THE DYSMETABOLIC SY DROME – DEFI ITIO , HISTORY, COMPO E TS
Dr. icoleta Milici The Institute of Anthropology „Francisc I. Rainer”
Abstract
Some researchers tend to think of the group of researchers from OMS (the group dysmetabolic syndrome as being the most being concerned with studying diabetes). It important medical problem of the 21st century made precise the fact that the syndrome is beginning. defined by the presence of type II diabetes The dysmetabolic syndrome is rather mellitus or the altered tolerance to glucose difficult to estimate because of the numerous combined with at least 2 other factors existing points of view regarding the elements (hypertension, increased level of blood lipids, needed for the diagnosis. obesity and microalbuminuria). It isn’t about a singular disease, but an Starting with that first definition (initial association of impairments that can appear one) of the metabolic syndrome a range of simultaneously or gradually in the same alternative definitions was suggested. The individual, caused by associating the genetic most widely accepted definition was and environmental factors (+ lifestyle) with formulated by EGIR (European Group for the the insulin resistance, considered as the Study of Insulin Resistance) and NCEP (USA fundamental pathogenic component. National Cholesterol Education Panel). The first definition of the metabolic syndrome (MS) was formulated in 1998 by a
beginning. Recent studies showed the epidemic proportions that this affection Introduction reached worldwide (global numbers show a Such a great interest taken in this theme prevalence of 20 25%). The diagnosis, starts from the increased prevalence of the clinical evaluation and efficient treatment of metabolic syndrome and its association with a such a big number of patients are heavily decreasing hope for a longer lifespan, trying the public health systems. On the other especially by the increasing of the side, the delaying in curing the dysmetabolic cardiovascular mortality, the increasing of syndrome leads to an increasing of the diabetes, myocardial infarction and cardiovascular diseases and type II diabetes cerebrovascular disease risk. incidence, with disastrous consequences over Some researchers tend to think of the the human society. It is estimated that, in dysmetabolic syndrome as being the most 2020, approximately 2/3 of the world important medical problem of the 21 st century morbidity will be due to the non transmissible confirmed diseases. Passing to a food that is rich in refined products, food of (altered tolerance to glucose/ type 2 diabetes animal origin and fats plays an important part mellitus), the protein metabolism in the worldwide epidemics of obesity, (hyperuricemia), as well as the arterial diabetes mellitus and cardiovascular diseases hypertension (a hemodynamic disturbance (non – transmissible confirmed diseases). having a metabolic starting point) (2). Unfortunately, the obesity generating media, amplified by the number of cultural Terminology modifications associated with globalization, make it increasingly difficult to adopt a The term “syndrome” derives from the healthy lifestyle, especially among children Greek word sundromos (sun syn + dromos= a and teenagers (1). fugi) and it means “to run together” . The dysmetabolic syndrome is rather The dysmetabolic syndrome was diversely difficult to estimate because of the numerous named in time: the plurimetabolic syndrome, existing points of view regarding the elements the X syndrome, the X plus syndrome, the X needed for the diagnosis. It isn’t about a metabolic syndrome, the cardiovascular singular disease, but an association of metabolic syndrome, the insulin resistance – impairments that can appear simultaneously or dislipidemia syndrome, the atherogenic gradually in the same individual, caused by metabolic syndrome, the syndrome of associating the genetic and environmental atherogenic factors’ agglomeration, the deadly factors (+ lifestyle) with the insulin quartet). Recently, there was used the MetS resistance, considered as the fundamental acronym as replacing the term of Metabolic pathogenic component. The modern lifestyle, Syndrome. which is stressful, always in a rush after Out of the numerous terms suggested to success and fortune, associates the define this nosologic entity, the World Health hyperglucid/hyperlipid food with the Organization (OMS) –(WHO), the sedentariness promoted by the comfort of the International Diabetes Federation (IDF) and contemporary civilization. other international bodies agreed upon the term “metabolic syndrome”. Nevertheless, Definition from a semantical point of view, this term is not correct; let’s not forget that the According to the encyclopedic dictionary metabolism per se represents a natural of the Romanian language the term phenomenon. Thus, if we refer to its “syndrome” = group of signs and symptoms dysfunction, it would be logical to call it that appear together during a pathological “dysmetabolic” (ex.: we call the disturbance process, giving it the characteristic note. of the lipid metabolism “dyslipidemia”, not The dysmetabolic syndrome expresses a “lipidemia”). complex disturbance of the genetic metabolism of the organism, including disturbances of the lipid metabolism (obesity, dyslipidemia), the carbohydrate metabolism
