” cause, but an aggravating cause. Therefore, doctors might pay all attention at other factors (11), as hypertension, for instance, since decreasing hyperglycemia by itself has little or no value in preventing well-known complications of DM (5).

Analyzing this important relation between high glycemic blood concentrations and diabetic complications is really interesting, as regards its influences on the real value of “clinical” and “quantitative” evaluation of the various initial phases of DM, including obviously the diabetic constitution, by using Biophysical Semeiotics, which fortunately allows doctor to go beyond the mere glycemic level.

We are very delighted remembering, without any possibility of confutation, that over the last two-three decades the authors reproached us for not having admitted the high glycemic concentration as “primary” and “direct” cause of organ damage. Nowadays, at least, authors suspect that the relation between diabetes and hyperglycemia – assessed as glycosilated hemoglobin – on the one hand, and, heart-vascular diseases, on the other hand, has not yet been solved. In other words, nowadays the authors doubt the statements, which appeared as truth until ’80 years.

At this point, interesting are the data, referred above, about beneficial results obtained with metformin therapy (this drug ameliorates insulin receptors sensitivity) a part from decreasing glycemic blood level.

In a few words, in these years authors speak abundantly of hyperinsulinaemia-insulin resistance, that is a “clinical” diagnosis with the aid of Biophysical Semeiotics (3), as a “cause” of macro- and micro-vascular disorders.

The old discussion on the real nature of the relation between DM and hyperglycemia, on the one hand, and heart-angiopathies, on the other hand, has not probably until now solved by UKPDS Study. However, as allows us to state a 45 years- long clinical experience, the fact that diabetic patients, with glycemic blood levels higher than the average diabetic patients, do not present the most severe complications, which really are observed also in patients whose glycemia is light elevated, the positive results of statins, ACE-inhibitors and sartans in secondary prevention, and, ultimately, the results of anthypertensive drugs in primary prevention of diabetic complications ought to remember all of us to think deeper, since, although the discussion could seem academic, it really urges us to find new, original pathways of primary prevention and ameliorate DM definition, especially in initial stage and particularly in the phase of diabetic constitution.

To conclude this necessary introduction, we think that DM is somewhat very different from the “simple” pathological increasing of glycemia and that it is possible now recognize since birth-day individuals at “real” risk of this metabolic disorder, conditio sine qua non for the “primary” prevention of type 2 DM (NIDDM) and consequently of its dangerous complications.

Due to these reasons, deeply illustrated and discussed later on, we differentiate the science, a large number of doctors practise at beginning of third millennium, i.e. glycemology, in which we are not concerned, from the clinical diabetology (1, 2, 3, and the site, cited above).

Some preliminary considerations, useful in biophysical-semeiotic diagnosis of diabetic constitution and diabetes mellitus.

Before learning biophysical semeiotic diagnosis of both diabetic constitution and diabetic syndrome, in our opinion, the readers must pay all attention to our former researches, we carried out over the last three decades, which allow us to state that the very initial stage of whatever “degenerative” disorders begins really as microcirculatory modifications, both functional and structural, particularly at the level of Endoarterial Blocking Devices (EBD) of related biological system, that in the course of years will be involved by the disease itself (1, 2, 3).

In addition, these microcirculatory alterations, well localized in a gland, apparatus, organ, only apparently “healthy”, can be evaluated at the bed-side in a “quantitative” manner, permitting thus the therapeutic monitoring of interesting pre-pathological conditions, characterizing the “gray zone”, the real site and moment of “primary” prevention, located between the “white zone” (physiology) and the “blach zone” (pathology).

In other words, as we formerly described, as regards biophysical semeiotic constitutions (See above-cited site, Page Constitutions; “Oncological Terrain”; and www.Staibene.it, November 2001; www.Piazzetta.sfera.it, Cose Serie, Professione Medica), interestingly, genetic factor reveals in both parechymal and related microangiological level, allowing doctor nowadays to assess this pathological symptomless condition, starting from the first decade of individual life.

