Scavenger Receptor Class B Type I Regulates Plasma Apolipoprotein E Levels and Dietary Lipid Deposition to the Liver.

Scavenger receptor class B type I (SR-BI) is primarily responsible for the selective uptake of cholesteryl esters (CE) of high-density lipoprotein (HDL) by the liver and other tissues. In the present study, we show that SR-BI-deficient (scarb1(-/-)) mice are resistant to diet-induced obesity, hepatic lipid deposition, and glucose intolerance after 24 weeks of being fed a western-type diet. No differences in energy expenditure or mitochondrial function could account for the observed phenotype. Kinetic and gene expression analyses suggested reduced de novo fatty acid synthesis in scarb1(-/-) mice. Furthermore, adenosine monophosphate-activated protein kinase (AMPK)-stimulated hepatic FFA catabolism was reduced in these mice, leaving direct dietary lipid uptake from plasma as the major modulator of hepatic lipid content. Analysis of the apolipoprotein composition of plasma lipoproteins revealed a significant accumulation of apolipoprotein E (ApoE)-containing HDL and TG-rich lipoproteins in scarb1(-/-) mice that correlated with reduced plasma LpL activity. Our data suggest that scarb1(-/-) mice fed a western-type diet for 24 weeks accumulate CE- and ApoE-rich HDL of abnormal density and size. The elevated HDL-ApoE levels inhibit plasma LpL activity, blocking the clearance of triglyceride-rich lipoproteins and preventing the shuttling of dietary lipids to the liver.

The role of the gastric fundus in glycemic control.

PURPOSE: Ghrelin, one of the most studied gut hormones, is mainly produced by the gastric fundus. Abundant evidence exists from preclinical and clinical studies underlining its contribution to glucose regulation. In the following narrative review, the role of the gastric fundus in glucose regulation is summarized and we investigate whether its resection enhances glycemic control. METHODS: An electronic search was conducted in the PubMed® database and in Google Scholar® using a combination of medical subject headings (MeSH). We examined types of metabolic surgery, including, in particular, gastric fundus resection, either as part of laparoscopic sleeve gastrectomy (LSG) or modified laparoscopic gastric bypass with fundus resection (LRYGBP + FR), and the contribution of ghrelin reduction to glucose regulation. RESULTS: Fourteen human studies were judged to be eligible and included in this narrative review. Reduction of ghrelin levels after fundus resection might be related to early glycemic improvement before significant weight loss is achieved. Long-term data regarding the role of ghrelin reduction in glucose homeostasis are sparse. CONCLUSION: The exact role of ghrelin in achieving glycemic control is still ambiguous. Data from human studies reveal a potential contribution of ghrelin reduction to early glycemic improvement, although further well-designed studies are needed.

Diabetes Remission After LRYGBP With and Without Fundus Resection: a Randomized Clinical Trial.

BACKGROUND: Glycemic control, after metabolic surgery, is achieved in two stages, initially with neuroendocrine alterations and in the long-term with sustainable weight loss. The resection of the gastric fundus, as the major site of ghrelin production, is probably related with optimized glucose regulation. The aim of the present study is to investigate whether the modification of laparoscopic Roux-en-Y gastric bypass (LRYGBP) with fundus resection offers superior glycemic control, compared to typical LRYGBP. MATERIALS AND METHODS: Participants were 24 patients with body mass index (BMI) ≥40kg/m2 and type II diabetes mellitus (T2DM), who were randomly assigned to undergo LRYGBP and LRYGBP with fundus resection (LRYGBP+FR). Gastrointestinal (GI) hormones [ghrelin, glucagon-like-peptide-1 (GLP-1), peptide-YY (PYY)] and glycemic parameters (glucose, insulin, HbA1c, C-peptide, insulinogenic index, HOMA-IR) were measured preoperatively, at 6 and 12 months during an oral glucose tolerance test (OGTT). RESULTS: Ninety-five percent of patients showed complete remission of T2DM after 12 months. LRYGBP+FR was not related with improved glycemic control, compared to LRYGBP. Ghrelin levels were not significantly reduced at 6 and 12 months after LRYGBP+FR. GLP-1 and PYY levels were remarkably increased postprandially in both groups at 6 and 12 months postoperatively (p<0.01). Patients who underwent LRYGBP+FR achieved a significantly lower BMI at 12 months in comparison to LRYGBP (p<0.05). CONCLUSION: Fundus resection is not associated with improved glycemic regulation, compared to typical LRYGBP and the significant decrease in BMI after LRYGBP+FR has to be further confirmed with longer follow-up.