Jurnalul Român de Diabet. utriţie i Boli Metabolice / Vol. 14 / nr. 2 /2007 2 History diseases. From the point of view of the school from Cluj, the atherosclerosis is represented As early as 250 years ago, long before the by a complex disturbance of the metabolism, MS description, the Italian physician and vaso – motility, coagulation, hydro anatomist Morgagni identified the association electrolytic and mineral equilibrium (8). between visceral obesity, HTA (arterial The cardiologists were the first to notice hypertension), atherosclerosis, the high levels the connection between the major disturbances of uric acid in the blood and the frequent of the dysmetabolic syndrome. Making an respiratory disorders during sleep (the inventory of the risk factors for the coronary obstructive apnea) (4). diseases, alongside with HTA they recorded In 1920, Nicolae Paulescu, speaking about dyslipidemia (hypercholesterolemia/hypertri obesity and diabetes, said that “most glyceridaemi) obesity, diabetes and hyperuri frequently, the obese people become caemia, as well as food factors, the sedentary glycosuric, as if the two affections (obesity lifestyle, environment factors, psychosocial and fat diabetes) represent two consequent factors, etc. phases of the same pathological process” (5). Towards the end of the 80’s, the assembly In 1927, Maranon, the founder of modern of glucose, insulin metabolism disorders, endocrinology in Spain, explicitly described obesity, dyslipidemia and HTA received the the fact that the arterial hypertension is a pre mysterious name of “X syndrome”. In 1988, diabetical stage and this concept is similarly Reaven G., an endocrinologist physician from applied to obesity. Maranon also underlined Stanford University, was the one who took a the fact that food is essential for preventing big stride forwards, interpreting the and treating these disturbances (4). association of diabetes, obesity, dyslipidemia th At the middle of the 20 century (1947), and arterial hypertension by their pathogenic Vague, a French physician, was the first to relationship with the peripheral insulin identify android obesity (adiposity of the resistance. He named this association “X superior part of the body) as being the syndrome”, the name underlining the condition the most frequently associated with doubtfulness that accompanied the emitting of diabetes mellitus (Dz) and cardiovascular the apparently new concept (9). The insulin diseases. resistance and the compensatory The often simultaneous presence of hyperinsulinism were associated with each obesity, the high level of blood lipids, diabetes component of the dysmetabolic syndrome, mellitus and HTA (arterial hypertension) was offering thus a physio pathological first mentioned under the name of connection between them. Continuing this plurimetabolical syndrome in the 60’s. logical chain, one can naturally reach the In the 70’s, Moga, Orha, Haragus (6,7) conclusion that the dysmetabolical syndrome from Cluj supported the idea of the existence represents a complex disturbance of the of a close connection among the components energetic metabolism, in close connection that constitute the dysmetabolic syndrome at with the insulin secretion altering, influenced present, correlating them to the cardiovascular
Jurnalul Român de Diabet. utriţie i Boli Metabolice / Vol. 14 / nr. 2 /2007 3 in its turn by the sensitivity/resistance to In 1998, the first definition of the insulin (2). metabolic syndrome (MS) was formulated by Ferranini and collab. resumed this idea, a group of researchers from OMS (the group confirming that this assembly of disturbances being concerned with studying diabetes) One is provoked by the insulin – resistance and, year later, the OMS definition was after several years, they called it the “insulin – accompanied by a criteria list meant to the resistance syndrome” (4). clinical diagnosis. It made precise the fact that Afterwards, it was found out that the the syndrome is defined by the presence of spectrum of metabolic disturbances is larger. type II diabetes mellitus or the altered Zimmet and Serjentson (10) speak about the tolerance to glucose combined with at least 2 “plus X syndrome” signaling the association other factors (HTA, increased level of blood with hyperuricaemia, sedentariness and old lipids, obesity and microalbuminuria). age. The X syndrome generates high degrees The term dysmetabolic syndrome of free radicals, which are harmful to the cell, corresponds better to the biochemical reality. causing a premature aging. Vladimir Dilman, It is envisaged an increase of the biochemical coauthor to the paper “The Neuroendocrine disturbance number that can be identified. Theory of Aging” refers to the insulin – resistance as being a pathology connected to Data about the dysmetabolic age. The blood glucose level tends to increase syndrome prevalence with age, accelerating aging by connection to proteins (11). During mid 70’s, the biologist Current estimations show that, in the Anthony Cerami discovered the fact that the USA, almost 1 out of 4 adults have, at present, chronically increased glucose levels represent the dysmetabolic syndrome (MS) and the the main trigger in the chemical process of prevalence is increasing (13); even more manufacturing the final glycolsylation alarming are the reports that show an ever products (AGE = Advanced Glycosylation increasing number of obese children who are End). AGE are involved in the processes of going to advance MS until they are 20 (14). normal and accelerated aging, by chemical The most documented data about the reactions between glucose and molecular prevalence of the dysmetabolic syndrome are proteins, producing serious damages at the the ones coming from NHANES III (National level of cellular membranes and collagen Health And Nutrition Examination Survey III, fibers (12). USA) (13). According to these data, in the The appearance of the metabolic USA, the prevalence of the dysmetabolic syndrome notion was due to the fact that, syndrome is 23 – 24%, but with higher more often than not, the risk factors associate variations of this percentage depending on for the same individual. This suggests that, on age, ethnical group or race. Thus, the the one side, there is possible a common prevalence of MS is <10% between 20 29 etiopathogeny, and, on the other side, it was years of age, 20% between 40 49 years of age considered that it offers a better capacity to and 45% between 60 – 69; the higher predict risks and, therefore, to intervene. prevalence was recorded for the Americans of