As far as DM is concerned, from technical biophysical-semeitoc view-point, it is necessary to remember that the “mean” intensity stimulation of trigger-points of VI thoracic dematomere – in practice, the skin of epigastrium immediately below costal arch at right and/or at left, about 5 cm. away from sternal angle, where are localized the pancreatic trigger-points – brings about pancreatic-“middle” urethral reflex, which permits the assessment of both structure and function of Endoarterial Blocking Devices (EBD), located in pancreatic small arterioles and arterioles, according to Hammersen: in individuals involved by diabetic constitution and in those with “real” diabetic risk, in IGT-subjects, and, of course, in “all” diabetic patients, such microcirculatory structures show abnormalities since birth-day, revealing alterations of different severity, varying from patient to patient: “middle” urethral reflex lasts for < 20 sec. (NN = 20 sec.) and then disappears for > 6 sec. (NN = 6 sec.), indicating a shorter opening and a prolonged closure of EBD, and consequently reduced capillary-venular blood-flow in Langheran’s islets (Fig. 1).

In our case, in fact, EBD show opening duration (= duration of the “middle” urethral reflex) < 20 sec. (NN = 20 sec.) and/or closure duration (= duration of the reflex disappearance) more than 6 sec. (physiological value), which becomes particularly intense during stress tests, as the test of two pressures, which is easy to perform also by physician with scarce experience in Biophysical Semeiotics: firstly, doctor has to evaluate the diverse reflex parameters during stimulation of pancreatic trigger-points, illustrated above, by a lasting pinch of “mean” intensity. Then, after an interval of at least 10 sec., he assesses for the second time the identical parameters during “intense” stimulation, that activates physiologically the pancreatic microvessels, bringing about, speaking technically, according to Clinical Microangiology terms, associated microcirculatory activation, type I [ = small arteries and arterioles as well as capillaries and venules oscillate maximally: in practice, upper urethral reflex and, respectively, the lower one fluctuate 6 time per minute with “maximal” intensity, 1,5 cm., lasting the highest opening, 7-8 sec. (NN “basal” value = 6 sec.)]

In subjects at “real” risk of diabetes mellitus, the duration of EBD opening does not modify (NN > 20 sec.) or ameliorates in a not statistically significant manner, while the duration of closure does not become shorter (NN < 6 sec.). These very interesting EBD modifications, caused by diverse stress, aim to increase the blood supply to the histangium of pancreatic isles, thus providing pancreatic isles with matter-energy-information, and, obviously, they play a major role in the activation of the Functional Microcirculatory Reserve (FMR).

Interestingly, a further tool of assessing local FMR, always present in healthy tissue, is the biophysical semeiotic preconditioning (See later on), easy to perform, especially by doctor with poor experience in the new physical semeiotics.

To summarize this essential aspect of Clinical Microangiology, Biophysical Semeiotics allow doctor to recognize, starting from the first decade of life, in easy, quick, and reliable manner, initial EBD dysfunction of whatever biological systems, indicating a defective activation of MFR and, therefore, the “real” risk for the localized disorder, permitting, thus, to perform the primary prevention, in our case, of type 2 diabetes mellitus or NIDDM.

Obviously, the results, referred above, regarding endocrine pancreas, are the same we obtain from every tissue-microvascular-unit, i.e. to EBD of whatever biological system, in both physiological and pathological conditions.

For instance, let’s think over the dysfunction of coronary EBD in healthy individuals, but at “real” risk of coronary disease, as well as the dysfunction of ocular EBD in children of glaucomatous patients.

For these reasons, since a long time, we had foreseen and foretold the origin of a new branch of Clinical Microangiology, exclusively devoted to the study of EBD alterations, both congenital and acquired, by means of original physical semeiotic methods, with favorable influence on primary prevention and diagnosis.

We suggested to term this discipline Clinical Microangiology of Endoaerterial Blocking Devices.

Biophysical-semeiotic signs and syndromes of diabetic constitution and diabetes mellitus.

In diagnosing diabetic constitution and diabetes mellitus, doctor must ascertain the Congenital Acidosic Enzyme-Metabolic Histangiopathy (CAEMH) – a , since this mitochondrial cytopathology represents the conditio sine qua non of type I and II DM, and of commonest human diseases (1, 6, 11).

