[New antidiabetic medications: at the dawn of a revolution? New therapeutic options for type 2 diabetes are challenged for cardiovascular disease prevention]. / Nouveaux antidiabétiques : A l'aube d'une révolution ? Les nouvelles options thérapeutiques du diabète de type 2 à l'épreuve de la prévention cardiovasculaire.

Despite advances in the management of type 2 diabetes, cardiovascular disease remains a major concern. Large glycemic control intervention trials have taught us that at least ten years are needed to see the benefits of a conventional diabetes therapy on morbidity and mortality of cardiovascular disease. Following the controversy about rosiglitazone in 2008, the FDA required cardiovascular safety data for all new antidiabetic medications and early studies to comply with this regulation are now published. They showed first the cardiovascular neutrality of gliptins, a result not really surprising for a median follow-up of less than 3 years. However, EMPA-REG-OUTCOME and LEADER studies were very surprising. Both were performed in type 2 diabetic patients with a history of cardiovascular disease. In the f irst of these studies, empaglif lozine prescribed over the usual antidiabetic treatment reduced by 14 % (P ⟨ 0,04) the composite primary endpoint (nonfatal myocardial infarction or nonfatal stroke or cardiovascular death), and this mainly through a reduction in cardiovascular mortality by 38 % (P ⟨ 0,001). Thereafter, LEADER has similarly shown that liraglutide reduced by 13 % the same primary endpoint (P = 0,01) along with a 22 % reduction in cardiovascular mortality (P = 0,007). In both cases, the median follow-up was less than four years. In conclusion, these two studies demonstrate that powerful, although still unknown mechanisms for cardiovascular protection exist. These mechanisms are able to improve survival by a glucose independent way, in a very high risk diabetic population already heavily treated by sartans/ACE inhibitors, statins and antiplatelet agents.

Malgré les progrès dans la prise en charge du diabète de type 2, la maladie cardiovasculaire reste une préoccupation principale. Les grandes études interventionnelles de contrôle glycémique nous ont appris qu'il faut patienter plus de 10 ans avant d'espérer les bénéfices d'un traitement antidiabétique classique sur la morbimortalité cardiovasculaire. Suite à la controverse de la rosiglitazone, la FDA impose depuis 2008 de disposer de données de sécurité cardiovasculai re pour tous les nouveaux anti - diabétiques, et les premières études réalisées pour s'y conformer sont maintenant publiées. Elles montrèrent d'abord une neutralité cardiovasculaire des gliptines, un résultat somme toute peu étonnant pour un suivi médian de moins de 3 ans. Par contre, EMPA-REG OUTCOME puis LEADER réalisées chacune chez des diabétiques de type 2 avec antécédent cardiovasculaire furent une surprise : dans la première de ces études, l'empagliflozine prescrite au-dessus des antidiabétiques habituels a réduit de 14 % (P ⟨ 0,04) le critère principal (infarctus myocardique ou AVC non fatals ou mortalité cardiovasculaire), et ce principalement grâce à une réduction des décès cardiovasculaires de 38 % (P ⟨ 0,001). LEADER a montré similairement pour le liraglutide une réduction de 13 % du même critère composite principal (P = 0,01) accompagné d'une baisse de 22 % de la mortalité cardiovasculaire (P = 0,007). Dans les deux cas, le suivi médian était inférieur à 4 ans. En conclusion, ces deux études démontrent qu'il existe des mécanismes de protection cardiovasculaire puissants mais encore méconnus, indépendants du contrôle glycémique, capable d'améliorer la survie d'une population diabétique à très haut risque et déjà largement protégée par sartans/IECs, statines et antiagrégants plaquettaires.

Correlates of fractures in elderly, diabetic outpatients.

It is widely recognized that patients presenting diabetes are at increased risk for fractures. In a retrospective case-control study, 101 cases were selected from medical charts of outpatients older than 70 with diabetes mellitus and a fracture within the past 5 years. Glycosylated hemoglobin (HbA1c) had been measured within 4 months around the assessment. Each case was matched for sex and age with one control, diabetic patient with no fracture. HbA1c level was similar in both groups. Patients with fractures presented significantly lower BMIs than controls, and had a higher rate of declared osteoporosis and comorbidity. A small number of cases were using vitamin D supplements while more were treated with benzodiazepine, opiates and Selective serotonin reuptake inhibitors (SSRI). This study suggests that, rather than the tight control of blood glucose, other factors such as medication and comorbidity could be associated with fracture risk in elderly diabetics.

