Biomedical subjects
Publications and source records attributed to A J Scheen.
Type 1 diabetes mellitus results from autoimmune destruction of pancreatic beta cells. After having described genetic, immunological and metabolic factors, some researchers have hypothezised that environmental factors might trigger the autoimmune process. Based on epidemiological, anatomoclinical and animal studies, they suggest a role for virus infections.
Premelle, commercialised by Wyeth-Lederle, is a combination of conjugated estrogens 0.625 mg and medroxyprogesterone acetate 5 mg which is indicated in the treatment of menopause-associated problems, among which vasomotor symptoms, atrophic vaginitis and/or urethritis, and in the prevention and treatment of post-menopausal osteoporosis. It is presented in two formulations, Premelle cyclic 5 and Premelle 5. The former, in which the progestagen is only given during the last 14 out of 28 days of the treatment cycle, is accompanied by regular bleeding and thus preferably indicated during perimenopause whereas the latter, in which the progestagen is given continuously and results in amenorrhea, is mostly indicated after menopause in order to improve long-term compliance.
Neuropathy is a classical complication of diabetes mellitus, to the same extent as micro- and macroangiopathy. Diabetic neuropathy can be schematically divided into peripheral neuropathy, especially in the lower limbs (distal polyneuropathy), and autonomic neuropathy, present in all systems (cardiovascular, gastrointestinal, urogenital and even pulmonary abnormalities). Detection should be based on an oriented anamnesis and a careful physical examination. Complementary exams may be performed in order to confirm the diagnosis and assess the severity of the neuropathy. While the diagnosis of peripheral neuropathy is essentially based on clinical examination, that of autonomic neuropathy has been markedly facilitated by simple standardised tests for early detection of cardiac autonomic neuropathy. Depending on the terminology, the diagnostic criteria and the characteristics of the population, the prevalence of diabetic neuropathy can range from 15 to 100%. However, all studies agree that prevalence is important in both types of diabetes (Type 1 and Type 2), that it increases with age and disease duration, and that it is inversely related to the quality of glycaemic control. Detection of neuropathy is an essential step in the clinical approach to diabetic patients, mainly because of the prognosis linked to such a diagnosis, at both an early and late stage of the disease. Once neuropathy is diagnosed, the physician should provide specific advice to diabetic patients in order to prevent possible dramatic complications.
Besides the classical dietary regimen, it is possible to use specific pharmacological approaches, targeted at the intestine, in order to treat some metabolic disorders. Three approaches will be described: anionic resins for treating hypercholesterolaemia, alpha-glucosidase inhibitors for treating diabetes mellitus and reactive hypoglycaemia, and intestinal lipase inhibitors for treating obesity. All these drugs are based on original concepts, but their clinical use is often limited by the occurrence of digestive side-effects. The latter may generally be reduced by progressive and individual titration of the dosage of each drug and/or by following an appropriate diet.
A decrease in plasma HDL cholesterol concentration is considered as a major cardiovascular risk factor and is a prevalent lipid abnormality among patients with coronary heart disease. This condition is most often observed in the presence of hypertriglyceridaemia, generally linked to the insulin resistance syndrome, but may also be associated to elevated LDL cholesterol level or even be present alone (hypoalphalipoproteinaemia). The decision to treat a patient with low HDL level depends on the individual overall cardiovascular risk which should be evaluated as carefully as possible. The investigation should look for causes which may favour this metabolic condition, such as bad life habits or possible pharmacological interferences.
Formoterol, commercialized by Astra under the trade name Oxis, is a new potent and selective agonist of beta-2 adrenergic receptors, which is used with a specific device (Turbohaler) allowing effective inhalation. Bronchodilatation occurs rapidly, within 1-3 minutes after inhalation, and lasts about 12 hours after the administration of a unique dose. Oxis Turbohaler is indicated to reduce symptoms associated with bronchial obstruction in asthmatic patients when the control of asthma is not achieved with inhaled corticoid therapy. It is not indicated for the treatment of acute crisis. It is presented as powder vials for inhalation (4.5 or 9 micrograms per dose). The usual dose in adults is 1-2 inhalations 1-2 times per day, in the morning and/or in the evening (bedtime administration should be recommended in case of nocturnal asthma). There is not enough data for treating children. The lowest dose allowing adequate control of asthma should be selected for chronic treatment.