Briefly, to recognize CAMH in easiest manner, doctor must perform the following maneuver: digital pressure applied upon the right side of skull (= trigger-points of right cerebral hemisphere), of an individual lying down in supine position and pscho-physically relaxed, provokes a gastric aspecific reflex, after a latency time (lt) of 6 sec. (NN = 7-8 sec., in age-dependent manner), more intense of that caused, under identical condition, when doctor stimulates the trigger-points of left cerebral hemisphere, whose lt results 7 sec. (NN = 7-8 sec.) (Fig. 3).

In following, some interesting biophysical semeiotic parameters, easily and quickly observed, are illustrated; they are useful in bed-side diagnosing DM, starting from its very initial stages, including diabetic constitution.

However, the doctor can diagnose, in a “quantitative” manner, the various phases of diabetic syndrome at the bed-side by numerous other methods, more refined, sophisticated and reliable, clinical-microangiologic in nature, as the reader, whose knowledge of this new semeiotics is steady, understands surely.

1) VI thoracic dermatomere-gastric aspecific reflex (Fig. 2 and 3).

Cutaneous, prolonged pinching, of “mean-intense” intensity, of pancreatic trigger-points, i.e. VI-VII thoracic dermatomeres (as above referred, at the level of cutaneous crossing of hemiclavicular line and/or para-sternal one and costal arch, at right or at left), in healthy, after latency time of 12 sec. exactly, brings about gastric aspecific reflex of intensity < 2 cm., which lasts for £ 4 sec. and then disappears for > 3 sec. < 4 sec.: i.e. fractal dimension (fD) 3,81 (See above-cited site, Technical Pages, in which auscultatory percussion of both pancreas and stomach is fully described).

Three parameters of this fundamental reflex, well-known to doctor who has steady knowledge of the original semeiotics, play a primary role in the application of Biophysical Semeiotics.

Fig. 2: Physiologically, cutaneous, persistent pinching of VI (VII) thoracic dermatomere, illustrated above, brings about, simultaneously with previous reflex, increasing of pancreatic size (volume) – in practice, low pancreatic margin lowers – after latency time Fig 2:VI thoracic dematomere-pancreatic reflex. (lt) of 2 sec. for a duration of 10 sec. exactly (Fig. 2). It is noteworthy that this value (2 sec. + 10 sec.) is the same of the former reflex parameter (NN = 12 sec.), indicating histangium acidosis, and outlining the internal as well as external coherence of biophysical semeiotic theory.

Fig. 3: Cutaneous pinching, prolonged and “mean-intense”, at the level of pancreatic trigger-points (i.e. VI-VII thoracic dermatomeres. See above), after a lt. of 12 sec., physiologically provokes also the caecal reflex (caecum dilates: Fig. 4) for a duration of about £ 4

sec., followed by its disappearing, after a “differential” latency time of > 3 sec. > 4 sec.: fD = 3,81.
Once more the diverse values of numerous parameters outline the internal and external coherence of biophysical semeiotic theory, conditio sine qua non of the scientific truth, although really it does not coincide with the second.

4) Bilancini-Lucchi’s sign. In healthy, both digital or manual pressure of “light” intensity, applied upon the internal side of an arm (= specific occlusion of lymphatic superficial vessels), after lt. of about 6 sec., brings about the gastric aspecific reflex (Fig. 3), which increases again after further 3-4 sec. (7) (Fig. 2). An interesting “variant” of this sign is the manual pression on lymphatic vessels at the base of breast quadrants, e.g. external upper breast quadrant, which causes gastric aspecific reflex, showing identical parameters. Really, these two signs are based on identical patho-physiological mechanism, whose discussion is beyond the aim of this paper.

 

In case of DM, lt. of the first reflex is characteristically only 3-4 sec. (NN = 6 sec.). Moreover, the “slow and progressive” increasing of gastric aspecific reflex persists for 3-4 sec. (NN = 2 sec.). At this point, we would like to outline this characteristic behaviour , i.e. slow and continuous “ascending” of gastric aspecific reflex, that parallels the behaviour of the same reflex, which takes part at “diabetic diagram of tissue micro-vascular unit” of the finger-pulp (See later on).

