Biomedical subjects
Publications and source records attributed to V Durlach.
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Two different types of therapy with magnesium are used: physiological oral magnesium supplementation which is totally atoxic since it palliates magnesium deficiencies by simply normalizing the magnesium intake and pharmacological magnesium therapy which may induce toxicity since it creates iatrogenic magnesium overload. Primary and secondary magnesium deficiencies constitute the sole indication of physiological oral magnesium therapy. It is therefore necessary to be well acquainted with the clinical and paraclinical pattern of magnesium deficit and to discriminate between magnesium deficiency due to an insufficient magnesium intake which only requires oral physiological supplementation and magnesium depletion related to a dysregulation of the control mechanisms of magnesium status which requires more or less specific regulation of its causal dysregulation. Physiological oral magnesium load constitutes the best tool for diagnosis of magnesium deficiency and the first step of its treatment. Physiological oral magnesium supplementation (5 mg/kg/day) is easy and can be carried out in the diet or with magnesium salts, with practically only one contra-indication: overt renal failure. Specific and aspecific treatments of magnesium depletion are tricky using for example magnesium sparing diuretics, pharmacological doses of vitamin B6, physiological doses of vitamin D and of selenium. In order to use the pharmacological properties of induced therapeutic hypermagnesaemia, high oral doses of magnesium (> 10 mg/kg/day) are advisable for chronic indications and the parenteral route is suitable for acute indications. There are 3 types of indications: specific (for the treatment of some forms of magnesium deficit i.e. acute), pharmacological (i.e. without alterations of magnesium status) and mixed--pharmacological and aetiopathogenic--(for example complications of chronic alcoholism). Today pharmacological magnesium therapy mainly concerns the obstetrical, cardiological and anaesthesiological fields. The main indications are eclampsia, some dysrhythmias (torsades de pointe particularly) and myocardial ischaemias. But it is now difficult to situate the exact place of the pharmacological indications of magnesium. Magnesium infusions can only be envisaged in intensive care units with careful monitoring of pulse, arterial pressure, deep tendon reflexes, hourly diuresis, electrocardiogram and respiratory recordings. High oral magnesium doses besides their laxative action may bring latent complications which may reduce lifespan. There may remain some indications of the laxative and antacid properties of non soluble magnesium, particularly during intermittent haemodialysis. Lastly local use of the mucocutaneous and cytoprotective properties of magnesium is still valid, in cardioplegic solutions and for preservation of transplants particularly.
The euglycaemic hyperinsulinaemic glucose clamp is usually considered as the reference technique to evaluate insulin sensitivity. As it is an expensive and time-consuming tool, we therefore tried to validate a simple insulin tolerance test (ITT) (IV bolus of 0.1 IU/kg of regular insulin, with glucose sampling at -5, 0, 3, 5, 7, 10 and 15 min) and to demonstrate its usefulness. Insulin sensitivity was measured by DG/G0 ratio (G0 = initial glycaemia, DG is the variation between G0 and the glycaemia obtained at 15 min by the calculation of the regression plot). We confirmed the existence of a correlation between the glucose uptake (mg/kg per min) evaluated by glucose clamp and the DG/G0 index (r = 0.9, P < 0.01). There was no stimulation of hormonal counter regulation during the test. The ITT was significantly correlated both with fasting insulin (r = -0.43, P < 0.01), and post-glucose load insulin concentration (r = -0.67, P < 0.01); each measurement expressing insulin sensitivity. Four groups of patients with different insulin sensitivity: controls, NIDDM, gynoid and android obese subjects, were clearly separated by ITT. We showed that fasting glycaemia and DG/G0 were correlated (y = 2.63/x - 0.093; r = 0.82, P < 0.01). These results suggest that ITT could be an easy, quick and low cost method to evaluate insulin resistance in clinical practice and epidemiological studies.
Lipoprotein (a) status has been evaluated in a population of 602 non insulin-dependent diabetics and compared to 74 healthy controls. There was no significant difference in concentration and no obvious influence of glycaemic, coronarian or renal status.