Emerging roles of Keap1/Nrf2 signaling in the thyroid gland and perspectives for bench-to-bedside translation.

The signaling pathway centered on the transcription factor nuclear erythroid factor 2-like 2 (Nrf2) has emerged during the last 15 years as a target for the prevention and treatment of diseases broadly related with oxidative stress such as cancer, neurodegenerative and metabolic diseases. The roles of Nrf2 are expanding beyond general cytoprotection, and they encompass its crosstalk with other pathways as well as tissue-specific functions. The thyroid gland relies on reactive oxygen species for its main physiological function, the synthesis and secretion of thyroid hormones. A few years ago, Nrf2 was characterized as a central regulator of the antioxidant response in the thyroid, as well as of the transcription and processing of thyroglobulin, the major thyroidal protein that serves as the substrate for thyroid hormone synthesis. Herein, we summarize the current knowledge about the roles of Nrf2 in thyroid physiology, pathophysiology and disease. We focus specifically on the most recent publications in the field, and we discuss the implications for the preclinical and clinical use of Nrf2 modulators.

Metabolic regulation of the neural stem cell fate: Unraveling new connections, establishing new concepts.

The neural stem cell niche is a key regulator participating in the maintenance, regeneration, and repair of the brain. Within the niche neural stem cells (NSC) generate new neurons throughout life, which is important for tissue homeostasis and brain function. NSCs are regulated by intrinsic and extrinsic factors with cellular metabolism being lately recognized as one of the most important ones, with evidence suggesting that it may serve as a common signal integrator to ensure mammalian brain homeostasis. The aim of this review is to summarize recent insights into how metabolism affects NSC fate decisions in adult neural stem cell niches, with occasional referencing of embryonic neural stem cells when it is deemed necessary. Specifically, we will highlight the implication of mitochondria as crucial regulators of NSC fate decisions and the relationship between metabolism and ependymal cells. The link between primary cilia dysfunction in the region of hypothalamus and metabolic diseases will be examined as well. Lastly, the involvement of metabolic pathways in ependymal cell ciliogenesis and physiology regulation will be discussed.

Brown adipose tissue responds to cold and adrenergic stimulation by induction of FGF21.

Fibroblast growth factor-21 (FGF21) is a pleiotropic protein involved in glucose, lipid metabolism and energy homeostasis, with main tissues of expression being the liver and adipose tissue. Brown adipose tissue (BAT) is responsible for cold-induced thermogenesis in rodents. The role of FGF21 in BAT biology has not been investigated. In the present study, wild-type C57BL/6J mice as well as a brown adipocyte cell line were used to explore the potential role of cold exposure and ß3-adrenergic stimulation in the expression of FGF21 in BAT. Our results demonstrate that short-term exposure to cold, as well as ß3-adrenergic stimulation, causes a significant induction of FGF21 mRNA levels in BAT, without a concomitant increase in FGF21 plasma levels. This finding opens new routes for the potential use of pharmaceuticals that could induce FGF21 and, hence, activate BAT thermogenesis.

The role of the antioxidant and longevity-promoting Nrf2 pathway in metabolic regulation.