Jurnalul Român de Diabet. utriţie i Boli Metabolice / Vol. 14 / nr. 2 /2007 4 Hispanic origin/Mexicans (32%), for Afro – Europe is due to the different study Americans being 22%, and for the white methodology, the different structure of the population (Caucasian) being 24%. studied populations and, especially, to the Other studies, also from the USA, report adopted diagnosis criteria. incidences of 55.2% for the Amerindians (of We don’t have exact data for the ages ranging between 45 – 75 years) (15), prevalence of the dysmetabolic syndrome in 17% for the American Arabs (of ages ranging the population of Romania. Preliminary data between 20 75 years) (16) or 13.1% for the from the Urziceni Study (19) showed a Inuits (17). prevalence of about 23% in adults. More recent observations show that these percentages are increasing, especially for the rd Risk factors 3 age group (18). Probably, this increase is also due to the fact that obesity is more The main risk factors associated with the rd frequent with the 3 age subjects. It is sad that dysmetabolic syndrome are: the “epidemic” of obesity will continue to • Abdominal obesity, determine an increase of MS prevalence. • Arterial hypertension (HTA) The researches demonstrate the fact that • Low levels of HDL – cholesterol obesity is obviously associated with MS, (“good” cholesterol) especially in children and young adults. Weiss • Low levels of blood triglycerides and collaborators (14) found out that MS Other factors that may favor the prevalence is 0% in children and teenagers of developing of the dysmetabolic syndrome are: a normal weight and in overweight ones, but it • Cardiovascular diseases increases to 39% in the moderately obese • Polycystic ovary syndrome ones, reaching up to 50% in the severely obese • Nonalcoholic fat liver ones. • Alcanthosis nigricans The data that are comparable for the • Non Caucasian ethnic (obesity and prevalence of the syndrome in Europe indicate CV diseases are more frequent in its presence in almost 30% of the population persons of African origin rather than in aging over 50. The European Group for the the populations of Caucasian origin) Study of Insulin – Resistance (EGIR), by analyzing 8 European studies, found a • Sedentary lifestyle frequency of the dysmetabolic syndrome in • Age >40years (the hormonal variations non diabetic subjects of ages ranging at menopause, for example, are between 40 – 55 years old (according to the associated with an increase of the total OMS criteria of defining the syndrome) as adiposity and a fat distribution at being between 7% and 36% for men and 5% abdominal level and, therefore, a and 22% for women (the MS prevalence is of higher risk for the metabolic syndrome 14% in Finland, 23% in Ireland, 25% in developing) Scotland, <10% in France). The big variation • Gestational diabetes history or in the incidence of the dysmetabolic system in intolerance to glucose
Jurnalul Român de Diabet. utriţie i Boli Metabolice / Vol. 14 / nr. 2 /2007 5 • Familial history of type 2 diabetes cases, while obesity and the lack of physical mellitus, arterial hypertension, activity each represent 25% of the causes (21). cardiovascular diseases Stress can also play a part in the metabolic At present, there are known numerous syndrome. Researches showed that the other cardiovascular risk factors (pro increase of the cortisol levels, probably caused inflammatory status, pro thrombosis status, by the daily stress in the individuals having a micro – albuminuria, etc), their number being genetic susceptibility, may lead to the on the increase and bringing into discussion metabolic syndrome developing by the the metabolic syndrome itself. increase of the abdominal obesity (and of the The presence of the dysmetabolic number of persons having the metabolic syndrome confers a three times higher risk of syndrome) among the subjects who are at a appearance for the coronary disease and the low social – economic level as against those at cerebral vascular accident, doubling mortality a high social – economic level (23). The data on these accounts. If diabetes mellitus isn’t come from a male subgroup belonging to the already present, the dysmetabolic syndrome same specimen category showed increases the risk of type 2 diabetes mellitus modifications in the levels of cortisol and appearance by 5 times. epinephrine (adrenaline), which suggest an In addition to the risk of cardiovascular increased actuation by stress in those with diseases and diabetes mellitus, the metabolic metabolic syndrome as compared to those who syndrome was associated with an increased showed no signs of MS (24). The increased incidence of cancer, being supposed to be cortisol levels, especially when they are induced by the excess of insulin in the blood accompanied by emotional stress, lead to a circulation, a consequence of the resistance to bigger accumulation of fat at the level of the insulin (20). The Canadian researchers abdominal adipose tissue that contains an studied