Our insistence on underscoring the coincidence of data, regarding the “same” event, gathered by different methods and observations, apparently repeated over and over again, and perhaps unpleasant to reader, aims to show the coherence of every part of the discussion about the theories of Biophysical Semeiotics and, consequently, of Clinical Microangiology, the later originated by the essential clinical method of investigation.

In IGT and type I and II DM, A phase, i.e. gastric aspecific reflex after lt < 6 sec. in lymphatic diagram, i.e., Bilancini-Lucchi’s sign, is delimited by a characteristic “ascending” line, rather than 6 sec. horizontal one, as in healthy. The underlying patho-physiological mechanism of this abnormal pattern of lymphatic diagram is really complex. In fact, this particular behaviour –A phase “ascending” line – is related to diabetic histangiopathy, present “ab initio”, when there is alterations of venous-arteriolar reflex (VAR), about which all authors agree.

Upon the abnormalities of VAR is based the test of two pressures or differential pressures test (DPT) as well as the biophysical-semeiotic preconditioning. The later tool allows to show, in easy and practical way, the diabetic constitution: Bilancini-Lucchi’s sign, normal (lt 6 sec.) when evaluated at rest – basal line – results not modified and of identical duration, after the second assessment, performed soon after an interval of 5 sec. exactly from the basal evaluation: in healthy, on the contrary, lt of the reflex increases from 6 sec. to ≥ 8 sec.: physiological preconditioning.

To summarize, biophysical-semeiotics “quantitative” evaluation of diabetic constitution can be performed, in the easiest manner, as follows: at first, doctor assesses, at rest, the diverse parameters of pancreatic-gastric aspecific and/or caecal reflexes. In practice, it is sufficient to evaluate the basal lt. (NN: lt = 12 sec.). After an interval of exact 5 sec. – pancreatic preconditioning – doctor performs the second “quantitative evaluation: in presence of diabetic constitution lt either results the same, e.g. 12 sec., or even shorter, in relation to the severity of diabetic “real” risk, while in healthy increases to ≥ 14 sec.

As regards the diagnosis of type 2 DM, the biophysical-semeiotic evaluation of pancreatic amyloid proved to be reliable and useful at the bed-side.

(See www.semeioticabiofisica.it; and http://digilander.libero/Piazzetta.sfera.it, Cose Serie, Professione Medica).

Diabetic Microangiopathy in “pre-diabetic” stages.

In order to understand what follows, doctor needs the mere knowledge of stomach auscultatory percussion and gastric aspecific reflex, described above.

Bed-side examination of microcirculatory bed, e.g. of finger-pulp, in both diabetic constitution and Impaired Glucose Tolerance (IGT) gives noteworthy diagnostic information. Particularly interesting is the diagram of tissue microvascular unit, obtained in a refined and reliable way, due to its clinical information (Fig.4).

Really, the evaluation of tissue microvascular unit diagram is so full of data, useful in both bed-side diagnosis and differential diagnosis, that all physicians must know it, so that the analysis of tissue microvascular unit diagram would become an essential component of common clinical examination.

Figure 5 is a diagram of tissue microvascular unit of finger-pulp of a patient involved by Impaired Glucose Tolerance Digital pressure of mean intensity, applied upon a finger-pulp of a patient, psycho-physically relaxed and in supine position, brings about the gastric aspecific reflex, followed by three further increasing, and ultimately by tGC and a last gastric aspecific reflex or Z wave, related to local microcirculation metabolic events, and tissue pH. Fig. 5 ( For further information, See the text). In Fig. 4, latency time less than 6 sec., i.e. physiological value, indicates characteristically aspecific histangium suffering; this lt is inversely proportional to the severity of the underlying disorder and directly related with tissue acidosis (= lt of caecal and/or gastric aspecific reflex).

Apnea test (= the subject does not take breath for 5 sec.) normalizes transitorily latency time and causes disappearing of Dilation Area (DA), which, in healthy, is £ 1 cm., in an age-dependent manner: sympathetic hypertonus brings about increasing of resistance vessels tonus, demonstrating that the damage of initial phase, is mainly functional in origin, according to Ditzel’s functional diabetic microangiopathy.