PURPOSE OF REVIEW: The vertebrate cap'n'collar family transcription factor Nrf2 and its invertebrate homologues SKN-1 (in worms) and CncC (in flies) function as master mediators of antioxidant and detoxification responses and regulators of the cellular redox state. Nrf2 controls gene expression programs that defend various tissues against diverse electrophilic stressors and oxidative insults, thus protecting the organism from disorders that are caused or exacerbated by such stresses. Moreover, studies on model organisms implicate the Nrf2 pathway in the prevention of aging-related diseases and suggest that SKN-1-regulated and CncC-regulated gene expression can promote longevity. These facets of Nrf2 signaling have been thoroughly reviewed. This article discusses another aspect of the Nrf2 pathway's function that has not yet received the same degree of attention, but emerges as a topic of increasing interest and potential clinical impact: its role in metabolic regulation and its interaction with central signaling systems that respond to nutritional inputs. RECENT FINDINGS: Recent evidence identifies Nrf2 signaling as a mediator of the salutary effects of caloric restriction. Nrf2 signaling also crosstalks with metabolic signaling systems such as the insulin/Akt pathway as well as with the metabolism of lipids. Moreover, Nrf2 has a protective role in models of diabetic nephropathy. SUMMARY: The emerging role of Nrf2 as an effector of metabolic and longevity signals offers new therapeutic perspectives. The potential impact of pharmacological manipulation of Nrf2 signaling as a strategy for the prevention and treatment of metabolic disease can be envisioned.

Mice Hypomorphic for Keap1, a Negative Regulator of the Nrf2 Antioxidant Response, Show Age-Dependent Diffuse Goiter with Elevated Thyrotropin Levels.

Background: Familial nontoxic multinodular goiter (MNG) is a rare disease. One of the associated genes is Kelch-like ECH-associated protein 1 (KEAP1), which encodes the main inhibitor of nuclear factor erythroid 2-related transcription factor 2 (Nrf2), a central mediator of antioxidant responses. The association of KEAP1 with familial MNG is based on only two loss-of-function mutations identified in two families, only one of which included proper phenotyping and adequate demonstration of co-segregation of the phenotype and the mutation. There is no experimental evidence from model organisms to support that decreased Keap1 levels can, indeed, cause goiter. This study used mice hypomorphic for Keap1 to test whether decreased Keap1 expression can cause goiter, and to characterize the activation status of Nrf2 in their thyroid. Methods: C57BL/6J Keap1flox/flox (Keap1 knock-down [Keap1KD]) mice were studied at 3 and 12 months of age. Plasma and thyroid glands were harvested for evaluation of thyroid function tests and for gene and protein expression by real-time polymerase chain reaction and immunoblotting, respectively. Results: Keap1KD mice showed diffuse goiter that began to develop in early adult life and became highly prominent and penetrant with age. The goiter was characterized by a markedly increased size of thyroid follicles, most notably of the colloid compartment, and by absence of thyroid nodules or hyperplasia. Keap1KD mice also showed decreased T4 levels in early adult life that were eventually well compensated over time by increased thyrotropin (TSH) levels. Nrf2 was activated in the thyroid of Keap1KD mice. Despite a known stimulatory effect of Nrf2 on thyroglobulin (Tg) gene transcription and Tg protein abundance, the expression levels were decreased in the thyroid of Keap1KD mice. No clear patterns were observed in the expression profiles of other thyroid hormone synthesis-specific factors, with the exception of Tg-processing and Tg-degrading cathepsins, including an increase in mature forms of cathepsins D, L, and S. Conclusions: Keap1KD mice develop age-dependent diffuse goiter with elevated TSH levels. The precise mechanism accounting for the thyroidal phenotype remains to be elucidated, but it may involve enhanced Tg solubilization and excessive lysosomal Tg degradation.

Simvastatin lowers reactive oxygen species level by Nrf2 activation via PI3K/Akt pathway.

The beneficial effects of HMG-CoA (3-hydroxy-3-methyl-glutaryl-CoA) reductase inhibitors (statins) have been attributed not only to their cholesterol lowering effect but also to their pleiotropic actions and especially to their anti-oxidant activity. Nrf2 (NF-E2-related factor 2) is a transcription factor that orchestrates the transcriptional response of cells to oxidative stressors and electrophilic xenobiotics. In this study, primary mouse embryonic fibroblasts from wild type or Nrf2 knock out C57BL6J mice and ST-2 cells were used to investigate the implication of Nrf2 in the mediation of the anti-oxidant effects of statins and the possible involvement of PI3K/Akt pathway in this process. We show for the first time that simvastatin lowers reactive oxygen species (ROS) by activating Nrf2 through the PI3K/Akt pathway.