Ageing constitutes a risk factor for magnesium deficit. Primary magnesium deficit originates from two aetiological mechanisms: deficiency and depletion. Primary magnesium deficiency is due to insufficient magnesium intake. Dietary amounts of magnesium are marginal in the whole population whatever the age. Nutritional deficiencies are more pronounced in institutionalized than in free-living ageing groups. Primary magnesium depletion is due to dysregulation of factors controlling magnesium status: intestinal magnesium hypoabsorption, reduced magnesium bone uptake and mobilization, sometimes urinary leakage, hyperadrenoglucocorticism by decreased adaptability to stress, insulin resistance and adrenergic hyporeceptivity. Secondary magnesium deficit in ageing largely results from various pathologies and treatments common to elderly persons, i.e., non-insulin dependent diabetes mellitus and use of hypermagnesuric diuretics. Magnesium deficit may participate in the clinical pattern of ageing, particularly in neuromuscular, cardiovascular and renal symptomatologies. The consequences of hyperadrenoglucocorticism-the simplest marker of which is non-response to the dexamethasone suppression test-may include immunosuppression, muscle atrophy, centralization of fat mass, osteoporosis, hyperglycaemia, hyperlipidaemia, atherosclerosis, and disturbances of mood and mental performance through accelerated hippocampal ageing particularly. It seems very important to point out that magnesium deficit and stress aggravate each other in a true 'pathogenic vicious circle', particularly in the stressful state of ageing. The importance of magnesium deficit in the aetiologies of insulin resistance, and the adrenergic, osseous, oncogenic, immune and oxidant disturbances of ageing is still uncertain. Oral physiological magnesium supplementation (5 mg Mg/kg/d) is the best diagnostic tool for establishing the importance of magnesium deficiency. Too few open and double blind studies on the effects of the treatment of magnesium deficiency and of magnesium depletion in geriatric populations have been done. Further study is necessary to assess the true place of magnesium deficit in the pathophysiology of ageing.
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The relationship between experimental magnesium deficiency and blood pressure is complex and still the subject of much debate. The effect of Mg deficiency and blood pressure in Wistar rats receiving a Mg deficient diet (0.080 g/kg) for 40 weeks was examined. Deficient rats, when compared to controls, showed an initial transitory phase of hypotension, followed by normalization of blood pressure and then hypertension beginning after 15 weeks on the deficient diet. During the whole experimental period, heart rate was significantly increased in deficient rats as compared to controls. The fact that hypotension resulting from Mg deficiency of short duration can be inhibited by antihistamines and by indomethacin suggests that various mediators seen during the inflammatory period of Mg deficiency could be involved. Mg deficiency of long duration was accompanied by hypertension. When Mg-deficient rats received the control diet for a period of 3 weeks, Mg supplementation only partially corrected the hypertension. The hypertension was not a consequence of stimulation of the renin-angiotensin system since the plasma renin activity was not modified and ACE activity was reduced. These deficient rats showed a significantly lower vasopressor response to noradrenaline than control rats. Several factors such as increase in collagen, changes in elastin and arterial elasticity, total lipid content, and calcifications may account for the hyporesponsiveness to contractile agonists.(ABSTRACT TRUNCATED AT 250 WORDS)
Magnesium deficit may be considered as a cardiovascular risk because of its aetiopathogenic role in the genesis of atherogenous dyslipidaemias and the so-called "idiopathic" mitral valve prolapse. It does not, however, constitute a major antihypertensive factor, though it may sometimes be an accessory co-factor. Plasma magnesium is generally normal in untreated hypertensive patients and normotension is the rule during magnesium deficit. An inverse relationship between magnesium and renin in the plasma of hypertensives has not been confirmed. In practice, plasma magnesium seems to be related to the evolution of the disease. An inverse correlation between blood pressure and erythrocyte total and free magnesium levels has been observed in diverse selected populations but no adjustment has been made in these studies for important covariables. A weak positive association between blood pressure and erythrocyte free magnesium was lost in a multivariate regression analysis. As a rule there is no difference between erythrocyte, leucocyte, and lymphocyte magnesium in hypertensives and controls. More often no relation between urinary magnesium and blood pressure is observed. Daily urine magnesium may be increased with increased excretion of urine adrenaline. Epidemiological data on dietary magnesium, particularly in drinking water, should be carefully scrutinized: these studies do not establish a major role for magnesium as an antihypertensive factor but confirm the importance of magnesium deficit as a nephrocardiovascular risk factor and sometimes gives support for a role of magnesium as an antihypertensive cofactor. The use of magnesium-depleting drugs in hypertensive patients may induce magnesium depletion which must be palliated.(ABSTRACT TRUNCATED AT 250 WORDS)