In antibody-positive first-degree relatives of patients with type 1 diabetes, HLA-A*24 and HLA-B*18, but not HLA-B*39, are predictors of impending diabetes with distinct HLA-DQ interactions.

AIMS/HYPOTHESIS: Secondary type 1 diabetes prevention trials require selection of participants with impending diabetes. HLA-A and -B alleles have been reported to promote disease progression. We investigated whether typing for HLA-B*18 and -B*39 may complement screening for HLA-DQ8, -DQ2 and -A*24 and autoantibodies (Abs) against islet antigen-2 (IA-2) and zinc transporter 8 (ZnT8) for predicting rapid progression to hyperglycaemia. METHODS: A registry-based group of 288 persistently autoantibody-positive (Ab(+)) offspring/siblings (aged 0-39 years) of known patients (Ab(+) against insulin, GAD, IA-2 and/or ZnT8) were typed for HLA-DQ, -A and -B and monitored from the first Ab(+) sample for development of diabetes within 5 years. RESULTS: Unlike HLA-B*39, HLA-B*18 was associated with accelerated disease progression, but only in HLA-DQ2 carriers (p < 0.006). In contrast, HLA-A*24 promoted progression preferentially in the presence of HLA-DQ8 (p < 0.002). In HLA-DQ2- and/or HLA-DQ8-positive relatives (n = 246), HLA-B*18 predicted impending diabetes (p = 0.015) in addition to HLA-A*24, HLA-DQ2/DQ8 and positivity for IA-2A or ZnT8A (p ≤ 0.004). HLA-B*18 interacted significantly with HLA-DQ2/DQ8 and HLA-A*24 in the presence of IA-2 and/or ZnT8 autoantibodies (p ≤ 0.009). Additional testing for HLA-B*18 and -A*24 significantly improved screening sensitivity for rapid progressors, from 38% to 53%, among relatives at high Ab-inferred risk carrying at least one genetic risk factor. Screening for HLA-B*18 increased sensitivity for progressors, from 17% to 28%, among individuals carrying ≥ 3 risk markers conferring >85% 5 year risk. CONCLUSIONS/INTERPRETATION: These results reinforce the importance of HLA class I alleles in disease progression and quantify their added value for preparing prevention trials.

Four-year metabolic outcome of a randomised controlled CD3-antibody trial in recent-onset type 1 diabetic patients depends on their age and baseline residual beta cell mass.

AIMS/HYPOTHESIS: The aim of the study was to examine the 48 month outcome of treating recent-onset type 1 diabetic patients for 6 days with humanised CD3-antibody, ChAglyCD3. METHODS: Eighty patients, aged 12-39 years, were recruited for a phase 2 multicentre trial and randomised to placebo (n=40) or ChAglyCD3 (n=40) treatment by a third party member; participants and care-givers were blinded. The change in insulin dose (U kg(-1)day(-1)) over 48 months was chosen as primary endpoint and compared in 31 placebo-and 33 ChAglyCD3-treated patients. Adverse events were followed in 35 and 38 patients, respectively. RESULTS: Treatment with ChAglyCD3 delayed the rise in insulin requirements of patients with recent-onset diabetes and reduced its amplitude over 48 months (+0.09 vs +0.32 U kg(-1)day(-1) in the placebo group). Using multivariate analysis this effect was correlated with higher baseline residual beta cell function and a younger age. It was associated with better outcome variables in subgroups selected according to these variables. In the ChAglyCD3 subgroup with higher initial beta cell function, 0/11 patients became C-peptide-negative over 48 months vs 4/9 in the corresponding placebo subgroup. In the subgroup aged <27 years old, antibody treatment preserved initial beta cell function for 36 months (vs >80% decline within 24 months in the placebo subgroup <27 years old), resulted in lower HbA1c concentrations and tended to reduce glycaemic variability (p=0.08). No longterm adverse events were observed. CONCLUSIONS/INTERPRETATION: A 6 day ChAglyCD3 treatment can suppress the rise in insulin requirements of recent-onset type 1 diabetic patients over 48 months, depending on their age and initial residual beta cell function. In younger patients this effect is associated with reduced deterioration of metabolic variables. These observations help to define inclusion criteria for prevention trials. TRIAL REGISTRATION: ClinicalTrials.gov NCT00627146 FUNDING: Center grants from the Juvenile Diabetes Research Foundation (4-2001-434, 4-2005-1327) and grants from the Belgian Fund for Scientific Research-Flanders and from Brussels Free University-VUB.