The Transcriptomic Response of the Murine Thyroid Gland to Iodide Overload and the Role of the Nrf2 Antioxidant System.

BACKGROUND: Thyroid follicular cells have physiologically high levels of reactive oxygen species because oxidation of iodide is essential for the iodination of thyroglobulin (Tg) during thyroid hormone synthesis. Thyroid follicles (the functional units of the thyroid) also utilize incompletely understood autoregulatory mechanisms to defend against exposure to excess iodide. To date, no transcriptomic studies have investigated these phenomena in vivo. Nuclear erythroid factor 2 like 2 (Nrf2 or Nfe2l2) is a transcription factor that regulates the expression of numerous antioxidant and other cytoprotective genes. We showed previously that the Nrf2 pathway regulates the antioxidant defense of follicular cells, as well as Tg transcription and Tg iodination. We, thus, hypothesized that Nrf2 might be involved in the transcriptional response to iodide overload. METHODS: C57BL6/J wild-type (WT) or Nrf2 knockout (KO) male mice were administered regular water or water supplemented with 0.05% sodium iodide for seven days. RNA from their thyroids was prepared for next-generation RNA sequencing (RNA-Seq). Gene expression changes were assessed and pathway analyses were performed on the sets of differentially expressed genes. RESULTS: Analysis of differentially expressed messenger RNAs (mRNAs) indicated that iodide overload upregulates inflammatory-, immune-, fibrosis- and oxidative stress-related pathways, including the Nrf2 pathway. Nrf2 KO mice showed a more pronounced inflammatory-autoimmune transcriptional response to iodide than WT mice. Compared to previously published datasets, the response patterns observed in WT mice had strong similarities with the patterns typical of Graves' disease and papillary thyroid carcinoma (PTC). Long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) also responded to iodide overload, with the latter targeting mRNAs that participate mainly in inflammation pathways. CONCLUSIONS: Iodide overload induces the Nrf2 cytoprotective response and upregulates inflammatory, immune, and fibrosis pathways similar to autoimmune hyperthyroidism (Graves' disease) and PTC.

Simvastatin activates Keap1/Nrf2 signaling in rat liver.

Some of the statins' pleiotropic actions have been attributed to their antioxidant activity. The Nrf2 transcription factor controls the expression of a number of protective genes in response to oxidative stress. In the present study, wistar rats, primary hepatocytes as well as ST2 cells, were employed to explore the potential role of Nrf2 in mediating the reported antioxidant effects of statins. Simvastatin triggered nuclear translocation of Nrf2 in rat liver and in primary rat hepatocytes in a mevalonate-dependent and cholesterol-independent way. In liver, nuclear extracts from simvastatin-treated rats, the DNA-binding activity of Nrf2, was significantly increased and the mRNA of two known targets of Nrf2 (HO-1 and GPX2) was induced. In ST2 cells stably transfected with constructs bearing Nrf2-binding site (antioxidant responsive element), simvastatin enhanced Nrf2-mediated transcriptional activity in a mevalonate-dependent and cholesterol-independent fashion. In conclusion, activation of Keap1/Nrf2 signaling pathway by simvastatin might provide effective protection of the cell from the deleterious effects of oxidative stress.

Interaction of Genetic Variations in NFE2L2 and SELENOS Modulates the Risk of Hashimoto's Thyroiditis.

