Gender-based dimorphic pattern for interleukin-1 receptor antagonist in type 2 diabetes mellitus.

UNLABELLED: Adipose tissue secretes a variety of cytokines, some of which are increased in the serum of obese patients. The anti-inflammatory interleukin-1 receptor antagonist (IL-1Ra) is the most highly elevated known cytokine in human obesity, and its serum levels are strongly associated with the degree of insulin resistance in non-diabetic patients. AIM: The present study examined serum levels of IL-1Ra in type 2 diabetic patients (T2DM) and their relationships with three other adipokines (leptin, interleukin-6 [IL-6], adiponectin). Their correlation with anthropometric and biochemical variables was examined, as well as their intraindividual fluctuations. METHODS: Fifty T2DM patients, aged 58+/-13 years, were consecutively recruited among those electively hospitalized for a one-week intensive training course with our Diabetes Education Service. Anthropometric measurements and blood samples were taken after an overnight fast on admission (baseline) and after four days. RESULTS: Mean serum levels of IL-1Ra and leptin, but not of IL-6 and adiponectin, were significantly higher in women than in men (P<0.0006), and this difference persisted after correction for body mass index (BMI) (P<0.0004). In addition, IL-1Ra and leptin were strongly correlated with the BMI (P<0.0004). By contrast, no significant correlations were observed between IL-1Ra and glucose-control parameters. Finally, all four adipokines exhibited wide interindividual variability, but with limited intraindividual fluctuations over the short time period. CONCLUSION: IL-1Ra, leptin and adiponectin serum levels exhibit marked interindividual variation with high intraindividual consistency. A gender-based dimorphic pattern for IL-1Ra, independent of the degree of adiposity and glucose control, was also found.

[10 years of lipodystrophy--and so many uncertainties]. / Dix ans de lipodystrophie (1998-2008): un syndrome encore méconnu.

HIV lipodystrophy is characterized by peripheral, subcutaneous lipoatrophy in the face, arms, legs, and buttocks and central fat accumulation in the neck, breasts, and abdomen (referred as lipohypertrophy). Lipodystrophy is associated with atherogenic lipid abnormalities, low levels of HDL cholesterol, insulin resistance, and, less commonly, hyperglycaemia. Causes of lipodystrophy are not completely elucidated. The prevalence of lipodystrophy ranges from 20% to 70% of the patients after one year of ART, depending on the type of ART, with lower prevalence in more recent studies of newer agents. Treatment strategies are disappointing. A multidisciplinary approach is now proposed in the Geneva University Hospital in order to coordinate efforts from different department, including internal medicine, infectiology or esthetic surgery for example.

[Endocrinology]. / Endocrinologie.

There is now convincing evidence that the risks of hormone replacement therapy in post-menopausal women exceed its benefits. Similarly, it has now been shown that the current use of low-dose oral contraceptives significantly increases the risk for cardiac and arterial thrombotic events. With regard to hypothyroidism, it is now clearly established that the adjunction of T3 to T4 does not offer any benefits. Furthermore, a study has now demonstrated that patients with no symptoms of coronary heart disease can be started safely on the full replacement dose of T4 rather than titrating the dose over a prolong period of time. Finally, several theses are now well documented where chinese herbal products contain thyroid hormones or glucocorticoids potentially leading to serious side effects and our patients should be informed about these dangers.

Peroxisome proliferator-activated receptor-alpha and -gamma mRNA levels are reduced in chronic hepatitis C with steatosis and genotype 3 infection.

