DIABETIC CONSTITUTION, OBESITY, INSULIN
UNIFIED PATHOGENETIC THEORY: FROM DIABETIC AND DYSLIPIDAEMIC
BIOPHYSICAL-SEMEIOTIC CONSTITUTIONS TO TYPE 2 DIABETES.
( Sergio Stagnaro )
The Role of Insulinresistance-hyperinsulinaemia in type 2 Diabetes Mellitus Occurrence. ....... 7
Introduction.
Notoriously, as we referred elsewhere (1, 2, 3) (See in the HONCode web site: www.semeioticabiofisica.it
, Practical Application, Diabetes Mellitus, 6 articles), insulin resistance, impaired glucose tolerance, obesity and type 2 diabetes mellitus, major health problems worldwide, are considered to be closely related (4-10). In fact, fir the first time from the clinical view-point, I demonstrated that type 2 DM can involve exclusively individuals with both biophysical-semeiotic dyslipidemic and diabetic constitutions (3, 17) (See in above-cited web site, “Biophysical-Semeiotic
Constitutions”).
“Type 2 diabetes mellitus is now widely considered to be one possible component within a group of disorders called metabolic syndrome, both classic and “variant”, I described fully in early papers (1, 2, 3). Such as syndrome, also known formerly as dysmetabolic syndrome X, deadly quartet, etc., is formed by some characteristic factors: abdominal obesity, atherogenic dyslipidemia
(elevated triglyceride [TG] levels, small low-density lipoprotein [LDL] particles, low high-density lipoprotein cholesterol [HDL-C] levels), elevated blood pressure, insulin resistance (with or without glucose intolerance), and prothrombotic and only some times, in my experience, proinflammatory states” (1-3, 11-13).
In addition, metabolic syndrome (MS) through insulin resistance (IR), prediabetes (PD), and overt type 2 diabetes mellitus (T2DM), amplifies and accelerates the risk of atherosclerosis with its associated effect on morbidity and mortality.
“The multiple toxicities of this quartet, MS, IR, PD, which can include impaired glucose tolerance (IGT), impaired fasting glucose (IFG), and overt T2DM, result in accelerated atherosclerosis (macrovascular disease), or atheroscleropathy, according to my american friends
MR. Hayden e SC. Tyagi, in addition to microvascular disease” (12, 13).
The aim of this paper is to fully describe the diverse stages, from biophysical-semeiotic dyslipidaemic and diabetic constituions to type 2 diabetes, according to my Unified Pathogenetic
Theory (See in cited web site).
Analysis of early biophysicalsemeiotic Events: “latent” Constitutions.
The factor that play a paramount role in early stage of obesity as well as type 2 diabetes is the association of “ dyslipidaemic biophysical-semeiotic constitution” with or whitout “diabetic constitution” , described elsewhere (14, 17, 18, 24) (See above-cited web site); only subsequently,
after years or decades, in the course of this metabolic disorder, we can observe the permanent elevation of plasma free fatty acid (FFA) and the predominant utilization of lipids by muscles inducing a diminution of glucose uptake and insulin resistance (14), I have illustrated in detail from the biophysical-semeiotic view-point (See in the site, “Diabetes Mellitus, the first three articles).
Certainly, exclusively in presence of both constitutions, hyperinsulinemia-insulin-resistance
(HIR), which is the key phase of metabolic syndrome (in the “variant” form, hepatic insulin receptors sensitivity results typically normal), constitutes the major risk factor for the development of diabetes mellitus, appearing to be a compensatory mechanism that responds to increased levels of circulating glucose.
Now-a-days, thanks to Biophysical Semeiotics , doctor assesses easily at the bed-side the hyperinsulinemia-insulinresistance in a “quantitative” way as well as the different constitutions (1,
2, 3, 18).
Therefore, I consider incomplete, defective, only partially true the statement that people who pass through the phases of excessive adipogenesis (obesity), nuclear peroxisome proliferator activated receptors (PPARs) modulation, insulin resistance, hyperinsulinemia, pancreatic beta cells stress and damage (mainly brought about by ROS) develop type 2 diabetes, leading to progressively decrease of insulin secretion, impaired glucose postprandial and fasting levels (11-14).
Really, the individuals involved by type 2 DM are “always” positive for “diabetic and dyslipidemic” constitutions,
occurred on the base of Congenital Acidosic-Enzyme Metabolic
Histangiopathy-
(CAEMH), as allows me to state a 47 year-long clinical experience (17, 18, 24).