Background: Several single-nucleotide polymorphisms (SNPs) are known to increase the risk of Hashimoto's thyroiditis (HT); such SNPs reside in thyroid-specific genes or in genes related to autoimmunity, inflammation, and/or cellular defense to stress. The transcription factor Nrf2, encoded by NFE2L2, is a master regulator of the cellular antioxidant response. This study aimed to evaluate the impact of genetic variation in NFE2L2 on the risk of developing HT. Methods: In a case-control candidate gene association study, functional SNPs in the NFE2L2 promoter (rs35652124, rs6706649, and rs6721961) were examined either as independent risk factors or in combination with a previously characterized HT risk allele (rs28665122) in the gene SELENOS, encoding selenoprotein S (SelS). A total of 997 individuals from the north of Portugal (Porto) were enrolled, comprising 481 HT patients and 516 unrelated healthy controls. SELENOS and NFE2L2 SNPs were genotyped using TaqMan® assays and Sanger sequencing, respectively. Odds ratios (ORs) were calculated using logistic regression, with adjustment for sex and age. Expression of SelS was analyzed by immunohistochemistry in thyroid tissue from HT patients and control subjects. Molecular interactions between the Nrf2 and SelS pathways were investigated in thyroid tissues from mice and in rat PCCL3 thyroid follicular cells. Results: When all three NFE2L2 SNPs were considered together, the presence of one or more minor alleles was associated with a near-significant increased risk (OR = 1.43, p = 0.072). Among subjects harboring only major NFE2L2 alleles, there was no increased HT risk associated with heterozygosity or homozygosity for the SELENOS minor allele. Conversely, in subjects heterozygous or homozygous for the SELENOS risk allele, the presence of an NFE2L2 minor allele significantly increased HT risk by 2.8-fold (p = 0.003). Immunohistochemistry showed reduced expression of SelS in thyroid follicular cells of HT patients. In Nrf2 knockout mice, there was reduced expression of SelS in thyroid follicular cells; conversely, in PCCL3 cells, reducing SelS expression caused reduced activity of Nrf2 signaling. Conclusions: The NFE2L2 promoter genotype interacts with the SELENOS promoter genotype to modulate the risk of HT in a Portuguese population. This interaction may be due to a bidirectional positive feedback between the Nrf2 and SelS pathways.

NFE2-Related Transcription Factor 2 Coordinates Antioxidant Defense with Thyroglobulin Production and Iodination in the Thyroid Gland.

BACKGROUND: The thyroid gland has a special relationship with oxidative stress. While generation of oxidative substances is part of normal iodide metabolism during thyroid hormone synthesis, the gland must also defend itself against excessive oxidation in order to maintain normal function. Antioxidant and detoxification enzymes aid thyroid cells to maintain homeostasis by ameliorating oxidative insults, including during exposure to excess iodide, but the factors that coordinate their expression with the cellular redox status are not known. The antioxidant response system comprising the ubiquitously expressed NFE2-related transcription factor 2 (Nrf2) and its redox-sensitive cytoplasmic inhibitor Kelch-like ECH-associated protein 1 (Keap1) defends tissues against oxidative stress, thereby protecting against pathologies that relate to DNA, protein, and/or lipid oxidative damage. Thus, it was hypothesized that Nrf2 should also have important roles in maintaining thyroid homeostasis. METHODS: Ubiquitous and thyroid-specific male C57BL6J Nrf2 knockout (Nrf2-KO) mice were studied. Plasma and thyroids were harvested for evaluation of thyroid function tests by radioimmunoassays and of gene and protein expression by real-time polymerase chain reaction and immunoblotting, respectively. Nrf2-KO and Keap1-KO clones of the PCCL3 rat thyroid follicular cell line were generated using CRISPR/Cas9 technology and were used for gene and protein expression studies. Software-predicted Nrf2 binding sites on the thyroglobulin enhancer were validated by site-directed in vitro mutagenesis and chromatin immunoprecipitation. RESULTS: The study shows that Nrf2 mediates antioxidant transcriptional responses in thyroid cells and protects the thyroid from oxidation induced by iodide overload. Surprisingly, it was also found that Nrf2 has a dramatic impact on both the basal abundance and the thyrotropin-inducible intrathyroidal abundance of thyroglobulin (Tg), the precursor protein of thyroid hormones. This effect is mediated by cell-autonomous regulation of Tg gene expression by Nrf2 via its direct binding to two evolutionarily conserved antioxidant response elements in an upstream enhancer. Yet, despite upregulating Tg levels, Nrf2 limits Tg iodination both under basal conditions and in response to excess iodide. CONCLUSIONS: Nrf2 exerts pleiotropic roles in the thyroid gland to couple cell stress defense mechanisms to iodide metabolism and the thyroid hormone synthesis machinery, both under basal conditions and in response to excess iodide.