BACKGROUND: Steatosis in chronic hepatitis C is associated with inflammation and accelerated fibrogenesis. AIM: To assess the contribution of peroxisome proliferator-activated receptor-alpha and -gamma to the pathogenesis of hepatitis C virus associated steatosis is unknown. METHODS: We measured peroxisome proliferator-activated receptor (PPAR)-alpha and -gamma mRNA by quantitative polymerase chain reaction in liver biopsies of 35 genotype 1 and 22 genotype 3 infected patients and in Huh7 cells expressing hepatitis C virus 1b or 3a core protein. RESULTS: PPAR-alpha mRNA was significantly reduced in livers of patients with genotype 3 compared with genotype 1. Steatosis was associated to a decreased expression of PPAR-alpha in genotype 1, but not in genotype 3. PPAR-gamma expression was significantly lower in genotype 3 compared with genotype 1 and steatosis was associated to decreased levels of PPAR-gamma, but only in genotype 1. There was no significant relationship between PPARs mRNA levels and liver activity or fibrosis. Expression of the hepatitis C virus 3a core protein was associated with an increase in triglyceride accumulation and with a significant reduction of PPAR-gamma mRNA compared with hepatitis C virus 1b. CONCLUSIONS: The presence of steatosis and hepatitis C virus genotype 3 are both associated with a significant down-regulation of PPARs. These receptors, and also additional factors, seem to play a role in the pathogenesis of hepatitis C virus-associated steatosis.

Interleukin-1 receptor antagonist is upregulated during diet-induced obesity and regulates insulin sensitivity in rodents.

AIMS/HYPOTHESIS: The IL-1 receptor antagonist (IL-1Ra) is an anti-inflammatory cytokine known to antagonise the actions of IL-1. We have previously shown that IL-1Ra is markedly upregulated in the serum of obese patients, is correlated with BMI and insulin resistance, and is overexpressed in the white adipose tissue (WAT) of obese humans. The aim of this study was to examine the role of IL-1Ra in the regulation of glucose homeostasis in rodents. METHODS: We assessed the expression of genes related to IL-1 signalling in the WAT of mice fed a high-fat diet, as well as the effect of Il1rn (the gene for IL-1Ra) deletion and treatment with IL-1Ra on glucose homeostasis in rodents. RESULTS: We show that the expression of Il1rn and the gene encoding the inhibitory type II IL-1 receptor was upregulated in diet-induced obesity. The blood insulin:glucose ratio was significantly lower in Il1rn ( -/- )animals, which is compatible with an increased sensitivity to insulin, reinforced by the fact that the insulin content and pancreatic islet morphology of Il1rn ( -/- ) animals were normal. In contrast, the administration of IL-1Ra to normal rats for 5 days led to a decrease in the whole-body glucose disposal due to a selective decrease in muscle-specific glucose uptake. CONCLUSIONS/INTERPRETATION: The expression of genes encoding inhibitors of IL-1 signalling is upregulated in the WAT of mice with diet-induced obesity, and IL-1Ra reduces insulin sensitivity in rats through a muscle-specific decrease in glucose uptake. These results suggest that the markedly increased levels of IL-1Ra in human obesity might contribute to the development of insulin resistance.

[Focus on dehydroepiandrosterone (DHEA)]. / Mise au point sur la déhydroépiandrostérone (DHEA).

Secreted by the adrenal cortex, DHEA exerts its action either indirectly in peripheral tissues after its conversion to androgens and estrogens, or directly as a neurosteroid through the interaction with neuronal receptors. Analyses of randomized studies show that treatment with DHEA improves well-being and fatigue in patients with adrenal insufficiency and reduces disease activity in women with systemic lupus erythematosus. Interesting results have also been observed in the treatment of depressive disorders, but these studies require confirmation. In contrast, there is neither justification for DHEA supplementation in healthy elderly subjects nor clear evidence for beneficial effects of DHEA on muscle function, bone metabolism or cognition. Finally, there is no guarantee with regard to the quality of the product or its safety during long term use.

[Growth hormone treatment: pediatric to adult clinic transition]. / Traitement par hormone de croissance: phase de transition de l'enfance à l'âge adulte.

The diagnosis of GH deficiency is difficult to establish: clinical, radiological and hormonal data are combined to suspect the disease. GH stimulation tests are an essential part of the evaluation, although the cut-off values are determined arbitrarily. There are different stimulation tests. Their use depends on the patient's age. Once the diagnosis is ascertained, the treatment is started and maintened until the end of statural growth. The persistence of GH deficiency needs to be confirmed during the transition phase. If required, GH treatment can be continued until the achievement of peak bone mass. Thereafter the benefit of continuing GH treatment are mainly related to the quality of life. The long term effects on cardiovascular morbidity/mortality are not demonstrated.

Hypothyroidism in rats decreases peripheral glucose utilisation, a defect partially corrected by central leptin infusion.