the connection between the resistance increased number of receivers for cortisol to insulin, excess of insulin in the blood (25). stream and cancer. Obesity contributes with Despite the numberless publications 14 – 20% deaths owing to cancer, both in dedicated to this subject, the primary cause of women and in men, with a risk increase the energetic metabolism disturbances, as well especially for the colon and rectum, stomach, as the genesis of the various disturbances that pancreas and liver cancer in men, and ovary, make up the picture of the dysmetabolic non – Hodgkin lymphomas, breast, uterus and syndrome are not known yet. liver cancer in women (21). Not all overweight individuals develop the The components of the metabolic syndrome; it is supposed that a dysmetabolic syndrome genetic factor is involved. The genetic susceptibility and the lifestyle are known to There are numerous points of view as play a role in being insulin sensitive to regards the elements needed for diagnosing insulin. It seems that the genetic factors are at the dysmetabolic syndrome. Also, there are the basis of 50% of the sensibility to insulin differences of opinion as concerns the limits
Jurnalul Român de Diabet. utriţie i Boli Metabolice / Vol. 14 / nr. 2 /2007 6 from which a parameter can be considered as level, but without reaching diagnosis values being a pathological one. for the diabetes mellitus; at 2 h after Starting with the first definition (initial administering 75 g of glucose per os, the one) of the metabolic syndrome done by an glycemia level is normal. OMS working group (in 1998), a range of alternative definitions was suggested. The IGT (Impaired Glucose Tolerance) = most widely accepted definition was tolerance altered to glucose (glycemia at 2 h formulated by EGIR (European Group for the after oral loading with 75 g of glucose 140 – Study of Insulin Resistance) and NCEP (USA 199 mg/dl) (OMS classification 1980, 1985). National Cholesterol Education Panel). Non diabetic values of the à jeun glycemia Nevertheless, OMS and EGIR definition is (from normal values to increased ones, but limited as concerns the clinical applicability <126 mg/dl of the venous plasma) and and acceptance. NCEP introduced the ATP III increased glycemia values of over the normal definition (Adult Treatment Panel III) that had level at 2 h after the oral administrating of 75 more success owing to its simplicity. g of glucose (between 140 and 199 mg/dl), without reaching, though, the values that The definition of the dysmetabolic characterize the diabetes mellitus. syndrome according to OMS (The World During the last years, IGT and IFG were Health Organization) (26) reunited under the term of prediabetes. Diabetes mellitus/IFG/IGT/insulin The method of the hyperinsu resistance (evaluated by the linemic/euglycemic clamp represents a euglycemic clamp method) and at least truthful indicator of the sensibility/resistance 2 of the following parameters: to insulin. This is determined during a BMI>30 kg/m 2 or the waist/hip ratio> continuous perfusion of a solution that 0.90 in men contains insulin in a concentration that allows >0.85 in women the keeping of insulinemia constant at a value TG serous ≥ 150 mg/dl (>1.7 mmol/l) of 50, 75 or 100 μU/ml. This increased or concentration is accomplished in order to HDL cholesterol < 35 mg/dl (<0.9 ensure an as high as possible occupying of the mmol/l) in men 39 mg/dl (< 1.0 mmol/l) in insulin receivers from the peripheral tissues. women Normally, the maintaining of this insulinemia The rate of excretion of the urine would rapidly lead to hypoglycemia. Its albumin > 20 μg/min or avoiding, in parallel with the insulin albumin/creatinine ratio ≥30 mg/g administrating, is done by introducing i.v., Blood presure ≥ 140/90 mmHg with the help of a pump of controllable capacity (delivery rate), a glucose quantity IFG (Impaired Fasting Glucose) = (basal) (variable) that is necessary to keep glycemia à jeun glycemia modified/affected (110 – 125 within normal and constant values. The mg/dl) (OMS classification 1998). Increased à quantities of glucose administered for jeun glycemia values that are over the normal preserving euglycemia indirectly reflect the
Jurnalul Român de Diabet. utriţie i Boli Metabolice / Vol. 14 / nr. 2 /2007 7 sensibility to insulin; the higher the glucose Other definitions of the dysmetabolic need is, the better the tissue insulin syndrome were suggested, complicating the sensibility. The lower the insulin need is possibility of an accepted international (owing to the low peripheral using), the higher definition. the insulin resistance. AACE definition (American College of EGIR definition (European Group for the Endocrinology) (30) Study of Insulin resistance) (27) The presence of at least 1 factor Insulin resistance or hyperinsulinemia à out of the following: jeun >25% and, at least, 2 of the following Diagnosis of CV, HTA, polycystic parameters: ovary syndrome, nonalcoholic fat o Plasm glucose à jeun ≥ 6.1 mmol liver or acanthosis nigricans (excluding diabetes) disease o Blood presure ≥ 140/90 mmHg or Family history of type II diabetes treatment for HTA mellitus, HTA or CV diseases o TG ≥ 2 mmol/l or HDL cholesterol < 1 Gestational diabetes history or mmol/l or treatment for dyslipidemia intolerance to glucose o Waist circumference ≥ 94 cm for men Non Caucasian ethnic and ≥ 80 for women Sedentariness 2 BMI > 25 kg/m and/or waist The definition of the dysmetabolic circumference > 102 cm with men syndrome according to CEP ATP III (the and > 88 cm with women USA Cholesterol Education Panel, Adult Age > 40 years Treatment Panel III) (28,29) And at least 2 out of the following At least 3 of the following parameters: parameters: Waist circumference > 102 cm with Serous TG ≥ 150 mg/dl men, >88 cm with women HDL cholesterol < 40 mg/dl Serous triglycerides ≥ 150 mg/dl (>1.7 with men, < 50 mg/dl with mmol/l) women HDL cholesterol < 40 mg/dl (1.0 Blood presure ≥ 130/85 mmHg mmol/l) with men, < 50 mg/dl (1.3 À jeun glucose 110 – 125 mg/dl or at 2 h mmol/l) with women post – prandial 140 – 200 mg/dl (diabetes is Blood presure ≥ 130/85 mmHg excluded from the AACE definition. Serous glucose ≥ 110 mg/dl (> 6.1 mmol/l)
