A SDHB malignant paraganglioma with dramatic response to temozolomide-capecitabine.

Ten percent of paragangliomas are malignant and one-third occurs in a genetic background. We report a case of succinate dehydrogenase subunit B (SDHB)-related malignant paraganglioma with dramatic response to temozolomide and capecitabine regimen (decrease in tumor size of 70% with RECIST criteria). Tumor cells harbored a new mutation in SDHB gene and showed aberrant hypermethylation of O6-methylguanine-DNA-methyltransferase promoter. Our report suggests the importance of molecular predictive factors of response for the selection of chemotherapeutic as well as targeted agents. This observation points to a possible genotype response to treatment relationships, which could help to design tailor-made treatments in the future.

Patient versus general practitioner perception of problems with treatment adherence in type 2 diabetes: from adherence to concordance.

OBJECTIVES: To determine the prevalence of problems with treatment adherence among type-2 diabetic patients with regards to medication, dietary advice, and physical activity; to identify the associated clinical and psychosocial factors; and to investigate the degree of agreement between patient-perceived and GP-perceived adherence. METHODS: Consecutive patients were solicited during visits to 39 GPs. In total, 521 patients self-reported on treatment adherence, anxiety and depression, and disease perception. The GPs reported clinical and laboratory data and patients' adherence. A multivariate analysis identified the factors associated with adherence problems. RESULTS: Problems of adherence to medication, dietary advice, and physical activity recommendations were reported by 17%, 62%, and 47% of the patients, respectively. Six independent factors were found associated with adherence problems: young age, body-mass index (BMI) > 30 kg/m(2), glycosylated haemoglobin (HbA(1c)) > 8%, single life, depression, and perception of medication as a constraint. Agreement between patients' and GPs' assessments of treatment problems reached 70%. CONCLUSION: In type 2 diabetes, problems with dietary advice or physical activity are far more frequent than problems with medication, and not all physicians are fully aware of patients' problems. More active listening and shared decision-making should enhance adherence and improve outcomes.

Atypical thyrotropin-secreting pituitary microadenoma revealed by severe osteoporosis in a young man.

For 10 years, a young man was followed for a severe osteoporosis associated with a considerable reduction in height and a massive weight loss. The constant increase of signs of tissue impregnation with thyroid hormones and the molar ratios of alpha-TSH suggested an inappropriate secretion of thyrotropin. Magnetic resonance imaging finally revealed a thyrotropic microadenoma of the pituitary gland. This case gives some new additional information on thyrotropin-induced osteoporosis. To our knowledge such a case has never been reported in the literature.

Mifepristone for ectopic ACTH secretion in metastatic endocrine carcinomas: report of two cases.

Ectopic adrenocorticotropin secretion (EAS) remains a therapeutic challenge whenever the tumor responsible for the syndrome is not amenable to curative resection. Two cases of EAS related to metastatic foregut-derived endocrine carcinomas led us to use mifepristone, an antagonist of both progesterone and glucocorticoids. Mifepristone clearly improved skin lesions and diabetes associated with hypercorticism. The beneficial effect lasted for about 10 months. In both cases, recurrent hypertension and hypokalemia eventually required adrenalectomy.

CCAAT/enhancer-binding proteins (C/EBPs) regulate the basal and cAMP-induced transcription of the human 11beta-hydroxysteroid dehydrogenase encoding gene in adipose cells.

Android obesity is often associated with a metabolic syndrome characterized, in particular, by a type 2 diabetes and cardiovascular problems. This could be induced by an excess of local production of glucocorticoids (GC) by adipose tissue (or other tissues). This production of GC by its target tissues depends on the 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) enzyme. Our aim was to characterize some mechanisms which control the expression of the human 11betaHSD1 gene (hHSD11B1) in preadipocytes. By using different luciferase constructs containing fragments of the hHSD11B1 promoter, we demonstrate that two members of the CCAAT/enhancer-binding protein family, C/EBPalpha and C/EBPbeta, are required for the basal transcriptional activity of HSD11B1 in 3T3-L1 preadipocyte cells. This effect depends on the binding of each isoform to specific binding sites. Mutation of either one of these sites induced a 40-50% decrease of the constitutive activity of the hHSD11B1 promoter. A forskolin treatment of 3T3-L1 preadipocyte cells induced an increased endogenous expression of HSD11B1. By transfection studies using the hHSD11B1 luciferase constructs, it appears that C/EBPbeta was strongly involved in this induction, as the forskolin stimulation was suppressed after mutation of the C/EBPbeta binding site. Part of the mechanism involved the increase of nuclear C/EBPbeta protein levels induced by forskolin and a phosphorylation step associated with an enhanced binding of the transcription factor to its site. These data indicate that members of the C/EBP family control intracellular levels of GC in preadipocytes via the regulation of the constitutive and cAMP-dependent expressions of HSD11B1.

Reduced activation of phosphatidylinositol-3 kinase and increased serine 636 phosphorylation of insulin receptor substrate-1 in primary culture of skeletal muscle cells from patients with type 2 diabetes.