Obesity plays a crucial role in type 2 diabetes pathophysiology and a major weight loss markedly improves glycaemic control. The common failure of classical treatments leads to the use of more aggressive weight-reduction approaches, such as very-low-calorie diets (VLCDs), anti-obesity drugs or even bariatric surgery. VLCDs are very successful in the short-term but rather disappointing in the long-term. Anti-obesity compounds only induce a modest mean weight reduction, even if some patients appear to be better responders. Interestingly, serotoninergic agents increase insulin sensitivity and glycaemic control, independently of weight loss. Bariatric surgery provides the most impressive results. In well-selected subjects, gastroplasty (either vertical ring gastroplasty or adjustable silicone gastric banding) generally induces a considerable weight loss which results in a remarkable and sustained glycaemic control improvement and allows the reduction, or even the suppression, of any antidiabetic treatment. This ultimate solution should not be neglected after failure of medical approaches, provided that the indication is correct, the surgical procedure is performed in a specialized centre and the followup is well organized by a multidisciplinary team.
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The decision to treat an individual with low HDL cholesterol level depends on his overall cardiovascular risk profile and the therapeutic strategy is based upon the characteristics of the lipid profile (isolated abnormality, associated hypertriglyceridaemia or combined elevation of LDL cholesterol). The treatment must favour diet and exercise, before considering a possible pharmacological approach. Results are usually acceptable with better life habits and appropriate diet when low HDL cholesterol level is associated to hypertriglyceridaemia. From a pharmacological point of view, the best results are obtained with fibrates or nicotinic acid. However, results are often disappointing when low HDL cholesterol level is isolated.
Necrolytic migratory erythema (NME) is generally associated with glucagonoma. It waxes and wanes by successive relapses and remissions. The clinical and microscopical diagnosis is complex. In addition to glucagonoma treatments, the administration of corticoids, aminoacids, zinc or essential fatty acids can be helpful. There exist several etiological hypotheses for NME. These are based on modifications of pancreatic enzyme activities and on variations of aminoacids, fatty acids, zinc or glucagon concentrations.
From a metabolic point of view, anorexia nervosa may be viewed as a mirror image of obesity. We compared insulin secretion, clearance and action on glucose metabolism during an intravenous glucose tolerance test in nine women with anorexia nervosa and in nine age-matched normal-weight controls. Insulin secretion (ISR) was derived by deconvolution of plasma C-peptide levels, insulin clearance (MCR(I)) was obtained by dividing the area under the curve (AUC(0-180 min)) of ISR by the corresponding AUC of plasma insulin levels, insulin sensitivity (S(I)) and glucose effectiveness index (S(G)) were calculated by Bergman's minimal model. The anorectic women had markedly lower BMI values (13.7+/-0.6 vs 23.2+/-0.8 kg/m2, p<0.0001) and serum basal leptin levels (2.8+/-0.6 vs 8.9+/-1.8 ng/mL, p=0.005) than control women. The anorectic women exhibited clear-cut lower fasting and post-glucose plasma insulin levels but similar corresponding plasma C-peptide concentrations when compared to controls. Consequently, ISR was similar in both groups while MCR(I) was significantly increased in anorexia nervosa (MCR(I): 3320+/-881 vs 822+/-79 mL x min(-1) x m(-2), p<0.02). The index S(I) tended to be higher in anorectic women than in normal-weight subjects, but without reaching the level of statistical significance because of a high between-subject variability (20.2+/-5.7 vs 12.5+/-2.2 10(-5) x min(-1)/pmol x L(-1), NS). The index S(G) was similar in both groups (0.022+/-0.004 vs 0.018+/-0.002 min(-1), NS). In conclusion, low plasma insulin levels observed in women with anorexia nervosa result from high MCR(I) rather than from depressed insulin secretion. Insulin sensitivity is not systematically increased and glucose effectiveness is unchanged in anorectic women when compared to normal-weight controls.