In fact, fasting glucose remain normal as long as insulin hypersecretion can compensate for insulin resistance, and that is possible if Langheran’s islets are well functioning (1-3) (See in the above cited website, Diabetes Mellitus). Exclusively in individuals involved by both diabetic and dyslipidaemic biophysical-semeiotic constitutions , we can observe – before or later in relation to the severity of diabetic constitution – the fall in insulin secretion, leading to hyperglicemia, that occurs, therefore, as a late phenomenon.
As a consequence, we can now fortunately understand the real reason that allows us to separate clinically, in a clear-cut way, the patients with metabolic syndrome in two groups : patients with and without overt diabetes.
In other words, the evolution to overt diabetes is possible exclusively if there are present the two biophysical-semeiotic constitutions , diabetic as well as dyslipidemic . Under only the later condition, there is HIR, an independent severe risk factor of atherosclerosis (15-16), but not diabetes in absence of diabetic constitution, as I referred in above-cited articles in this site.
From the technical view-point, the most correct evaluation of all constitutions (likely every biophysical-semeiotic events, as Oncological Terrain) is that based on the “preconditioning” (1, 2,
20): even in the case of normal data in three first evaluations, I suggest to perform two or better three further assessements.
In healthy, basal value of gastric aspecific reflex latency time ameliorates in the second evaluation, reaching the highest intensity in the third assessement, and persists unchanged subsequently.
On the contrary, in case of “ latent
” biophysical-semeiotic constitution (or of other “latent” pathological situation, as above-mentioned) we observe that the highest, physiological value
(observed in the third evaluation: e.g., 14 sec.: physiological, tipe I preconditioning) more or less quickly appears to be reduced of one point (e.g., from 14 sec to 13 sec.) during further evaluations, allowing both recognizing and quantifying such as singular condition.
Interestingly, the reflex duration plays a pivotal role in rapid recognizing a “latent” pathological condition: in healthy, the reflex lasts less than 4 sec. A duration of 4 sec. or more indicates the presence of “latent” disorder, suggesting to prolonge the preconditioning, as described above.
To demonstrate the practical importance of this knowledge it is sufficient to consider that
“latent” diabetic constituion can thruly provoke type 2 DM, obviously in presence of dyslipdaemic
constitution of different intensity, but exclusively in conseguence of prolonged, multiple, and really intense environmental risk factors.
Metabolic syndrome, classic and “variant”, which follows pre-metabolic one, is a term used to define a patient with 3 or more of 5 risk factors:
1)
2)
3) abdominal obesity and waist circumference for men greater than 102 cm or 40 inches, and for women greater than 88 cm or 35 inches;
elevated triglycerides, defined as equal to or greater than 150 mg/dL;
low HDL cholesterol. Overall for the Adult Treatment Panel (ATP)-III guidelines, low HDL cholesterol is defined as under 40 mg/dL; previously it was
4) under 35 mg/dL (for the purposes of the metabolic syndrome, there are different values for men and women: less than 40 mg/dL; for men and less than 50 mg/dL for women);
elevated blood pressure, defined according to lower values than those usually used to define hypertension: systolic over 130 mmHg or diastolic over 85 mmHg.;
fasting glucose equal to or greater than 110 mg/dL [10,15]. 5)
From biophysical-semeiotic view-point, illustrated in the above-cited articles in former website, one speaks of metabolic syndrome if it is demonstrated a dysequilibrium between the intensity of microcirculatory activity of pancreas, on the one hand, and liver and/or adipose and/or skeletric muscle tissues, on the other hand, during Absorptive as well as Post-absorptive State (See also in the web site www.semeioticabiofisica.it/microangiologia ).
I agree completely, from the clinical biophysical-semeiotic point of view (20) (See in the former web site), with the 2001 ATP III guidelines, which have called specific attention to the importance of targeting the cardiovascular risk factors of the metabolic syndrome as a method of risk reduction therapy (16), however, in the sense also of Single Patient Based Medicine, I have described in detail elsewhere (53) (See above-mentioned web site).
In addition, we have to consider type 2 diabetes mellitus as "cardiovascular disease risk equivalent"; that indicates that patients with type 2 diabetes are considered to have an increased risk, equivalent to those who have established heart disease.
In following, we are going to consider briefly both molecular-biological and microcirculatory, biophysical-semeiotic events, characteristic of diverse stages, from diabetic “and” dyslipidaemic constitutions to type 2 diabetes.
From Dyslipidaemic and Diabetic Constitutions to Pre-Metabolic and
Metabolic Syndromes, classical and “variant”.
In the genesis of the pre-metabolic and metabolic syndrome are included overweight, physical inactivity, and high carbohydrate diet in some individuals in which the carbohydrate intake makes up more than 60% of the total caloric intake.