The human amniotic membrane may be considered a model for the prescreening evaluation of the membrane effects of several Mg salts because it is an asymmetrical membrane (polarity of the 2 sides: the ratio between the total ionic conductance Gt both ways and the ratio between the ionic flux from the mother to the fetus (F1) and the ionic flux from the fetus to the mother (F2) are different from 1), samples of which can be obtained without ethical problems, and which is easily usable. Whatever the tested salt, the ratio F1/F2 must be constant or increased without alterations of the ionic fluxes (+/-20%), because a toxic metal (As) has no effect on F1/F2, but strongly decreases the ionic fluxes. To apply this model to the study of the effects of Mg salts, two conditions should be considered: 1) Mg oral therapy: Mg deficit increases the membrane fluidity and the increase of Mg concentration rigidifies the membrane, i.e. decreases Gt; the plasma level of Mg being equal to 1 mM, Mg salts would be tested at 1 mM and Gt should be decreased; and 2) Mg parenteral therapy: the Mg effects should be opposite to those of pollutants and alcohol, which reduce Gt; a dose of 3 mM is chosen and Gt should be increased. The general scheme to study Mg salts is the following: observation of the variation of F1/F2 at 1 mM and of the evolution of Gt, and identical observations at 3 mM. This in vitro prescreening method, indirectly applicable to in vivo effects, gives a classification of Mg salts which may be completed by a study of the 10 components of Gt in the case of identical results for Mg salts.
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Over the last four years, we have done a prospective study of insulin requiring diabetes (IRD). We offered 59 patients insulin therapy during 10 to 14 days by means of continuous subcutaneous insulin injection with the help of a pump in order to maintain the patient under oral hypoglycemic agents (OHA). We divided our population into two characteristic groups and isolated parameters that were predictive of post-insulin therapy evolution by means of C peptide assays. In one group, in 50% of cases, endogenous insulin production appeared impaired and could not be restored by insulin therapy. The patients in this group suffered a renewed drug failure within 3 months. In the other group, 50% of cases, endogenous insulin production was preserved and the CP/blood glucose level ratio improved. On insulin treatment interruption, we observed a significantly improved fasting blood glucose level and we observed decreased insulin needs. The patients, who were probably insulin resistant, suffered only late failures or went into remission, often for longer than one year. The data bring us to the logical conclusion of IRD heterogeneity. Only some of these patients can benefit from temporary insulin therapy and the remission attempt should be limited to them.
Fructosamine test using a Nitroblue Tetrazolium (NBT) method offers many advantages: quickness, reproducibility, easy automation and unexpansiveness, but a standardization of the different methods is needed. The results can be expressed in absolute value of equivalent DMF per liter, except in pregnancy where mumol per g of protein is used. The interpretation of the results can be difficult in case of quantitative and/or qualitative proteins abnormalities: icterus and severe chronic renal insufficiency. Fructosamine is significantly higher in diabetic patients. It gives a good correlation with glycated haemoglobin but the provided information is different, concerning a shorter period of 2 to 3 weeks and perhaps more sensitive to recent glycaemic variations. Fructosamine test does not seem to be a good screening test for diabetes and impaired glucose tolerance. The test indications of the assay could be: situations where the dosage of glycated haemoglobin is not interpretable, diabetic pregnancy follow-up and short term evaluation of a therapeutic change on glycaemic control. However, the individual significance of fructosamine concentration remains to be assessed and seems to be less accurate than glycated albumin.