The parameters of defining the dysmetabolic syndrome, as employed by the “ .C.Paulescu” Institute (2):
The syndrome composition The defining parameter and level
Jurnalul Român de Diabet. utriţie i Boli Metabolice / Vol. 14 / nr. 2 /2007 8 Abdominal circumference > 102 cm with men and > Abdominal obesity 88 cm with women Plasmatic triglycerides ≥ 150 mg/dl HDL – Cholesterol < 40 mg/dl with women and < 50 mg/dl with men
À jeun plasmatic glucose ≥ 110 mg/dl (ADA recommends > 100 mg/dl)
Plasmatic uric acid ≥ 7 mg/dl with men and ≥ 5.7 mg/dl with women
Arterial pressure ≥ 130/85 mmHg ADA = American Diabetes Association
There isn’t any view unity as regards the measured (in clino or ortho static – parameters that define the dysmetabolic postural position). Such ambiguities syndrome, the various bodies of an affect the sensibility and specificity of the international renown in the field having own diagnosis and, undoubtedly, led certain exigencies in their nominalization, a fact that physicians to wrong diagnoses (+). can be corrected by a constructive dialogue II. It is clear that the definition of the based on scientific data. syndrome differs in the listed criteria. For The lack of a minimal consensus example, micro albuminuria appears in regarding the basic elements of the the OMS definition, but not in the ATP III dysmetabolic syndrome expresses the different one; the insulin – resistance is relevant for levels of thoroughgoing into and interpreting the OMS definition, but not for the NCEP of the syndrome by the researchers in the ATP III one. Until at present, there has domain; we exclude the priority subjectivisms been published no survey of the clinical and the hierarchic differentiation vainglory of records in favor of including or excluding the organizations. any criterion for any of the 2 definitions Recently, the controversies on the MS (OMS and NCEP ATP III). intensified themselves. An all inclusive (and III. Certain criteria (for example the waist official) analysis regarding the metabolic circumference, HDL – cholesterol) differ syndrome was published by Kahn and by gender, implying the fact that the collaborators (31). The authors present a series relationship between the risk factor level of criticisms concerning the definition and the and the results differs as depending on physio pathological basis of the MS: gender; there was found no proof that I. Some of the criteria used for defining MS could justify the establishing of certain are ambiguous or incomplete. For guide marks by taking into account one’s example, it is not clear if the definition of gender (used as criteria the way those the blood pressure refers to values of the connected to CV diseases are). Foe systolic pressure that has to be > 130 example, it is not known if the same mass mmHg or of the diastolic pressure > 85 of adipose intra abdominal tissue carries mm Hg, or if both conditions have to be various risks in men as compared to fulfilled; also, there isn’t either specified women. An analogous reason can be put the way blood pressure should be forth as concerns the variation of these
Jurnalul Român de Diabet. utriţie i Boli Metabolice / Vol. 14 / nr. 2 /2007 9 criteria depending on race and ethnic 5) The CV disease risk, associated with group. the syndrome, doesn’t seem to be higher than IV. Finally, the reason supporting the criteria the sum of its component parts. is that the syndrome components are One of the initial purposes of the MS, the associated with the insulin – resistance amelioration of the CV disease risk prediction, (26, 28), but one could notice the fact that proved to be a disappointing one. There are not all the subjects with the dysmetabolic needed subsequent studies that should syndrome are insulin – resistant. Recently, ascertain if modifying the actual MS the ATP III definition went through definition, with adding the risk parameters for reviewing, enlarging the MS etiological the CV disease, can optimize its predictive basis from the “insulin – resistance” taken value. The second purpose of the syndrome, singularly, to “obesity and disturbances of namely identifying a group of CV disease risk the adipose tissue”, as a “constellation of factors that confer a higher risk when analyzed independent factors” that indicates specific together, proves an unrealistic one at MS components (31). The studies also present.