In fact, in the “initial, functional” stage, venous arteriolar reflex (VAR) is still present (= lt of caecal-finger-pulp reflex is the same during the “test of three positions”).

Actually, for the time being, due to hyperinsulinemia-insulin resistance, microvessels are abnormally dilated showing a moderate, small basal membrane thickening and light increase of PAS-positive material. Interestingly, the urethral interstitial reflex, i.e. “in toto” urethral reflex, results greater than normal (NN £ 1 cm.), because of amyloid storage, already present in this stage, revealing the possibility of diagnosing DM type II in a refined manner (See DM, in the site and Piazzetta).

The “slow” raising of Ascending Line (AL) in A Phase, caused by increasing of interstitial space as well as thickening of arteriolar basal membrane, altered since very initial stage of diabetic syndrome, which oppose to vasomotility and vasomotion (= microvessels movements of arterioles and little arteries and, respectively, capillaries and post-capillaries venules) can be correctly interpreted in its patho-physiological mechanisms, even observing the behaviour of upper third urethral reflex (= interstitium of arterioles): during the first 6 sec., “in toto” urethral reflex appears “slowly” , with an intensity > 1 cm., and a “slow” reflex-increasing follows (= “slow”, slanting, oblique line, i.e. AL of A Phase, of which, however, exists still an horizontal, normal, tract, never present in overt DM: Fig. 4).

At this point, we have to remember interstitium typical behaviour, that is now really large.

Consequently, the characteristic A Phase of “initial” diabetic microvascular-tissue-unit diagram, and especially that of overt DM, is related to the situation of fundamental matrix as well as the entire interstitium, and the alteration progressively more severe of the small arterioles and arterioles wall, as we demonstrated clinically (1-4, 6).

All other parameters values are in normal ranges: “Critic Acidosis Point” (PC) – intensity of 5 cm. – is present – individual 30 years old – although it is localized in D Phase, without being exceeded, indicating the absence of pathological events at the base of diagram verticalization with shifting to the left, technically speaking.

Interestingly, the “slow” achievement of tGC (= stomach contraction) and its rapid disappearing (2 sec.), when digital pressure on patient’s finger-pulp has been withdrawn, as well as the presence of Z wave, indicating physiological capillaries elasticity (normal capillary structure), all corroborate our interpretation about the positive influence of apnea test on diagram pattern.

Of course, in absence of a correct diet, ethimologically speaking, patients immediately have to undergo, in following months or years, the apnea test will result abnormal, and local microcirculation will be worsened.

From the practical point of view, in fact, the correct diet and, if necessary, histangioprotective drugs (Co Q10, Carnitine, Bioflavonoids, a.s.o.) normalize IGT diagram abnormalities in almost all cases.

Nowadays, authors do not agree about the definition of little vessels alterations in the “pre-diabetic” stages (8). Some authors think that basal membrane thickening, initially small from biophysical semeiotic view-point, involves exclusively individuals particularly predisposed. Arterioles sclerosis, described by Butturini in digitals biopsies of obese subjects involved by “latent” diabetes (9), concerns more advanced stages of the disorder than those we consider, as demonstrates the temporary normalization of diagram, caused by apnea test as well as by venous-lympho-manual drainage. Therefore, Biophysical Semeiotics allows doctor to recognize the diabetic constitution in a “quantitative” manner.

As regards both glomical Arterio-Venous Anastomoses (AVA) and Endoarterial Blocking Devices (EBD), we can observe alterations similar to those described above, characterized by prolonged closure and shorter opening, which cause consequently insufficient blood-flow in local microvessels, at this moment at least, really counter-balanced successfully by microcirculatory activation, type III, incomplete. In a few words, arterioles and little arteries fluctuations are actually “intense”, but local capillaries and venules oscillation are “normal”.

In fact, the physiological temporal inhomogeneity is not present, and doctor can observe the above-illustrated microcirculatory activation, which represents the “zero stage” of the so-called pathological spatial inhomogeneity.