AIMS/HYPOTHESIS: The aims of this work were to determine the effect of hypothyroidism on insulin-stimulated glucose turnover and to unravel the potential mechanisms involved in such an effect. METHODS: Hypothyroidism was induced by administration of propylthiouracil, with partial T4 substitution. Euglycaemic-hyperinsulinaemic clamps, associated with the labelled 2-deoxy-D-glucose technique for measuring tissue-specific glucose utilisation, were used. To assess a possible involvement of leptin in the modulation of glucose metabolism by hypothyroidism, leptin was infused intracerebroventricularly for 6 days. A group of leptin-infused rats was treated with rT3 to determine a potential role of T3 in mediating the leptin effects. RESULTS: Compared with euthyroid rats, hypothyroid animals exhibited decreased overall glucose turnover and decreased glucose utilisation indices in skeletal muscle and adipose tissue. Leptinaemia in hypothyroid rats was lower while resistin mRNA expression in adipose tissue was higher than in euthyroid animals. Intracerebroventricular leptin infusion in hypothyroid rats partially restored overall, muscle and adipose tissue insulin-stimulated glucose utilisation and improved the reduced glycaemic response observed during insulin tolerance tests. The leptin effects were due neither to the observed increase in plasma T3 levels nor to changes in the high adipose tissue resistin expression of hypothyroid rats. The administration of leptin to hypothyroid animals was accompanied by increased expression of muscle and adipose tissue carnitine palmitoyl transferases, decreased plasma NEFA levels and reduced muscle triglyceride content. CONCLUSIONS/INTERPRETATION: Hypothyroidism is characterised by decreased insulin responsiveness, partly mediated by an exaggerated glucose-fatty acid cycle that is partly alleviated by intracerebroventricular leptin administration.

[Endocrinology]. / Endocrinologie.

Several large studies regarding the treatment of endocrine tumors have been published during the past year. Since pituitary tumors and medullary thyroid carcinomas are rare, their treatment largely depended on the data from small series and personal experience and these new studies now contribute to the better treatment of these pathologies. On the other hand, important data from clinical trials have appeared regarding the substitution with thyroid hormone during pregnancy as well as the role of leptin in women with hypothalamic amenorrhea.

Adrenal cortical phaeochromocytoma: a case report of a rare entity.

Adrenal cortical phaeochromocytomas (pseudo-phaeochromocytomas) are a very rare entity and a diagnostic challenge. Of the few cases previously reported, most have incomplete data or lack clinical and biochemical follow-up documenting the cure of the excess secretion of catecholamines after resection of the tumour. We report herein a 62-year-old patient with clinical and biochemical findings diagnostic of a phaeochromocytoma associated with a 2-cm adrenal mass on CT scan. Surgery revealed the presence of an adrenal cortical adenoma with positive staining for the neuroendocrine marker synaptophysin, but negative for chromogranin, as has been previously reported for these rare cortical phaeochromocytomas. After removal of the tumour the clinical symptoms resolved and biochemical markers normalized, demonstrating the causal relationship between the cortical tumour and the excess production of catecholamines.

Leptin directly induces the secretion of interleukin 1 receptor antagonist in human monocytes.

Besides its actions on the regulation of appetite, leptin has also been implicated in regulating reproductive and immune functions. Because leptin-deficient mice are more susceptible to lipopolysaccharide- and tumor necrosis factor-alpha-induced shock, which is associated with lower levels of interleukin 1 receptor antagonist (IL-1Ra), we investigated whether leptin is a direct regulator of IL-1Ra in human monocytes. In human moncytic cells, leptin was capable of inducing a 6- to 10-fold increase in secreted IL-1Ra in a time- and dose-dependent manner. Moreover, leptin induced the messenger RNA for IL-1Ra within 8 h and specifically activated the promoter for this gene. However, leptin had no effect on the expression or secretion of IL-1 in THP-1 cells. This effect of leptin on monocytic cells requires the presence of the functional leptin receptor OB-Rb, which we have shown to be present in human monocytes by RT-PCR and by measuring the activation of the Jak/STAT pathway. In summary, we have demonstrated that leptin is capable of inducing the expression and secretion of IL-1Ra by human monocytes, an effect that is potentially mediated through the presence of functional leptin receptors on these cells. These findings suggest that leptin may have immunomodulatory functions in vivo.