Seasonality in clinical onset of type 1 diabetes in belgian patients above the age of 10 is restricted to HLA-DQ2/DQ8-negative males, which explains the male to female excess in incidence.

AIMS/HYPOTHESIS: Type 1 diabetes arises from an interplay between environmental and genetic factors. The reported seasonality at diagnosis supports the hypothesis that currently unknown external triggers play a role in the onset of the disease. We investigated whether a seasonal pattern is observed at diagnosis in Belgian Type 1 diabetic patients, and if so whether seasonality varies according to age, sex and genetic risk, all known to affect the incidence of Type 1 diabetes. METHODS: The seasonal pattern at clinical diagnosis was assessed in 2176 islet antibody-positive diabetic patients aged 0 to 39 years diagnosed between 1989 and 2000. Additional stratification was performed for age, sex and HLA-DQ genotype. RESULTS: Overall, a significant seasonal pattern at clinical diagnosis of diabetes was observed (p<0.001). More subjects were diagnosed in the period of November to February (n=829) than during the period of June to September (n=619) characterised by higher averages of maximal daily temperature and daily hours of sunshine. However, the seasonal pattern was restricted to patients diagnosed above the age of 10 (0-9 years: p=0.398; 10-19 years: p<0.001; 20-29 years: p=0.003; 30-39 years: p=0.015). Since older age at diagnosis is associated with a male to female excess and a lower prevalence of the genetic accelerator HLA-DQ2/DQ8, we further stratified the patients aged 10 to 39 years (n=1675) according to HLA-DQ genotype and sex, and we found that the seasonal pattern was largely restricted to male subjects lacking DQ2/DQ8 (n=748; p<0.00 vs all others: n=927; p=0.031). CONCLUSIONS/INTERPRETATION: In a subgroup of male patients diagnosed over the age of 10, the later stages of the subclinical disease process may be more driven by sex- and season-dependent external factors than in younger, female and genetically more susceptible subjects. These factors may explain the male to female excess in diabetes diagnosed in early adulthood.

[The endocrinology department]. / Le Service d'Endocrinologie.

The clinical activities of the department of endocrinology encompass the care and treatment of diabetes, thyroid diseases, hypothalamo-pituitary, adrenal, gonadic and parathyroid diseases, obesity, hypercholesterolemia and paraneoplastic endocrine syndromes. These domains are briefly described. The research activities of the department have investigated the regulation of thyroid metabolism in vitro, the intrathyroid H2O2 generating system, the physiopathology of toxic thyroid nodules and the effects of ageing on the thyreotropic function of the normal ageing male. Studies of "jet lag" conditions have shed a new light on hormonal chronophysiology. Other investigations have considered the regulation of ketone body metabolism, the relationship between nutritional status and glucose metabolism, and some aspects of immunodiabetology.

Uptake of tritiated D-mannoheptulose by liver, pancreatic exocrine and endocrine cells.

Tritiated D-mannoheptulose, a ketoheptose known to inhibit D-glucose metabolism in hepatocytes and pancreatic islets, but not so in pancreatic acinar cells, was injected intravenously in streptozotocin-induced diabetic mice transplanted under the kidney capsule with islets from control mice of the same strain. One hour after the injection of the tritiated heptose, the radioactive content was 5-8 times higher in the liver and transplanted islets than in the pancreatic gland. It is proposed that suitably radiolabelled D-mannoheptulose could be used to label preferentially the endocrine moiety of the pancreatic gland, e.g., in the perspective of its non-invasive imaging.

[Orlistat (Xenical)]. / Orlistat (Xénical).

Orlistat, a potent inhibitor of the pancreatic and intestinal lipases, is the first member of a new therapeutic class approved for the treatment of obesity. Its administration with fat-containing foods results in a partial inhibition of triglyceride hydrolysis in the digestive lumen and subsequent reduction of the free fatty acids and monoglycerides absorption. At the usual dosage of 120 mg tid, about 30% of ingested fat are excreted non digested in feces. When administered with a mildly hypocaloric diet, orlistat contributes to loss of weight by a additional caloric deficit and promotes further compliance of the obese patient to the dietary recommendations. Several double-blinded, placebo-controlled studies have shown a statistically significant loss of weight of about 10% when orlistat was prescribed with a well balanced, mildly hypocaloric diet to obese patients during one year. Moreover, small but significant beneficial changes in the serum lipid levels occurred in these patients. Because the orlistat molecule is not reabsorbed, its side effects are mostly due to the gastrointestinal effects and consist in steatorhea after fatty meals. However, the treatment is generally well tolerated. Since the recent withdrawal from the worldwide market of the anorectic agents, phentermine and fenfluramine, orlistat is at this time the only drug approved by the European Community for the treatment of obesity. However, its long-term value are not currently known.