Beside acquired causes, like these, there are genetic causes, which have not been clearly defined by the authors all around the world, altough from more than two decades I suggested that the Congenital Acidosic Enzyme-Metabolic Histangiopathy-
(CAEMH-
), illustrated in previous articles (21-24) (See above-cited web site), represents the conditio sine qua non of all constitutions and diverse components of metabolic syndrome.
As regards the biophysical-semeiotic and microcirculatory view-point, biophysicalsemeiotic constitutions as well as pre-metabolic syndrome are characterized by microcirculatory activation type II, intermediate, of different intensity of course, also in relation to interstitium size
(small, in absorptive state, and large, in posta-absorptive state), in liver (only in the classical form), skeletal muscle (continuously in absorptive state), central adipose tissue (= intense and prolonged
AL + PL only in vasomotility versus nomal vasomotion) in both absorptive and post-absorptive state.
On the contrary, in healthy, pancreatic vasomotion is at all times comprehensively activated, according to type I, associated, in both vasomotility and vasomotion, during absorptive as well as post-absorptive state: interestingly, such as activation is tipically of type II, intermediate, in case of diabetic constitution.
As a consequence, biophysical-semeiotic preconditioning of above-mentioned biological systems shows the type II, resulting to be of the same intermediate type, as microcirculation activation: i.e., the second evaluation shows a tissue-aspecific gastric reflex latency time (lt) identical to basal one, at this moment normal (24).
In conclusion, in the pre-metabolic syndrome, classic and variant, a part from the wellknown microcirculatory and biophysical situation of liver, the biological systems are in normal condition as regards material-energy-information supply, although at low physiological levels, thanks to increased vasomotility (AL + PL: in vasomotility 8-9 sec., and in vasomotion 6 sec.).
Therefore, basal lt results normal, but preconditioning appears to be of type II, intermediate, showing microcirculatory activation of type II, intermediate, even at rest.
Interestingly, at this point, one must remember the singular “latent” costitution, wherein preconditioning must be repeated five or more times in order to ascertain a slight pathological inherited disorder, as described above.
Under this condition, moreover, molecular-biological metabolic events go on regularly, like
PPARs activity. In fact, from the molecular-biological view-point, our understanding of the metabolic syndrome has been improved by the discovery of nuclear peroxisome proliferator-activated receptors (PPARs) (25-29). However, PPARs are ligand- activated transcription factors belonging to the nuclear receptor superfamily, which also includes the steroid and thyroid hormone receptors.
As transcription factors, PPARs regulate the expression of numerous genes and affect: glycaemic control, lipid metabolism, vascular tone, inflammation. There are currently three known subtypes of PPAR: alpha, delta and gamma (
1 and
2). Activated PPAR-alpha stimulates the expression of genes involved in fatty acid and lipoprotein metabolism. In addition, PPAR-alpha ligands (e.g., bezafibrate and gemfibrozil) also mediate potentially protective changes in the expression of several proteins not involved in lipid metabolism but implicated in the pathogenesis of heart disease.
Activation of the isoform PPAR-gamma improves insulin sensitivity, decreases inflammation, plasma levels of free fatty acids and blood pressure, and consequently leading to inhibition of atherogenesis, improvement of endothelial function and reduction of cardiovascular events.
Interestingly, the thiazolidinedione group of insulin-sensitizing drugs are
PPAR-gamma ligands, and these have beneficial effects on serum lipids in diabetic patients and have also been shown to inhibit the progression of atherosclerosis in animal models, although their efficacy in the prevention of cardiovascular-associated mortality has yet to be determined.
However, there are currently no drugs in clinical use that selectively activate this receptor.
The modulation of the expression of genes by either PPAR alpha or gamma activators, correlates with the relatively tissue-specific distribution of the respective PPARs: PPAR gamma is expressed predominantly in adipose tissues, whereas PPAR alpha in the liver (25-29).
According to the “thrifty gene hypothesis”, individuals living in an environment with an unstable food supply could increase their probability of survival if they could maximize storage of surplus energy, for instance as abdominal fat. Exposing this energy-storing genotype to the abundance of food typical in western societies is detrimental, causing insulin resistance and, subsequently, type 2 diabetes (30) (For further information, See in abovementioned web site: Diabetes Mellitus, three articles).
In addition to PPAR, we have to consider a lot of other so-called thrifty genes, such as those that regulate lipolysis or code for the beta-3-adrenergic receptor, the hormone-sensitive lipase, and lipoprotein lipase. In my opinion, based on a 47-year-long clinical experience, only the hostile association of both diabetic and dyslipidemic biophysical-semeiotic constitutions allows DM to develop, under an affluent environment.