(33). illustrate another deficiency of the present The International Diabetes Federation dwelling upon the MS diagnosis. Both the (IDF) recorded an important achievement in OMS definition and the ATP III one weigh MS physiopathology and diagnosis, each risk component equally; still, it is suggesting that the key element is the central obvious that certain risk factors that are obesity (34). All the MS components, included into the definition have a bigger suggested by all the actual definitions are to be predictive importance than others. It is found in the clinical and biological survey of extremely important to know from a list of the central obesity (abdominal one) (35). all the cardiovascular risk factors (known ones) the hierarchy of the combination The FID definition (the International having the highest predictive value. Diabetes Federation)(34) Briefly, the conclusions reached by Kahn 1) The central obesity (defined by the waist and collaborators pursuant to the carried out circumference ≥ 94 cm with the European analysis are the following: men and ≥ 80 cm with the European 1) The criteria are ambiguous or women, with characteristics values for incomplete. The motivation for thresholds various ethnic groups) and ≥ 2 of the (limit values) is badly defined. following parameters: 2) The insulin – resistance as a unique 2) Low level of the TG ≥ 1.7 mmol/l (150 etiology is unsure. mg/dl) or a cure that is specific for 3) There is no clear basis for including or hyperlipidemia. excluding other risk CV factors. 3) Low level of the HDL – cholesterol <1.03 4) The value of the cardiovascular risk is mmol/l (40 mg/dl) with men and varying and depending on the specific risk < 1.29 mmol/l (50 mg/dl) with women factor presence. or specific cure for dyslipidemia.
Jurnalul Român de Diabet. utriţie i Boli Metabolice / Vol. 14 / nr. 2 /2007 10 4) HTA, systolic blood presure ≥ 130 mmHg 3) Glycemia of values ≥ 110 mg/dl includes or dyastolic blood presure ≥ 85 mmHg or not only the “pre diabetes” stages (IFG cure for hypertension that was previously and IGT), but also the manifest clinical diagnosed. diabetes. The type II diabetes mellitus is 5) The increased levels of the venous the most illustrative clinical manifestation glycemia ≥ 5.6 mmol/l (100 mg/dl) or of the dysmetabolic syndrome (of insulin – previously diagnosed type 2 DM (with resistance). values > 5.6 mmol/l or 100 mg/dl, there is 4) The including of the uric acid among the recommended an oral test of tolerance to components of the dysmetabolic syndrome glucose, but it isn’t needed for defining the has a peculiar significance, although the MS presence). increasing of the plasmatic uric acid is met During the last years, by carefully with in less than 50% of the persons who analyzing the elements (original or further on present other signs of insulin – resistance. added ones) that make up the dysmetabolic This increase expresses the alteration of syndrome, there was found out that they have the protein metabolism, which is not a different significance. Some of them are indicated by other available parameters; “primary” genetic disturbances (the insulin – nevertheless, a normal value of the resistance and hyperinsulinism), others are the plasmatic uric acid does not exclude the metabolic consequences of these disturbances existence of the insulin – resistance. and, finally, the last category includes the final 5) The presence of the hemodynamic complications of the syndrome, which are modifications among the metabolic represented by the generalized cardiovascular disturbances (as the ‘dysmetabolic disease. syndrome’ name would suggest), Professor Ionescu – Tirgoviste, in “The apparently, is not a correct one. The Paulescu Diabetes Treatise” (2) makes the arterial hypertension refers to the altering following remarks: of the intravascular hemodynamics; yet, 1) The abdominal obesity, also called one could accept the idea that hypertension “visceral” obesity, should also include the could be triggered by the insulin – hepatic obesity (the dysmetabolic resistance (50% of the hypertensive hepatopathy or the fat – loaded non – persons are insulin – resistant) by means alcoholic liver) and, especially, the of the metabolic disturbances. The hyper muscular obesity (including the one at the tensiogenous mechanism of myocardium level). The muscular hyperinsulinism was connected to the triglyceride quantity can be as high as with increasing of the sodium and water the normal weight people, both in the retention at the level of the distal nephron, type 2 diabetes mellitus and in other as a consequence of the natrium – uresis insulin – resistance states. suppression induced by insulin; the 2) Plasmatic TG à jeun can be normal, but phenomenon seems to be dependent the the post – prandial triglyceridemic curve is stimulation of the rennin – angiotensin – abnormally high and persistant. aldosterone system. These lead to the
Jurnalul Român de Diabet. utriţie i Boli Metabolice / Vol. 14 / nr. 2 /2007 11 expansion of the circulatory volume, to the evidence that the high levels of circulating increasing of the cardiac diabetes and to insulin (hyperinsulinism), which accompany HTA. Another explanation of the HTA the insulin resistance, play a part in the arterial from the dysmetabolic syndrome can be hypertension increasing and the altering of the connected to the presence in the cholesterol and triglycerides (36). hyperinsulinemic subjects of an increased The excess of visceral adipose or intra sympathetic tonus, followed by abdominal tissue determines an increase of the vasoconstriction and the increasing of the free fat acids (FFA) in the blood circulation, a peripheral vascular resistance. Finally, fact that leads to an increase of glycemia and, another explanation regarding the respectively, to the insulinemia (hyperinsulin relationship between the metabolic factor emia) increase, compensatorily, leading also and the hemodynamic one is connected to to the decreasing of the receiver sensibility to the increased endothelin production – 1 ( a insulin. The lower the insulin requirement is, product that secrets the immense mass of owing to the low peripheral use (especially in endothelial tissue). the muscular and adipose tissue), the higher The initial hyperinsulinism induced by the the