Thyroid function in humans with morbid obesity.

Morbidly obese subjects may present with abnormal thyroid function tests but the reported data are scarce. Therefore, we studied the thyroid parameters in 144 morbidly obese patients, 110 females and 34 males, to assess the prevalence of hypothyroidism. Eleven percent (11.8%) carried the diagnosis of hypothyroidism and were undergoing levothyroxine (LT4) replacement therapy, 7.7% had newly diagnosed subclinical hypothyroidism, 0.7% had subclinical hyperthyroidism and 7.7% were euthyroid with positive antibodies (anti-thyroid peroxidase antibodies [TPOAb]). From the 144 subjects, we selected a cohort of 78 euthyroid subjects with negative TPOAb, who did not receive LT4 replacement or suppression therapy (the experimental group) and compared them to 77 normal-weight euthyroid subjects, TPOA-negative, matched for age and gender who served as controls. The experimental group had higher serum levels of triiodothyronine (T3), thyroxine (T4), free triiodothyronine (FT3), and thyrotropin (TSH) compared to the control group. Serum TSH concentration was associated with fasting serum insulin levels and insulin resistance but not with serum leptin levels, body mass index (BMI), fat mass, and lean body mass. In conclusion, in morbidly obese individuals, the prevalence of overt and subclinical hypothyroidism was high (19.5%). The morbidly obese subjects have higher levels of T3, FT3, T4, and TSH, probably the result of the reset of their central thyrostat at higher level.

Capecitabine-induced hypertriglyceridemia: a report of two cases.

BACKGROUND: Capecitabine is a tumor-activated oral fluoropyrimidine with established antitumor activity in breast and colorectal cancer. Hypertriglyceridemia associated with this drug has rarely been reported in the literature. CASE REPORT: This is a report of two patients who developed capecitabine-induced severe hypertriglyceridemia, together with an increase in total cholesterol levels. The first patient developed hyperlipidemia during long-term capecitabine treatment in combination with trastuzumab for metastatic breast carcinoma (triglycerides: from 219 mgldl to 1409 mg/dl, 543% increase; cholesterol: from 239 mg/dl to 363 mg/dl, 52% increase). The second patient developed abnormalities in the lipid profile after the second cycle of chemotherapy with capecitabine and oxaliplatin for metastatic colorectal cancer (triglycerides: from 101 mg/dl to 1510 mg/dl, 1395% increase; cholesterol: from 203 mg/dl to 310 mgldl, 52% increase). An analysis of the possible underlying pathogeneic mechanisms is provided. CONCLUSION: Physicians should be aware of the possibility of dyslipidemia, particularly hypertriglyceridemia, following treatment with capecitabine.

Fibrocalculous pancreatic diabetes in patient residing in the Mediterranean region.

A 40-year old male residing in the Mediterranean region and afflicted with chronic pancreatitis and diabetes is presented. This is a case of chronic calcific non-alcoholic pancreatitis with characteristic intraductal calculi on abdominal X-ray. Five years following the initial episode of pancreatitis, the patient developed insulin-requiring diabetes mellitus. This case accords with the criteria for fibrocalculous pancreatic diabetes with the unique feature of the patient having been born in Greece and being a resident of Greece.

Calciphylaxis: a complication of end-stage renal disease improved by parathyroidectomy.

A 43-year old Caucasian male with end-stage renal disease presented with painful skin lesions and high calcium phosphate product that did not respond to medical treatment. Skin biopsy confirmed the diagnosis of calciphylaxis. Urgent parathyroidectomy was performed and resulted in decrease in the calcium phosphate product and improvement of his symptoms and signs.