Autologous stem cell infusion for acute myeloblastic leukemia in an HIV-1 carrier.

We present the case of an asymptomatic HIV carrier, who presented with acute myeloblastic leukemia in third relapse and successfully underwent autologous stem cell transplantation as a rescue treatment. This observation supports the conclusion that tolerance of autologous bone marrow or stem cell transplant in patients with HIV may correlate with a low viral burden and relatively good immune function.

A case of rapidly fatal systemic capillary leak syndrome in a kidney transplant recipient.

Idiopathic Systemic Capillary Leak Syndrome (SCLS) is a rare entity characterised by idiopathic increasing of capillary permeability associated with recurrent attacks of hypovolaemic shock. We report the case of a 39-year-old man with a SCLS fourteen years after a cadaveric renal transplantation. The clinical evolution was rapidly fatal despite treatment with corticoids, aminophylline and terbutaline which are the most efficient drugs known to prevent attacks.

[Disseminated intravascular coagulation syndrome as a manifestation of breast adenocarcinoma metastasis]. / Syndrome de coagulation intravasculaire disséminée révélateur de la généralisation d'un adénocarcinome mammaire.

Disseminated intravascular coagulation is a well known complication of malignancies especially of mucin-secreting cancers. However, it rarely occurs as the first clinical manifestation of a neoplasm. We report the case of a subacute disseminated intravascular coagulation syndrome revealing a metastatic breast carcinoma.

Low response to high-dose intravenous immunoglobulin in the treatment of acquired factor VIII inhibitor.

Prednisone is the classic first-line therapy to suppress an acquired factor VIII inhibitor and may achieve complete remission in about 30% of patients. More recently, promising results have been reported with high-dose intravenous immunoglobulin (IVIg). However, after an extensive review of the literature, we found only three complete remissions (12%) among the 26 assessable patients treated by IVIg. These data are in agreement with the low response to IVIg that we experienced in our series of patients. This study suggests that steroids should still be preferred to IVIg, an expansive therapy, to suppress an acquired factor VIII inhibitor.

Restoration by corticosteroids of the hyperaldosteronism in hyponatraemic rats with panhypopituitarism.

1. In the syndrome of inappropriate secretion of antidiuretic hormone, hyponatraemia is associated with a normal bicarbonate concentration despite dilution. This normal bicarbonate concentration is related to the development of a hyperaldosteronism, which is attributed to a direct stimulation of the zona glomerulosa by the hyponatraemic state. Some workers have suggested that, to develop this hyperaldosteronism requires the presence of a pituitary factor. To determine whether the pituitary gland plays a role in this hyponatraemia-induced hyperaldosteronism, water intoxication was performed for 24 h in normal and in panhypopituitaric rats. 2. In normal rats, hyponatraemia (108 mmol/l), induced by the administration of 1-desamino-8-D-arginine vasopressin and 2.5% D-glucose-0.45% NaCl by gavage (15% body weight) was associated with a mild increase in bicarbonate concentration, and blood acid-base equilibrium showed a mixed metabolic and respiratory alkalosis (pH 7.57, partial pressure of CO2 29 mmHg, base excess +5.5 mmol/l), and aldosterone concentration was increased 3-fold as compared with the control value. When hyponatraemia (110 mmol/l) was induced in a similar manner in panhypopituitaric rats, we observed a very low aldosterone concentration (< 50 pg/ml) and a compensated respiratory alkalosis (pH 7.45, partial pressure of CO2 30 mmHg, base excess -2.6 mmol/l). The restoration of a hyperaldosteronaemic state in this group of rats was related essentially to corticosteroid intake. 3. These data suggest that corticosteroids play a critical role in the development of hyponatraemia-related hyperaldosteronism, a phenomenon not necessarily dependent on a pituitary factor.