To understand better the defects in the proximal steps of insulin signaling during type 2 diabetes, we used differentiated human skeletal muscle cells in primary culture. When compared with cells from control subjects, myotubes established from patients with type 2 diabetes presented the same defects as those previously evidenced in vivo in muscle biopsies, including defective stimulation of phosphatidylinositol (PI) 3-kinase activity, decreased association of PI 3-kinase with insulin receptor substrate (IRS)-1 and reduced IRS-1 tyrosine phosphorylation during insulin stimulation. In contrast to IRS-1, the signaling through IRS-2 was not altered. Investigating the causes of the reduced tyrosine phosphorylation of IRS-1, we found a more than twofold increase in the basal phosphorylation of IRS-1 on serine 636 in myotubes from patients with diabetes. Concomitantly, there was a higher basal mitogen-activated protein kinase (MAPK) activity in these cells, and inhibition of the MAPKs with PD98059 strongly reduced the level of serine 636 phosphorylation. These results suggest that IRS-1 phosphorylation on serine 636 might be involved in the reduced phosphorylation of IRS-1 on tyrosine and in the subsequent alteration of insulin-induced PI 3-kinase activation. Moreover, increased MAPK activity seems to play a role in the phosphorylation of IRS-1 on serine residue in human muscle cells.

Microarray profiling of human skeletal muscle reveals that insulin regulates approximately 800 genes during a hyperinsulinemic clamp.

Insulin action in target tissues involved precise regulation of gene expression. To define the set of insulin-regulated genes in human skeletal muscle, we analyzed the global changes in mRNA levels during a 3-h hyperinsulinemic euglycemic clamp in vastus lateralis muscle of six healthy subjects. Using 29,308 cDNA element microarrays, we found that the mRNA expression of 762 genes, including 353 expressed sequence tags, was significantly modified during insulin infusion. 478 were up-regulated and 284 down-regulated. Most of the genes with known function are novel targets of insulin. They are involved in the transcriptional and translational regulation (29%), intermediary and energy metabolisms (14%), intracellular signaling (12%), and cytoskeleton and vesicle traffic (9%). Other categories consisted of genes coding for receptors, carriers, and transporters (8%), components of the ubiquitin/proteasome pathways (7%) and elements of the immune response (5.5%). These results thus define a transcriptional signature of insulin action in human skeletal muscle. They will help to better define the mechanisms involved in the reduction of insulin effectiveness in pathologies such as type 2 diabetes mellitus, a disease characterized by defective regulation of gene expression in response to insulin.

Expression and regulation by insulin of low-density lipoprotein receptor-related protein mRNA in human skeletal muscle.

Evidence suggests that increased hydrolysis and/or uptake of triglyceride-rich lipoprotein particles in skeletal muscle can be involved in insulin resistance. We determined the steady state mRNA levels of the low-density lipoprotein-related receptor (LRP) and lipoprotein lipase (LPL) in skeletal muscle of eight healthy lean control subjects, eight type 2 diabetic patients and eight nondiabetic obese individuals. The regulation by insulin of LRP and LPL mRNA expression was also investigated in biopsies taken before and at the end of a 3 h euglycemic hyperinsulinemic clamp (insulinemia of about 1 nM). LRP mRNA was expressed in human skeletal muscle (1.3+/-0.1 amol/microg total RNA in control subjects). Type 2 diabetic patients, but not nondiabetic obese subjects, were characterized by a reduced expression of LRP (0.8+/-0.2 and 1.3+/-0.3 amol/microg total RNA in diabetic and obese patients, respectively; P<0.05 in diabetic vs. control subjects). Insulin infusion decreased LRP mRNA levels in muscle of the control subjects but not in muscle of type 2 diabetic and nondiabetic obese patients. Similar results were found when investigating the regulation of the expression of LPL. Taken together, these results did not support the hypothesis that a higher capacity for clearance or hydrolysis of circulating triglycerides in skeletal muscle is present during obesity- or type 2 diabetes-associated insulin resistance.

Eicosapentaenoic acid induces mRNA expression of peroxisome proliferator-activated receptor gamma.

OBJECTIVE: To verify whether polyunsaturated fatty acids (PUFAs) can regulate the expression of the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) in human adipose tissue. RESEARCH METHODS AND PROCEDURES: The effect of various PUFAS on PPARgamma1 and -gamma2 mRNA expression was investigated in freshly isolated adipocytes prepared from fat samples obtained during surgery. PPARgamma mRNA levels were also determined in subcutaneous adipose tissue biopsies of 11 obese women, in the fasting state, to search for in vivo associations between PPARgamma expression and plasma PUFA concentrations. PPARgamma mRNA levels were determined by reverse-transcription competitive polymerase chain reaction. RESULTS: Eicosapentaenoic acid (EPA) significantly increased PPARgamma1 mRNA levels in isolated adipocytes, without affecting the expression of PPARgamma2. The other tested fatty acids (linolenic acid, docosahexaenoic acid and omega-6 PUFAs) had no effect. The effect of EPA was dependent on the concentration (maximal effect after 6 hours with 50 microM) and was not reproduced by activators of the different members of the PPAR family. In addition, a strong positive correlation was found between plasma EPA concentrations and PPARgamma mRNA levels in adipose tissue of obese subjects. DISCUSSION: Our results demonstrate that adipose tissue PPARgamma1 mRNA concentration is positively regulated by EPA, suggesting that the composition of dietary lipids may affect PPARgamma gene expression in vivo in humans. These data also suggest that an induction of the expression of this nuclear receptor isoform might be involved in the mechanism of action of EPA and in some of its beneficial effects.