Hepatic Fgf21 Expression Is Repressed after Simvastatin Treatment in Mice.

Fibroblast growth factor 21 (Fgf21) is a hormone with emerging beneficial roles in glucose and lipid homeostasis. The interest in Fgf21 as a potential antidiabetic drug and the factors that regulate its production and secretion is growing. Statins are the most widely prescribed drug for the treatment of dyslipidemia. However, the function of statins is not limited to the lowering of cholesterol as they are associated with pleiotropic actions such as antioxidant, anti-inflammatory and cytoprotective effects. The recently described effect of statins on mitochondrial function and the induction of Fgf21 by mitochondrial stress prompted us to investigate the effect of statin treatment on Fgf21 expression in the liver. To this end, C57BL6J male mice and primary mouse hepatocytes were treated with simvastatin, and Fgf21 expression was subsequently assessed by immunoblotting and quantitative real-time PCR. Hepatic Fgf21 protein and mRNA and circulating levels of FGF21significantly decreased in mice that had received simvastatin in their food (0.1% w/w) for 1 week. This effect was also observed with simvastatin doses as low as 0.01% w/w for 1 week or following 2 intraperitoneal injections within a single day. The reduction in Fgf21 mRNA levels was further verified in primary mouse hepatocytes, indicating that the effect of simvastatin is cell autonomous. In conclusion, simvastatin treatment reduced the circulating and hepatic Fgf21 levels and this effect warrants further investigation with reference to its role in metabolism.

Giant malignant insulinoma.

Insulinomas are the most common pancreatic neuroendocrine tumors. Most insulinomas are benign, small, intrapancreatic solid tumors and only large tumors have a tendency for malignancy. Most patients present with symptoms of hypoglycemia that are relieved with the administration of glucose. We herein present the case of a 75-year-old woman who presented with an acute hypoglycemic episode. Subsequent laboratory and radiological studies established the diagnosis of a 17-cm malignant insulinoma, with local invasion to the left kidney, lymph node metastasis, and hepatic metastases. Patient symptoms, diagnostic and imaging work-up and surgical management of both the primary and the metastatic disease are reviewed.

Cortisol in tissue and systemic level as a contributing factor to the development of metabolic syndrome in severely obese patients.

CONTEXT: Adrenal and extra-adrenal cortisol production may be involved in the development of metabolic syndrome (MetS). OBJECTIVE: To investigate the activity of the hypothalamic-pituitary-adrenal (HPA) axis and the expression of HSD11B1, nuclear receptor subfamily 3, group C, member 1 (glucocorticoid receptors) α (NR3C1α) and ß (NR3C1ß) in the liver, subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) of severely obese patients with and without MetS. METHODS: The study included 37 severely obese patients (BMI ≥ 40 kg/m(2)), 19 with MetS (MetS+ group) and 18 without (MetS- group), studied before and during bariatric surgery. Before the day of surgery, urinary free cortisol (UFC) and diurnal variation of serum and salivary cortisol were estimated. During surgery, biopsies of the liver, VAT and SAT were obtained. The expression of HSD11B1, NR3C1α and NR3C1ß was evaluated by RT-PCR. RESULTS: UFC and area under the curve for 24-h profiles of serum and salivary cortisol were lower in the MetS- group. In the MetS- group, mRNA levels of HSD11B1 in liver exhibited a negative correlation with liver NR3C1α (LNR3C1α) and VAT expression of HSD11B1 was lower than the MetS+ group. CONCLUSIONS: We observed a downregulation of the NR3C1α expression and lower VAT mRNA levels of HSD11B1 in the MetS- group, indicating a lower selective tissue cortisol production and action that could protect these patients from the metabolic consequences of obesity. In the MetS- group, a lower activity of the HPA axis was also detected. Taken together, cortisol in tissue and systematic level might play a role in the development of MetS in severely obese patients.