Can blood glucose value really be referred to as a metabolic parameter?

In clinical guidelines, near-normoglycaemia is recommended as the basic therapeutic target in diabetes mellitus. This proposal suggests that euglycaemia is associated with eumetabolism and that hyperglycaemia is an indicator of dysmetabolism. The authors analysed the relationship between short/long-term blood glucose values and cellular metabolism in various pathophysiological settings. The following types of dysmetabolism are suggested: "hyperglycaemic dysmetabolism based on insulin deficiency", "hyperglycaemic dysmetabolism based on glucose toxicity", "euglycaemic dysmetabolism", "dysmetabolism of ischaemic/reperfusional origin", and "chronic stress-mediated dysmetabolism". The relationship between dysmetabolic states of various origin was also analysed. The authors conclude that the blood glucose value can only be accepted as a general metabolic parameter with marked limitations. The main arguments of this statement are that euglycaemia is not necessarily associated with eumetabolism and that acute hyperglycaemia does not necessarily indicate dysmetabolism. Identical cell metabolic performance can be supported by different biochemical energy-producing mechanisms associated with identical blood glucose values. Both positive and negative metabolic balance of cell metabolism can occur at identical blood glucose values. A further finding is that chronic hyperglycaemia acts simultaneously as a marker and as a maker of dysmetabolism; therefore, the achievement of near normoglycaemia remains the basic therapeutic goal in diabetes treatment. Insulin administration can beneficially influence dysmetabolic states of various origins. In the evolution of and interrelationships among various dysmetabolic states, the central role of chronic stress is emphasized. Discrepancies between blood glucose values and cellular metabolism are substantiated by the transporter nature of the blood glucose value; this value reflects the result of bidirectional glucose movement into and out of the tissues.

[The blood glucose value not necessarily indicates correctly the cellular metabolic state]. / A vércukorértékek nem feltétlenül jellemzik megfeleloen a sejtanyagcsere-állapotot.

In clinical recommendations the normalized blood glucose level is declared as the main target in therapy of diabetes mellitus, i.e. the achievement of euglycemia is the main therapeutic goal. This approach suggests, that the normal blood glucose value is the marker of the normal carbohydrate metabolism (eumetabolism), and vice versa: hyperglycemia is associated with abnormal metabolism (dysmetabolism). However the question arises, whether identical blood glucose values do reflect the same intracellular biochemical mechanisms? On the basis of data published in the literature authors try to answer these questions by studying the relations between the short/longterm blood glucose level and the cellular metabolism in different clinical settings characterized by divergent pathophysiological parameters. The correlations between blood glucose level and cellular metabolism in development of micro-, and macroangiopathy, in the breakthrough phenomenon, as well as during administration of metabolic promoters, the discrepancies of relation between blood glucose values and cellular metabolism in type 1, and type 2 diabetes mellitus, furthermore association between blood glucose value and myocardial metabolism in acute and chronic stress were analyzed. Authors conclude, that the actual blood glucose values reveal the actual cellular metabolism in a very variable manner: neither euglycemia does mandatorily indicate eumetabolism (balance of cellular energy production), nor hyperglycemia is necessarily a marker of abnormal metabolic state (dept of cellular energy production). Moreover, at the same actual blood glucose level both the metabolic efficacy of the same organ may sharply vary, and the intracellular biochemical machinery could also be very different. In case of the very same longterm blood glucose level the metabolic state of the different organs could be very variable: some organs show an energetically balanced metabolism, while others produce a significant deficit. These inconsistencies between blood glucose level and cellular metabolism can be explained by the fact, that blood glucose value is a transport parameter, reflecting the actual steady state of glucose transport from the carbohydrate pools into the blood, and that from the blood into the tissues. Without knowing the speed of these transports of opposite direction, the blood glucose value per se can not reveal the quantitative and qualitative characteristics of cellular metabolism. Orv. Hetil., 2017, 158(11), 409-417.

[Chronic stress and epigenetics. Relation between academic sciences and theology]. / Krónikus stressz és epigenetika. Az akadémiai tudomány és a hittudomány kapcsolata.