Peroxisomal bifunctional enzyme binds and activates the activation function-1 region of the peroxisome proliferator-activated receptor alpha.

The transcriptional activity of peroxisome proliferator-activated receptors (PPARs), and of nuclear hormone receptors in general, is subject to modulation by cofactors. However, most currently known co-activating proteins interact in a ligand-dependent manner with the C-terminal ligand-regulated activation function (AF)-2 domain of nuclear receptors. Since PPARalpha exhibits a strong constitutive transactivating function contained within an N-terminal AF-1 region, it can be speculated that a different set of cofactors might interact with this region of PPARs. An affinity purification approach was used to identify the peroxisomal enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase (bifunctional enzyme, BFE) as a protein which strongly and specifically interacted with the N-terminal 92 amino acids of PPARalpha. Protein-protein interaction assays with the cloned BFE confirmed this interaction, which could be mapped to amino acids 307-514 of the BFE and the N-terminal 70 amino acids of PPARalpha. Moreover, transient transfection experiments in hepatoma cells revealed a 2.2-fold increase in the basal and ligand-stimulated transcriptional activity of PPARalpha in the presence of BFE. This stimulatory effect is preferentially observed for the PPARalpha isoform and it is significantly stronger (4.8-fold) in non-hepatic cells, which presumably express lower levels of endogenous BFE. Hence, the BFE represents the first known cofactor capable of activating the AF-1 domain of PPAR without requiring additional regions of this receptor. These data are compatible with a model whereby the PPAR-regulated BFE is able to modulate its own expression through an enhancement of the activity of PPARalpha, representing a novel peroxisomal-nuclear feed-forward regulatory loop.

[Thyroid cancers: the Geneva experience]. / Cancers de la thyroïde: expérience genevoise.

AIM OF THE STUDY: To study the survival of patients with thyroid cancer operated in the same centre from 1978 to 1999. PATIENTS AND METHOD: This retrospective study included 218 patients operated on for thyroid carcinoma from january 1978 to december 1999. Modified neck dissection was performed only in the presence of one or more suspected lymph nodes. The stage of the cancer was defined according to the last TNM classification (1997). Survival data were taken from the Geneva Tumour Registry (168 patients = 77% of the series, 109 papillary carcinomas, 37 follicular, 14 undifferentiated and 8 medullary carcinomas). RESULTS: The overall 5, 10 and 15-year survival rates were respectively 88%, 84% and 80%. Papillary carcinoma was associated with the best survival at 5, 10 and 15 years (99%, 97% and 93%), despite a recurrence rate of 20% treated mainly by surgery often associated with radioiodine therapy. Follicular carcinoma had a survival rate of 83% at 5 years and 75% at 10 years. Undifferentiated carcinoma had a median survival rate of 56 days. None of the 8 patients with medullary carcinoma had died from that cancer in this series. CONCLUSION: Thyroid carcinoma carries such a good prognosis (except for undifferentiated carcinoma) that invasive surgery at first operation, like radical neck dissection, is not justified, despite a high rate of recurrence.

Expression of peroxisome proliferator-activated receptors in lean and obese Zucker rats.

OBJECTIVE: Examination of the pattern of expression of peroxisome proliferator-activated receptor (PPAR) isoforms alpha and gamma in a model of obesity. DESIGN: Examination of adipose tissue and primary adipocyte cultures from lean and obese Zucker rats at different ages (28 days and 12 weeks). METHODS: mRNA levels were measured by RNase protection assay. RESULTS: The highest levels of PPARalpha and gamma mRNA were present in brown adipose tissue (BAT), followed by liver and white adipose tissue (WAT) for the alpha and gamma subtypes, respectively, at both ages examined. PPARalpha was expressed 100-fold higher in BAT compared with WAT, and PPARgamma mRNA levels were 2-fold higher in the WAT of obese compared with lean rats. PPARalpha and gamma expression was minimal in m. soleus, although higher levels of PPARgamma were found in the diaphragm. In marked contrast to the findings in vivo, virtually no PPARalpha mRNA could be detected in BAT cultures differentiated in vitro. CONCLUSION: PPARalpha and gamma are most highly expressed in BAT in vivo. However, PPARalpha is undetectable in brown adipose cells in vitro, suggesting that the expression of this receptor is induced by some external stimuli. In addition, the expression of PPARgamma was increased in WAT from young obese animals, compatible with an early adaptive phenomenon. Finally, the presence of PPARgamma mRNA is detectable only in particular muscles, such as the diaphragm, suggesting the possibility of an influence of fiber type on its expression, although exercise did not influence the expression of PPARgamma in other skeletal muscles.