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Magnesium deficiency (MD) may be either latent: i.e. without disturbances in blood Mg, calcium and intracellular potassium (Ki) or patent, with a rich symptomatology: i.e. with hypomagnesemia, hypocalcemia and decreased Ki. These two aspects are also found with magnesium excess. The discrepancy between these two opposite clinical forms leads one to postulate the existence of a control of Mg homeostasis, efficient in latent forms and deficient in patent forms of Mg disturbances. 4 'endocrine glands', (i.e.) adrenal medulla, parathyroids, thyroid and beta-islets in the pancreas are involved mainly in the homeostatic feed-back systems which regulate both Mg levels and the humoral consequences of the disturbances of Mg metabolism. Moreover, the high stability of intracellular Mg2+ in soft tissues also leads one to postulate the existence of cellular feedback regulatory mechanisms. Parallel variations of insulin and epinephrine secretion represent the first known mechanism which tends to maintain constancy of cellular Mg2+, and, secondarily, of 3':5'-cyclic adenosine monophosphate (cAMP). However, this regulation involves 3 types of side effects; i.e. in MD, the epinephrine-insulin hypersecretion may induce: membrane-depolarizing effects, calcinosis-promoting increase of cellular P and Ca influx, and an increase of the 3':5'-cyclic guanosine monophosphate (cGMP) level--the basic characteristics of cellular MD. These noxious side effects may be antagonized by an increase of taurine (TA) influx into the cell, which is actually stimulated by epinephrine-insulin hypersecretion. TA--and perhaps also gamma-L-glutamyl TA, new parathyroid hormone--may counteract all of these side effects by its membrane-stabilizing, Ca-binding and cGMP level-lowering effects. TA, through these nonspecific functions, and perhaps also through a specific action as an 'Mg-sparing hormone', thus appears to be an important factor in the regulation of Mg homeostasis.
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The sudden infant death syndrome (SIDS) remains a leading cause of death during the first year. The common epidemiological and pathological data which characterize SIDS include the curve for age at death (with 3 months as modal age), the stigmata of early maternal intrauterine injury, the seasonal predominance in winter, and the absence of an adequate cause of death at autopsy. Some data characterize risk factor subgroups: for example low socioeconomic level, environmental pollution, stress, and mistakes in baby care. Symptoms before death may be lacking, they may be common and non-specific, or rarely they may be acute, corresponding to "apparent life-threatening events" (ALTE). SIDS may be a magnesium-dependent disease of the transition from chemical to physical thermoregulation. This theory originates from a synthesis of our present knowledge of SIDS, maternal magnesium status, and thermoregulation in the baby. It is consistent with all the epidemiological and pathological prerequisites characterizing SIDS. It eliminates the hiatus between relatively minor thermal stress and induced lethal thermal stroke. Logical scepticism about the role of an implausible lethal superacute magnesium deficiency is no longer justified with regard to well established chronic marginal magnesium deficiency. Further experimental and clinical research will be interesting, i.e. ex vivo studies on brown adipose tissue (BAT) and magnesium deficiency under various conditions of thermal exposure. But even now the theory leads to three therapeutic consequences: (1) the need to define the importance of magnesium deficiency in diagnosis and treatment of ALTE; (2) an assessment of the use of new techniques of rewarming (i.e. extracorporeal circulation) in hypothermia cases to distinguish cot death from "apparent death"; (3) investigation of the prevention of SIDS with magnesium through a blinded and randomized multicentre prospective cooperative study of magnesium supplementation in pregnant and lactating women, followed not only in the mother, fetus, and neonate at birth, but also through the first year of life.
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