The author gives a short account on the principles of Selye's stress theory, and discusses similarities and dissimilarities of acute and chronic stress. Both the external, and the internal environment, as well as the psycho-mental status are involved in the notion of the environment. Basic principles of epigenetics are reviewed: interaction between environment and genes, neuroendocrine and enzymatic mechanisms involved in silencing and activation of genes, notions of phenotypic plasticity, and epigenetic reprogramming are discussed. Epigenetic mechanisms of interrelation between pathological clinical states (diseases) and the characteristic phenotypes, causative role of psycho-mental status in evoking pathological somatic alterations, and the potential therapeutic consequences are briefly discussed. The etiological role of chronic, civilization stress in producing the worldwide increment of cardiovascular morbidity is cited, argumentation and criticism of the current therapeutical practice is discussed. The author concludes that recent advances in epigenetic knowledge seem to solve the controversy between the academic and theological sciences.

[Questions in diabetology to be elucidated]. / Diabetológiai kérdojelek.

Despite advances in the management of cardiovascular diseases, the incidence of cardiovascular diseases is increasing both in developed and developing world. This phenomenon is associated with the worldwide pandemic of obesity and type 2 diabetes; both are related to the life style of urbanization. The association between life conduct of civilization and chronic stress resulting in augmentation of cardiovascular risk is detailed. Therapeutic policy practiced nowadays (polypill administration, achieving target values) in order to reduce cardiovascular risk is criticized. Primary causal role of chronic stress and life style, and secondary resultant nature of cardiovascular risk factors are stressed out in the pathogenesis of increased cardiovascular risk; therefore, limited value of an approach focusing on the management of cardiovascular risk factors, instead of targeting the primary cause, i.e. chronic stress and life conduct is emphasized. A short account is given about the similarities and dissimilarities in the pathogenesis of macro- and microangiopathy. The primary causal role of chronic stress in fetal and adult diabetes, furthermore possible triggers evoking chronic stress is discussed. Supportive experimental and clinical data are reported about the nature of basic metabolic dysregulation (dysmetabolism) in the pathogenesis of metabolic syndrome and type 2 diabetes. Besides the well documented significance of ischemic clinical manifestations of diabetes, the role of non-ischemic diabetic cardiomyopathy as an independent risk factor in evoking the total burden of cardiovascular risk in diabetes is emphasized. In reducing the cardiovascular risk in diabetics the management of high blood pressure and dyslipidemia is more effective compared to that of hyperglycemia. Besides managing cardiovascular risk factors, the successful treatment of dysmetabolism is importantly needed to eliminate the total excessive cardiovascular risk in diabetes. In order to achieve this goal the potential role of metabolic promoters is stressed out.

[Civilization stress, cardiovascular risk, evidence-based medicine, guidelines]. / Civilizációs stressz, cardiovascularis kockázat, evidence based medicine, guideline-ok.

Cardiovascular diseases have the pole-position on the list of morbidity and mortality statistics. Despite the great advances have been made in management of cardiovascular diseases, prevalence of these disorders increases worldwide, and even younger and younger ages are threatened. This phenomenon is strongly related to obesity and type 2 diabetes pandemic, which shows an unequivocal association with expansion of modernized life-style. The pathomechanism proposed to have central role is the chronic stress induced by civilized life-conduct. The authors criticizes the everyday practice suggested for management of cardiovascular diseases, focusing on normalization of cardiovascular risk factors, instead of fighting against the primary cause ie. chronic stress. There is growing evidence, that achieving the target values defined in guide-lines will not necessarily result in improvement of patient related clinical outcomes. The statistical approach generally practiced in randomized clinical trials is primarily striving for the drug-sale, instead of discovering novel pathophysiological relations. Pharmaceutical industry having decisive role in research and patient-care is mainly interested in profit-sharing, therefore patients' interest can not be optimally realized, and costs are unnecessarily augmented. Separation of patient-, and business-oriented medical care is an ethical question of fundamental importance.