At this moment, arteriolar sphygmicity (= third upper urethral reflex oscillations) increases clearly with subsequent increasing of interstitial and venular capillaries dynamics, where fractal dimension appears reduced, indicating the activation of Functional Microcirculatory Reserve (FMR) already at rest.

At this point, it seems very interesting that the second and third diagram evaluation, performed after exactly 5 sec. interval (preconditioning), results physiological, indicating the mainly functional nature of described alterations (Fig. 4).

The interstitium (= “in toto” urethral reflex, which is carried out slowly), since initials stages of DM, is > 1 cm. – pathological sign – outlining the enlargement of this perivasal space (NN £ 1 cm.), partially due to increasing of capillaries and arterioles permeability. In initial phases, manual lymphatic drainage as well as apnea test (= sympathetic hypertonus) normalize temporarily these modified parameters values of IGT tissue-microvascular diagram, proving the primary role on vasomotion, played by the interstitium.

The modification of venous-vasomotor reflex – evaluated clinically as latency time of finger-pulp gastric aspecific or caecal reflex during “3 posture test” (in healthy lt appears always identical: 8 sec.) – occurs mainly precociously, when light, but present, organic, structural lesions occur or worsen.

An easy, but refined, method, useful in recognizing venous-arteriolar reflex (VAR) is the following: “intense” digital pressure upon a finger-pulp of an individual, lying down in supine position and psycho-physically relaxed, brings about physiologically disappearing of upper urethral reflex (type II, group B, AVA) when the arm is in high position, i.e. perpendicular to the bed: FMR promptly activated and realized, as type II, group B, AVA closure clearly demonstrates.

These clinical microangiological data agree perfectly with the demonstration of remarkable structural alterations of type II, group B, AVA, according to Bucciante, in case of obesity in individuals with glucose utilization in normal ranges. There are some modifications especially of intermediate glomic segment, which bring about hyperstomy, while local capillaries basal membrane only occasionally is well outlined by PAS (8).

It seems, therefore, also from biophysical-semeiotic vie-point, that in “latent” DM the first alterations are localized in myoepithelioid segments of glomic AVA, rather than in capillaries and arterioles (8). Therefore, Biophysical Semeiotics corroborates, once again, Curri’s statements. More precisely, in our mind, the original semeiotics complete really Curri’s bioptic data, emphasizing the simultaneous modifications of EBD, we observed in a long well established experience, starting from the very initial phase, i.e. diabetic constitution.

Clearly, not completely differentiated cells, as myoblasts of both myoepthelioid media and EBD muscular cells, are apparently more sensitive to dysmetabolic noxae – and, we add, to mitochondrial disorders (CAEMH– a ), always present, representing the conditio sine qua non “also” of DM – than all other differentiated muscular cells, which notoriously contract for a shorter time and dilate more rapidly, showing the physiological, periodic break of their diastolic-systolic movements (temporal inhomogeneity).

A further and important fact, thus, is the demonstration in IGT with insulin hyper-secretion (in which pancreatic preconditioning appears to be pathological and lt. of pancreatic-gastric aspecific reflex is > 12 sec. – physiological value –, due to insulin hypersecretion) of initial asynergy of derivative structures, premise of histangic suffering: arterioles contraction happens when EBD are only partially “open” and AVA (strictly speaking) are maximally open, causing blood-reflux towards capillaries-venules, bringing about local endoluminal pressure increasing and consequently histangium damage (lower urethral reflex results “intense”).

In conclusion, as regards the pancreatic interstititum of “pre-diabetic” phase, it is larger than normal (> 1 cm.), due to amyloid storage, and likely to free-water prevalence, indicating impairment of interstitial matrix, although initial and light (e.g., manual lymphoid drainage provokes disappearing of such alteration), in agreement with data of other authors on precocious glucosaminoglycanes (GAG) modifications of fundamental connectival substance, and then of the differentiation ability of cells, mesenchymal in origin, especially as regards the fibroblasts activity, as well as myoblasts metabolism (8).

In this stage, there are likely altered relations between local cytokines, particularly TGF b 1, 2, 3 , with their well-known negative influences on the local microcirculation (10).

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