The prevalence of non-insulin-dependent diabetes mellitus dramatically increases with age. Older diabetic subjects have an increased frequency of complications from diabetes compared with their younger counterparts and higher morbidity and mortality rates compared with age-matched non-diabetic controls. Elderly patients with diabetes are generally treated following the same approach as in younger patients: dietary therapy first, followed by oral hypoglycaemic agents and ultimately insulin. However, several specificities should be pointed out. Changes associated with ageing may affect the pharmacokinetics and pharmacodynamics of both sulphonylureas (increasing the risk of severe hypoglycaemia) and biguanides (increasing the risk of lactic acidosis). The best insulin regimen in old age is not known, but a twice-daily injection of a pre-mixed insulin preparation is usually recommended. Goals of therapy must be realistic and not cause disabling side-effects. The general practitioner plays a crucial role in the care of elderly diabetic patients, but access to a multidisciplinary specialized team may be necessary.
Improving the action of insulin is a relatively new concept in therapy. It should, however, become more and more important because of the rapid expansion of the insulin resistance syndrome (including upper body adiposity, glucose intolerance, hypertension, dyslipidaemia, etc.) in industrialized countries and its dramatic consequences for public health. Insulin sensitivity can be improved by non-pharmacological means, essentially reduction of excessive body weight, promotion of regular physical activity and modification of dietary habits, as well as, possibly, cessation of smoking and correction of subclinical magnesium deficiency. Currently available pharmacological means mainly include the biguanide compound metformin and possibly anti-obesity agents, such as (d-) fenfluramine, fluoxetine and benfluorex. New compounds aiming at improving the action of insulin are in development, especially the thiazolidinedione derivatives (e.g. troglitazone), known as 'insulin sensitizers'. Treatment of insulin resistance may have important gynaecological applications, essentially in polycystic ovary syndrome and, possibly, after menopause. Hopefully, improving insulin sensitivity could ameliorate the cardiovascular prognosis of numerous individuals having some or all components of insulin resistance syndrome.
This study investigated the ability of two models to represent glucose kinetics in the basal steady state and during an intravenous glucose tolerance test (IVGTT). Six young nonobese male subjects were studied after an overnight fast. Two bolus injections of [U-13C]glucose were given 150 min apart, the first without and the second together with concomitant injection of unlabeled glucose. [3-3H]glucose was constantly infused throughout the study and served to provide an independent means for evaluation of system responses. A linear time-invariant three-compartmental model and the two-compartment time-variant model proposed by Caumo and Cobelli were used to interpret measured time courses of [U-13C]glucose and to reconstruct endogenous glucose production and glucose removal. The ability of the two models to describe the glucose tracer time course was comparable. Simulation studies showed that the two-compartmental time-variant system better predicted measured [3-3H]glucose concentration profiles than did the three-compartmental time-invariant model. However, endogenous glucose production and the integral of excess glucose removal over basal during the IVGTT derived from the two models were almost identical.
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Non-insulin-dependent diabetes mellitus (NIDDM, type 2 diabetes) is a heterogeneous disease resulting from a dynamic interaction between defects in insulin secretion and insulin action. There are various pharmacological approaches to improving glucose homeostasis, but those currently used in clinical practice either do not succeed in restoring normoglycaemia in most patients or fail after a variable period of time. For glycaemic regulation, 4 classes of drugs are currently available: sulphonylureas, biguanides (metformin), alpha-glucosidase inhibitors (acarbose) and insulin, each of which has a different mode and site of action. These standard pharmacological treatments may be used individually for certain types of patients, or may be combined in a stepwise fashion to provide more ideal glycaemic control for most patients. Adjunct treatments comprise a few pharmacological approaches which may help to improve glycaemic control by correcting some abnormalities frequently associated with NIDDM, such as obesity (serotoninergic anorectic agents) and hyperlipidaemia (benfluorex). There is intensive pharmaceutical research to find new drugs able to stimulate insulin secretion (new sulphonylurea or nonsulphonylurea derivatives, glucagon-like peptide-1), improve insulin action (thiazolidinediones, lipid interfering agents, glucagon antagonists, vanadium compounds) or reduce carbohydrate absorption (miglitol, amylin analogues, glucagon-like peptide-1). Further studies should demonstrate the superiority of these new compounds over the standard antidiabetic agents as well as their optimal mode of administration, alone or in combination with currently available drugs.
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