insulin resistance. The insulin resistant fat peripheral resistance from the muscular tissue cells (those having a volume enlarged by fat can induce a hyper expression of the accumulation – hypertrophic obesity ) do not endothelin – 1, of which increased production remove glucose or post prandial lipids from will finally lead to the accentuation of the circulation very well, so that these remain in insulin – resistance. the blood a longer while. This lipid excess in The NHANES III Study (National Health the circulatory stream determines and Nutrition Examination Survey III, malfunctions in the glucose transport, leading USA)(13) underlines the inconstancy of some to the insulin resistance in the liver and of the syndrome components that could have muscles (37). an explanation. The mechanisms of As early as 1956, Vague mentioned the controlling and adjusting a biochemical existence of the regional differences in the parameter (that formally belongs to a certain adipose tissue distribution. He came forward intermediate metabolism) can be genetically with the idea that the prevalence of diabetes, established as being vulnerable or resistant to dyslipidemia and vascular complications is the connected disturbances. The compensatory bigger in the obese people whose adipose mechanisms can quasi completely annul or mass is “centrally” disposed, especially within correct a biochemical abnormality. the abdominal area. This type of obesity was The initial description suggested by called “android” as to distinguish it from the Reaven gave the insulin resistance concept a “gynoid”, peripheral one. In the abdominal privileged position. He supported the obesity, the number of fat cells is normal, but hypothesis that insulin resistance (and the their volume is high and proportional to the compensatory increasing of the blood adiposity amount ( the hypertrophic obesity ). circulating insulin) is the first cause of all dis In the gynoid obesity, the weight excess is equilibriums. Other researchers brought solid effected based on the number increase of the
Jurnalul Român de Diabet. utriţie i Boli Metabolice / Vol. 14 / nr. 2 /2007 12 fat cells, of which volume is, nevertheless, b) The HDL – cholesterol and A normal ( the hyperplasic obesity) . The aplolipoprotein decreasing; metabolic disturbances that are characteristic c) Free fat acids (FFA) plasmatic to the dysmetabolic syndrome are more increasing; frequently met with in the central obesity and d) Small and dense LDL increasing. only exceptionally in the peripheral one. The The mechanism by which hyperinsulinism metabolism of the fat cells from the abdominal can induce the previously mentioned lipid compartment differs from that of the fat cells modifications is a complex one. It covers an from the gluteal – buttock one: the lipid increased TG hepatic production and also a activity (generating free fat acids) is a high decrease in their elimination from circulation, one in the abdominal adipose tissue as against secondary to decreasing the lipoprotein lipase in the peripheral adipose one. The increased (LPL). The decreasing of the LPL activity in presence of free fat acids (FFA) in the portal the skeletal muscle, secondary to insulin – circulation and, then, in the peripheral one has resistance, determines the directing of the two major negative effects: lipoprotein flow towards the fat cells (the a) it induces the insulin – resistance (by place of depositing the fat acids). In time, in the competition FFA creates against using the hepatocytes, there becomes stronger the glucose in the insulin – dependent, the VLDL synthesis by an increased inflow of fat decreasing of the peripheral capture of glucose acids with fat cell source. The decreasing of with the entraining of glycemia increase that the plasmatic levels of the HDL – cholesterol is sufficient to chronically stimulate the is, mainly, the consequence of the accelerated insulin secretion and to induce the catabolism of this group of lipoproteins characteristic hyper insulinism) and (consequent to the increased activity of the b) it increases the hepatic production of hepatic lipase and the transfer protein of the VLDL (very low density lipoproteins), cholesterol esters). particles that are rich in triglycerides, as well During the post – prandial period, there as the increasing of neoglucogenesis and of increase both the chylomicrons (synthesized the glucose hepatic production, major in the intestinal mucous membrane from the disturbances in the dysmetabolic syndrome). absorbed food lipids), and the VLDL The disturbing of the plasmatic lipids concentration (owing to the temporary within the dysmetabolic syndrome represents slowing of their metabolizing). To these, there one of the main factors invoked for explaining is added the mecha nism of exaggerated free the increased frequency of vascular fat acids (FFA) producing in the adipose complications recorded in these patients. The tissue, as a consequence of insulin – main recorded lipid disturbances are: resistance, and which will force, by substrate a) The plasmatic TG increasing (the excess, the increased VLDL hepatic consequence of altering the VLDL production. According to Randle’s theory of metabolism and of the B glucose/fat acid competition, the cause apolipoprotein increasing); for the glucose consumption decrease must be looked for in the more rapid intracellular