Recently PPAR
revealed to play a primary role in general transcriptional control of numerous cellular processes, with implications in cell cycle control, carcinogenesis, inflammation, atherosclerosis and immunomodulation (28, 29). This widened role of PPAR
will also establish that this receptor has a definite role as a primary link adapting cellular, tissue and whole body homeostasis to energy stores, linking, e.g., obesity to cancer, in presence of
Oncological Terrain.
In summary, dyslipidaemic and diabetic constitutions indicate a slow evolution to premetabolic syndrome, when the difference between vasomotility and vasomotion in pancreas and peripheral tissues, likely central adipose tissue, significantly increases from the values 7 sec. versus
6 sec. to 8 sec. or more versus 6 sec., while the preconditioning is worsening in a clear-cut way: under the first condition lt. value increases only of 1 sec. or persists identical, whereas in premetabolic syndrome decreases slightly.
The Role of oxidative Stress in type 2 Diabetes Onset.
Cellular respiration (electron flux along mitochondrial respiratory chain) allows us to survive on this planet not only at the cellular level but also as an organism. Homeostasis, in the sense of chaos theory, of course, is a key element to all healthy physiologic functions throughout the body and when there is loss of homeostasis, there is usually disease.
“Such as event describes the normal physiologic process of reduction and oxidation in order to re-pair unstable, damaging, reduced, reactive oxygen species (ROS) which will include the following oxygen free radicals (O2' – superoxide, H2O2 – hydrogen peroxide, -OH' hydroxyl radical, and singlet oxygen) and organic analogues which include reactive nitrogen species (RNS) primarily peroxynitrite ONOO' “(12, 13).
This balance between ROS and antioxidant capacity is in contrast to redox stress (redox imbalance) which implies a loss of this unique homeostasis resulting in an excess production of
ROS either through the process of reduction or oxidation.
Oxidative Stress implies a loss of redox homeostasis (imbalance) with an excess of ROS by the singular process of oxidation. Both redox and oxidative stress may be associated with an impairment of antioxidant defensive capacity as well as an overproduction of ROS, evaluated fortunately at the bed-side with the aid of Biophysical Semeiotics (31-38).
It has been known for some time that ROS are detrimental and toxic to cells and tissues as a result of injury to lipids, nucleic acids, and proteins: (A). Lipid peroxidation of membranes (loss of membrane function and increased permeability) and generation of lipid autoperoxidation reactions.
(B). DNA damage leading to mutation and death. (C). Cross linking or vulcanization of sulfhydryl rich proteins (leading to stiff aged proteins specifically collagen of the extracellular matrix) (39).
“The evolutionary process of redox homeostasis allows humans to survive in an atmosphere of high oxygen content. In addition our bodies have become "hard wired" to utilize the mechanism of redox stress injury to fend off invading infectious organisms and survive our environment” (12,
13).
“Paradoxically, as in case of oxidative stress, this protective mechanism turns on our own cells and tissues, and causes damage, especially the intima in the atheroscleropathy associated with
MS, IR, PD, and overt T2DM. This constellation of MS, IR, PD, and T2DM is associated with an elevated tension of redox stress within the intima (also the islet in MS, IR, PD, and T2DM) due to multiple toxicities”, according to M. Hayden (12, 13). Each of these toxicities result in the formation of damaging ROS (40, 41).
Not only are ROS involved in the development of type 1 diabetes mellitus (T1DM) and
T2DM but also play an important role in the long-term development of the associated complications, as atheroscleropathy, angiogenesis (accelerated) and arteriogenesis (impaired), diabetic cardiomyopathy and dermopathy, intimopathy, nephropathy, neuropathy, enteropathy, retinopathy”(12, 13, 40, 41).
The Role of Insulinresistance-hyperinsulinaemia in type 2 Diabetes Mellitus
Occurrence.
IR describes the condition whereby there is a resistance to insulin mediated glucose uptake by cells and is central to the clustering of multiple metabolic abnormalities and clinical syndromes.
The clustering phenomenon was first described by Kylin in 1923 when he described the association of three clinical syndromes: hypertension, hyperglycemia, and hyperuricemia (42).
In 1936 Himsworth (43) noted that a large number of diabetic patients were insulin insensitive and suggested that diabetics be divided into groups that were insulin sensitive and insulin insensitive.