Acquired angioedema associated with primary antiphospholipid syndrome in a patient with antithrombin III deficiency.

Acquired angioedema (AAE) due to the functional deficiency of the C1 inhibitor (C1-INH) is a rare disease characterized by recurrent bouts of edema that involve subcutaneous tissues, the larynx or the gastrointestinal tract. In the present paper, we report the case of a male patient with symptoms of AAE and recurrent deep venous and arterial thrombosis. As a trigger of AAE in the present patient, we revealed primary antiphospholipid syndrome accompanied by antithrombin III deficiency, along with malignancy in the history, and angiotensin-converting enzyme inhibitor therapy. Although anti-C1-INH titers (type I AAE) were normal initially, we observed a sharp increase in anti-C1-INH titers (suggestive of type II AAE) during follow-up. It seems that thrombosis might worsen angioedematous attacks in functional C1-INH deficiency. Thrombophilia should be considered a provoking factor of AAE and should be carefully sought for in these patients, as the key to successful management of AAE is the effective treatment of the underlying disease.

[Role of blood glucose in prediction of cardiovascular risk]. / A vércukor szerepe a cardiovascularis kockázat elorejelzésében.

Increased cardiovascular risk in diabetes mellitus has been well-documented. In contrast, it is not widely known, that the relation between degree of hyperglycemia and mortality of diabetics or nondiabetics with acute coronary syndromes (ACS) shows a positive correlation. Insulin treatment significantly improves survival of patients with both ACS and septicemia. New onset diabetes or impaired glucose tolerance can be detected in significant proportion of patients with AMI or coronary artery disease. New onset disturbance of carbohydrate metabolism has a powerful negative influence on clinical prognosis, therefore it's early diagnosis is considered an important new challenge for clinicians. The authors discuss prognostic significance of hyperglycemia-induced macroangiopathy, postprandial blood glucose, and concomitant metabolic state, respectively, furthermore potential therapeutic role of insulin in treatment of ischemic, reperfusional, and toxic metabolic disturbances.

[What is the most effective approach to the reduction of cardiovascular risk in type-2 diabetes mellitus?]. / Mi a cardiovascularis kockázat csökkentésének leghatékonyabb módja 2-es típusú diabetes mellitusban?

UNLABELLED: It is well known that the target blood glucose values are not fulfilled in treatment of patients with type 2 diabetes mellitus. (UKPDS) The high mortality rate in type 2 diabetes mellitus is associated with the augmented cardiovascular risk. It is well documented, that the beneficial influence of high blood pressure, dyslipidaemia, and hypercoagulation compared to hyperglycaemia, is a more powerful approach in reduction of cardiovascular risk in type 2 diabetes mellitus. The effect of medical interventions on alteration of cardiovascular risk and glucose homeostasis is not always concordant: beta-blockers automatically reduce cardiovascular risk, but may result in deterioration of blood glucose values, sulfanylurea drugs effectively reduce hyperglycaemia, but could paradoxically increase the cardiovascular risk. The acarbose, metformin, thiazolidindione, fibric acid treatment improves the profile of vascular risk factors, additionally could have a beneficial metabolic effect resulting in reducing cardiovascular risk in patients with type 2 diabetes mellitus. IN CONCLUSION: the cardiovascular risk in type 2 diabetes mellitus can be most effectively influenced by reduction of high blood pressure, dyslipidaemia, and dysfunction of haemostasis. The improvement of glucose homeostasis is, novel medical interventions seem to be important tools in reducing cardiovascular risk in patients with type 2 diabetes mellitus.

[Clinical significance of blood glucose levels in the pathogenesis of (atherosclerotic) macroangiopathy]. / A vércukorszint klinikai jelentósége a macroangiopathia (atherosclerotica) patogenezisében.