Normal acid-base equilibrium in acute hyponatremia and mixed alkalosis in chronic hyponatremia induced by arginine vasopressin or 1-deamino-8-D-arginine vasopressin in rats.

The effects of acute and chronic water intoxication induced by the administration of oral water and arginine vasopressin (AVP) or 1-deamino-8-D-arginine-vasopressin (DDAVP) on blood acid-base equilibrium and aldosterone, corticosterone, and thyroxine secretion were studied in rats. Acute hyponatremia (3 hours) was associated with normal bicarbonate and blood acid-base equilibrium and a decrease in aldosterone and thyroxine concentrations, while corticosterone was increased. When similar levels of hyponatremia (serum sodium 110 mEq/L) were maintained for 24 or 72 hours, a normal serum bicarbonate concentration was observed, but blood acid-base equilibrium showed a mixed respiratory and metabolic alkalosis. Blood pH was negatively correlated with serum sodium concentration (R = -0.65; p < 0.001), as was the metabolic alkalosis (base excess; R = -0.64; p < 0.001) and the aldosterone concentration (R = -0.52; p < 0.01), while the PCO2 was positively correlated (R = +0.49; p < 0.01). Hyperaldosteronism was similar whether hyponatremia was induced with AVP or DDAVP and was observed even for mild hyponatremia. When hyponatremia was induced by a high water and salt intake (2.5% D-glucose, 0.45% NaCl; 15% body weight), aldosterone concentration was as high (about three times control values) as in rats with similar levels of hyponatremia but with a salt-free diet. The high salt intake was associated with a more severe metabolic alkalosis (base excess +5,5 mEq/L). In chronic hyponatremia, corticosterone and thyroxine values were normal. In hyponatremia related to syndrome of inappropriate secretion of antidiuretic hormone, the normal serum bicarbonate level is an expected observation; as in acute water intoxication, it stays normal.(ABSTRACT TRUNCATED AT 250 WORDS)

Prevention of brain demyelination in rats after excessive correction of chronic hyponatremia by serum sodium lowering.

Brain myelinolysis occurs after correction of chronic hyponatremia in rats when the magnitude of increase in serum sodium (delta SNa) exceeds 20 to 25 mEq/liter/24 hr (the critical threshold for brain). We tested the hypothesis that after a sustained excessive correction, brain lesions (BL) could be prevented by subsequently decreasing the serum sodium below the critical threshold for brain through the administration of hypotonic fluids. After three days of severe (< 115 mEq/liter) chronic (3 days) hyponatremia, 55 rats were submitted to an excessive correction (delta SNa > 25 mEq/liter) by a single i.p. infusion of hypertonic saline (NaCl). This osmotic stress was maintained during 12 hours before the serum sodium decrease was initiated. Thirty-two rats reached the twelfth post-correction hour without symptoms. In group 1 after a large (delta SNa 32 mEq/liter) and sustained (12 hr) osmotic stress, the natremia was rapidly (2 hr) decreased by the administration of oral tap water and, at the end of the first 24 hours, the magnitude of correction was maintained below 20 mEq/liter/24 hr. All the rats fared well in this group and were free of neurologic symptoms. Mild BL were noticed in only 20% of them. On the contrary, in controls (no hypotonic fluids administration at the twelfth hour) whose serum sodium was left overcorrected, all the rats became symptomatic and 57% of them died rapidly. Brain damage developed in 100% of the surviving rats. In group 2, despite hypotonic fluids administration, the serum sodium decreased insufficiently and the correction was > 20 mEq/liter at the end of the first 24 hours (delta SNa 25 mEq/liter).(ABSTRACT TRUNCATED AT 250 WORDS)

Differential activity of bacteriocins and cefotaxime against Serratia marcescens clinical isolate SMG40 and its pigmented variant.

Strain Serratia marcescens SMG40 was nonpigmented but yielded pigmented variants at low frequency. Of 15 tested bacteriocins, 10 were active against the original strain, but only 7 were active against the pigmented variant Pdg+. Moreover, active cephalosporins, e.g., cefotaxime, were more active against the Pdg+ variant than against strain SMG40. These reciprocal differences in susceptibility to some bacteriocins and to cefotaxime were maintained in subclones derived from Pdg+/- sectored colonies. However, mutants of pigmentation isolated from the Pdg+ variant were not modified with regard to bacteriocins and cefotaxime. Other clinical isolates of Serratia were examined for comparison, but strain SMG40 appeared to be unique.