Yalow and colleagues in 1965 (44) were first to discover an insulin assay and reported that
IR was a condition in which insulin does not produce the same glucose lowering effects seen in insulin-sensitive individuals.
These concepts were rejuvenated and immortalized by Reaven in 1988 given as the Banting lecture (45). The clustering phenomenon has gone by many names since Dr. Reaven first described the metabolic and clinical associations of the many names of Syndrome X.
By 1999, the World Health Organization had chosen a unifying definition for this syndrome of many names – without success, I termed it some years ago Reaven’s syndrome (1, 2) – and elected to use the term metabolic syndrome rather than the insulin resistance syndrome because they felt it was not well established that insulin resistance was the cause of all components of the syndrome (46).
As illustrated in earlier papers (1, 2) (See above-cited website), metabolic syndrome is easily recognized clinically, since early stage (i.e., Pre-Metabolic Syndrome or Grey Zone ), by means of
Biophysical Semeiotics. Factors and findings in this syndrome occur together all to frequently to be considered a coincidence and there are common underlying factors that may explain this coexistence. In fact, all components of the syndrome are based on a common inherited mitochondrial cytopathology, I termed as Congenital Acidosic Enzyme-Metabolic Histangiopathy.
Biophysical-Semeiotic data allow me to agree completely with brilliant american scientist
M. Hayden, who states that the well documented hyperinsulinemia and the more recent hyperamylinemia and amylin derived islet amyloid can enlighten type 2 diabetes occurrence (13,
47) (See in my site 6 articles).
Clearly we have today no data on the percentage of people involved by Pre-Metabolic
Syndrome; interestingly, on the other hand, metabolic syndrome affects approximately 47 million or greater Americans (48). In my opinion, since only a part of these individuals are positive for both dyslipidaemic and diabetic constitutions, of these 47 million, only 20% will develop T2DM and the remaining 80% will be able to compensate (at least for a period of time) through the process of beta cell expansion, hypertrophy, and hyperplasia (utilizing the replicative pool of periductal cells) (49,
50).
The resulting hyperinsulinemia, hyperamylinemia (37.6 million = 80% of 47 million) does not come without a price to pay as this compensatory mechanism places these patients at risk for hypertension, atheroscleropathy, and subsequent coronary artery disease (51, 52). Really, the same author ignores biophysical semeiotics, its results, and its developments (= biophysical-semeiotic constitutions), and, therefore, cannot understand neither the real reason which explain the association of these disorders, neither the partial type 2 diabetes occurrence.
In patient with pre-metabolic syndrome, wherein laboratory data are jet in normal ranges, insulin secretion appears to be increasingly enhanced, from biophysical-semeiotics view-point, in relation to underlying disorder severity: latency time of VI thoracic demathomere-pancreatic reflex is always significantly prolonged (NN = 12 sec.), reflex duration pathologically increased, i.e.,
4
sec. (NN < 4 sec., parameter of paramount importance), beside all other biophysical-semeiotic signs of this insulin secretion abnormality (18). Obviously, the intensity of these signs results significantly augmented in metabolic syndrome, in relation to disease seriousness.
(Fur further informaton about both bed-side diagnosing hyperinsulinaemia-insulinresistance and hyperamylinemia, see in the web site www.semeioticabiofisica.it
, Diabetes Mellitus, 6 articles).
Conclusion.
In conclusion, analogously to ROS and Amilyn overproduction, PPARs role in the development of metabolic syndrome, type 2 diabetes and many cardiovascular disorders is certainly of paramount importance, but considering the exsistence of biophysical-semeiotic diabetic and dyslipidemic constitutions , based on CAEM-H, conditio sine qua non of both metabolic syndrome syndrome, classic and “variant”, and the most severe human diseases.
It is now well known that treating metabolic syndrome can prevent or ameliorate cardiovascular disease and type 2 diabetes (54). As I referred often in my articles on DM, the metabolic syndrome is a highly prevalent clinical entity. Therefore, I agree with the authors who suggest that obesity, PPAR modulation and insulin resistance are the central components of this complex syndrome, and diet and physical exercise can prevent a large number of DM (55, 56).
However, all these events can occur only in individuals with diabetic as well as dyslipidemic constitutions , that represent the first stage in the development of all disorders at the base of metabolic syndrome.
As regards the essential fact that the fall in insulin secretion, leading to hyperglicemia, separates patients with metabolic syndrome in two groups, with or without overt diabetes, we have to pay attention to the presence of the above-mentioned biophysical-semeiotic constitutions , associated or isolated, which enlighten the real reason of the two different events.
In fact, the fall in insulin secretion can occur exclusively in patients involved by both constitutions.
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