Numerous authors suggested postprandial blood glucose elevation as a significant contributor in development of macroangiopathy. Epidemiological studies and animal experiments delivered supportive data about causal relationship between postprandial hyperglycaemia and macroangiopathy in type 2 diabetes. Interestingly there is no chronological correlation between presence of hyperglycaemia and development of macroangiopathy neither in type 2, nor in type 1 diabetics. Strict metabolic control does not result in slowing progression of macroangiopathy (glucose paradox). Premature macroangiopathy documented in the prediabetes phase of type 2 diabetes is strongly related to presence of insulin resistance, hyperinsulinaemia, high blood pressure, and dyslipidaemia; development of atherosclerosis in advanced stage of type 1 diabetes is also rather associated with presence of high blood pressure and dyslipidaemia but not that of hyperglycaemia. With regard to role of postprandial hyperglycaemia it should be emphasized, that not the postprandial blood glucose elevation per se, but rather the postprandial complex metabolic cluster (hyperinsulinaemia, hypertrygliceriadaemia, etc) is supposed to be related with development of macroangiopathy in patients with metabolic syndrome and type 2 diabetes.

[Current views on stunned and hibernating myocardium]. / A kábult és a hibernált szívizomzat mai szemlélete.

A short review is presented about similarities and dissimilarities in pathophysiology of prompt reversible ischemia, stunned and hibernating myocardium. Definitions of these entities are given. Characteristics of clinical appearance, diagnostic procedures, natural history, prognosis and therapeutic modalities of stunned and hibernating myocardium are reviewed, respectively. Interrelations between prompt reversible ischemia, stunned, hibernating myocardium and ischemic preconditioning are briefly reported.

Effects of delayed preconditioning on myocardial regional contractility during repeated episodes of low-flow ischaemia in anaesthetized dogs: possible role of nitric oxide.

The effect of cardiac pacing on repeated low-flow ischaemia-induced changes in regional myocardial segmental contractility, and the role in these changes of nitric oxide, were investigated in anaesthetized dogs. Dogs were instrumented for cardiac pacing (pacing electrode in the right ventricle). Dogs were paced (four times for 5 min; pacing rate 220 beats.min(-1)) 24 h prior to the repeated ischaemic insults. Controls were instrumented, but not paced. After 24 h, the dogs were re-anaesthetized with pentobarbitone and subjected to four 20 min low-flow ischaemia and reperfusion cycles, by constricting the left anterior descending coronary artery (LAD) to achieve an approx. 50% reduction in resting coronary blood flow. In some dogs (both control and paced), N (G)-nitro-L-arginine methyl ester (L-NAME; a non-selective inhibitor of nitric oxide synthase) was infused into a side-branch of the LAD 10 min prior to the first ischaemia/reperfusion cycle. Regional contractile function was measured by ultrasonic microcrystals in the ischaemic and normal regions of the left ventricular wall supplied from the LAD and left circumflex coronary artery respectively, and expressed as percentage changes in segmental shortening (%SS). In some dogs, myocardial tissue blood flow (coloured microspheres) and lactate production (local coronary venous sampling) were measured; samples were also taken for histological analysis. In control dogs, the regional %SS was progressively reduced within the ischaemic segment during the four repeated occlusions (by 40+/-6, 59+/-6, 68+/-6, 70+/-6% during occlusions 1-4 respectively). These reductions were more pronounced, especially during the first two cycles (68+/-6, 68+/-6, 67+/-6, 67+/-6%, respectively), when the dogs had been previously subjected to cardiac pacing. In both paced and control dogs, these changes in contractile function were L-NAME-sensitive. Thus, in the presence of L-NAME, changes in regional segmental shortening in control dogs were 37+/-8, 40+/-8, 37+/-8, 42+/-11% and in the paced dogs 46+/-6, 45+/-7, 45+/-8, 45+/-7% respectively, during the four consecutive occlusions. There were no significant differences in tissue blood flow or in lactate production between the groups, and no structural changes indicative of infarction. These results show that the myocardium rapidly adapts to re-occurring acute ischaemia by reducing contractility within the ischaemic segment and, thereby, metabolic demand. Furthermore, cardiac pacing 24 h prior to these ischaemic challenges induces a similar adaptive response, a form of 'delayed preconditioning'. Since both the acute and delayed adaptation were L-NAME-sensitive, we suggest that this adaptation involves nitric oxide.