Thyroid nodules: pathogenesis, diagnosis and treatment.

Thyroid nodules are very frequently found and their prevalence steadily increases with age. The discovery of such lesions by high-resolution radiological imaging procedures that have been performed for other indications raises the problem of how incidentally discovered thyroid nodules should be investigated in a cost-effective manner to identify the rare patient with a clinically significant malignancy. In this review the clinical criteria that prompt the evaluation of thyroid nodules are discussed, as is the currently recommended diagnostic approach, which principally relies on fine needle aspiration biopsy. The clinical implications of the different cytological diagnoses are discussed, with a special emphasis on the management of indeterminate, microfollicular lesions. Finally, the evidence for and against suppressive thyroid hormone therapy for benign thyroid nodules and multinodular goitres is discussed, with particular consideration of high-risk patients with prior external radiation therapy to the neck region.

[Hyperthyroidism--advantages and disadvantages of pharmacologic, surgical, and radioactive iodine treatments]. / Hyperthyreose--Vor- und Nachteile der medikamentösen, chirurgischen und Radiojod-behandlung.

The choice of optimal therapy for hyperthyroidism is determined by the etiology. While radioiodine is the optimal choice for the treatment of autonomous nodules, the management of Graves' disease is somewhat controversial. Nevertheless, the detailed discussion of the advantages and disadvantages of the various therapeutic options allows to establish an individual treatment plan for each patient. Severely hyperthyroid or pregnant patients pose additional problems, which should be resolved in close collaboration of a general practitioner with an endocrinologist.

Conserved amino acids in the ligand-binding and tau(i) domains of the peroxisome proliferator-activated receptor alpha are necessary for heterodimerization with RXR.

The peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily. These ligand-activated transcription factors are implicated in the regulation of lipid metabolism and adipocyte differentiation and in the regulation of anti-inflammatory processes. In order to bind to DNA and activate transcription PPAR requires the formation of heterodimers with the retinoid X receptor (RXR). We have previously reported that replacement of a single leucine by an arginine at position 433 of hPPAR alpha (L433R), located in a highly conserved region of the ninth heptad repeat of a leucine-zipper-like motif in the ligand binding domain, abolished heterodimerization of PPAR with RXR and hence its trans-activating capacity. The aim of our present work was to investigate if other conserved amino acids of the ligand binding domain are important for heterodimerization of PPAR with RXR. We found that conserved leucines, L370 and L391, in a leucine-zipper-like motif of hPPAR alpha, as well as a highly conserved aspartic acid (D304) in the tau(i) domain are necessary for heterodimerization with RXR. In contrast, mutations of non-conserved amino acids within the leucine-zipper-like motif do not affect PPAR:RXR heterodimerization. Surprisingly, we found that some mutants deficient in heterodimerization with RXR (hPPAR alpha-L370R and -L391R) were still functional on specific peroxisome proliferator-activator response elements (PPREs). Both mutants could trans-activate on a PPRE from the P450 cytochrome promoter CYP4A1, whereas only the hPPAR alpha-L391R mutant could trans-activate from the acyl-CoA oxidase PPRE (ACOA) and, when stimulated with the peroxisome proliferator Wy14643, also from the bifunctional enzyme PPRE. We therefore hypothesize either that: (i) these mutants might be able to heterodimerize with a protein other than RXR and the affinity for this novel partner may depend on the nature of the PPRE and to some degree on the choice of the activator, or alternatively; (ii) that additional nuclear proteins might compensate in vivo for the decreased binding of RXR to these mutant PPARs observed in vitro.