Jurnalul Român de Diabet. utriţie i Boli Metabolice / Vol. 14 / nr. 2 /2007 13 accessing by the fat acids, which will lead to fats. When the mitochondria from the muscles the automatic decreasing (metabolically and liver lose its natural ability to oxidize the imposed) of the glucose consumption. The fat acids, the result is a fat intracellular relationship can be, nevertheless, reversely accumulation followed by the insulin – interpreted: the primary disturbance would be resistance (40). Thus, one can explain why the difficult accessing of glucose (at the level certain subjects who are not obese ones can of conveyance or, somewhere else, during its develop MS. This theory is supported by intracellular metabolizing), a fact that would researches that showed the fact that older, impose the covering of the energy requisites healthy, non obese adults presented a from another source (namely, from free fat stronger resistance to insulin (being non acids). The decreasing of the glucose diabetic ones), by comparison with the peripheral utilization as a metabolic younger subjects who presented similarities in disturbance will trigger the lipid and protein other respects (41). The researchers speculated adjusting modifications having an impact over that losing the sensibility to insulin in elderly all tissues. subjects would be the result of reducing the The LDL increases within the mitochondrial functions owing to aging. dysmetabolic syndrome have been only Reaven showed (9) that 25% of the persons occasionally reported; it is only known that, who are healthy, non overweight or having with diabetes mellitus, the small and dense no impaired glucose tolerance, present a LDL particles are increased, which, owing to level of insulin – resistance that is similar to their big contact surface, are more easily that of the precocious stages of type 2 diabetes subject to oxidation. mellitus. Other researchers have indicated the fact As part of the context of numerous that the hormones leptine and adiponectine definitions and systematizations suggested can play an important role in preventing MS until at present, the relationship between MS (38). Leptine seems to he a direct muscular and the insulin – resistance seems not to be and hepatic effect by intensifying fat oxidizing fully clarified (32). The insulin – resistance is and lipid accumulation diminishing within one of the many pathophysiology these tissues (muscles and liver). Researches characteristics of obesity, especially of the showed that the abdominal obesity is central obesity. It is included into the MS associated with MS to a much greater extent nosologic framework by means of obesity and than the hypodermic obesity, as the abdominal it may play an important part (3). The doubts fat cells secret leptine deficiency and, that regard the insulin– resistance situation are therefore, they cannot promote a sufficient determined by the practical difficulties of oxidation as to prevent the hepatic, muscular quantifying it; also, studies didn’t confirm its and pancreatic lipotoxicity (from the beta cell decisive presence in all the subjects having a level) (39). dysmetabolic syndrome (31). Another theory, which would explain the Other components of the dysmetabolic losing of the sensibility to insulin, is based on syndrome are represented by biochemical the inability of the body to completely oxidize markers, the list of these proliferating during
Jurnalul Român de Diabet. utriţie i Boli Metabolice / Vol. 14 / nr. 2 /2007 14 the last years, in parallel with developing the an “energetic” theory that should beforehand pro inflammatory theory of atherosclerosis envisage the appearance of the dysmetabolic and of endothelial dysfunction, the two of syndrome, because, in fact, the dysmetabolic them being common both to atherosclerosis syndrome is a major off balancing of the and to the diabetic macro angiopathy. human body in managing its own bioenergy The International Diabetes Federation (production + consumption). brought forth a number of other parameters The symptoms of the dysmetabolic that seem to be connected to MS, and that syndrome are not immediate and direct ones should be included into the research studies in (of the cause – effect type), but they are order to ascertain the predictive power of shifted in time and more finely interconnected, these supplementary factors for the CV so that, although the deteriorations are diseases and/or diabetes (34). The utilization obvious, it is quite hard to establish with of these factors in the research activity will absolute certainty how they were got to, the also allow the modifying of the definition, if decisive factors having still to be properly adequate, and the validation of a new clinical elucidated. definition: MS necessitates more thorough going General obesity studies, before its definition as a “syndrome” Fat cell products: high leptine levels, low would be fully justified and before its clinical adiponectine levels usability would be adequately defined. High Apolipoprotein B levels From an anthropological point of view, High LDL – cholesterol levels the metabolic syndrome can only be defined High free fat acids (FFA) levels by anthropometry, as the populational/racial Microalbuminuria anthropological studies are, for the tyme Proinflammatory status (high PCR, high being, at an incipient stage. inflammatory Citokins (TNF ∝, IL 6)) Paraphrasing the eminent scientist Jean Prothrombotic status (high PAI – 1, high Rostand, one may say that, the more various fibrinogen) the aggressions that the human body has to endure are, the more various the measures taken for protecting it should be. Instead of conclusion
I dare hope that, out of the enormous mass of biochemical results, which have not been sufficiently systemized so far, there will result
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