Crithmum maritimum Extract Restores Lipid Homeostasis and Metabolic Profile of Liver Cancer Cells to a Normal Phenotype.

Hepatocellular carcinoma (HCC) is an alarming epidemiological clinical problem worldwide. Pharmacological approaches currently available do not provide adequate responses due to poor effectiveness, high toxicity, and serious side effects. Our previous studies have shown that the wild edible plant Crithmum maritimum L. inhibits the growth of liver cancer cells and promotes liver cell differentiation by reducing lactic acid fermentation (Warburg effect). Here, we aimed to further characterise the effects of C. maritimum on lipid metabolism and markers of cellular metabolic health, such as AMP-activated protein kinase (AMPK), Sirtuin 1 (SIRT1), and Sirtuin 3 (SIRT3), as well as the insulin signalling pathway. To better mimic the biological spectrum of HCC, we employed four HCC cell lines with different degrees of tumorigenicity and lactic acid fermentation/Warburg phenotype. Lipid accumulation was assessed by Oil Red O (ORO) staining, while gene expression was measured by real-time quantitative PCR (RT-qPCR). The activation of AMPK and insulin signalling pathways was determined by Western blotting. Results indicate that C. maritimum prevents lipid accumulation, downregulates lipid and cholesterol biosynthesis, and modulates markers of metabolic health, such as AMPK, SIRT1 and SIRT3. This modulation is different amongst HCC cell lines, revealing an important functional versatility of C. maritimum. Taken together, our findings corroborate the importance of C. maritimum as a valuable nutraceutical, reinforcing its role for the improvement of metabolic health.

Microenvironmental stress drives tumor cell maladaptation and malignancy through regulation of mitochondrial and nuclear cytochrome c oxidase subunits.

After decades of focus on molecular genetics in cancer research, the role of metabolic and environmental factors is being reassessed. Here, we investigated the role of microenvironment in the promotion of malignant behavior in tumor cells with a different reliance on oxidative phosphorylation (OXPHOS) versus lactic acid fermentation/Warburg effect. To this end, we evaluated the effects of microenvironmental challenges (hypoxia, acidity, and high glucose) on the expression of mitochondrial-encoded cytochrome c oxidase 1 (COX I) and two nuclear-encoded isoforms 4 (COX IV-1 and COX IV-2). We have shown that tumor cells with an "OXPHOS phenotype" respond to hypoxia by upregulating COX IV-1, whereas cells that rely on lactic acid fermentation maximized COX IV-2 expression. Acidity upregulates COX IV-2 regardless of the metabolic state of the cell, whereas high glucose stimulates the expression of COX I and COX IV-1, with a stronger effect in fermenting cells. Our results uncover that "energy phenotype" of tumor cells drives their adaptive response to microenvironment stress.NEW & NOTEWORTHY How microenvironmental stress (hypoxia, acidity, and high glucose) supports tumor growth has not yet been fully elucidated. Here, we demonstrated that these stressors promote malignancy by controlling the expression of cytochrome c oxidase I (COX I), and COX IV-1 and COX IV-2 based on the "energy phenotype" of cancer cells (OXPHOS vs. fermentation). Our results uncover a novel process by which the "energy phenotype" of cancer cells drives the adaptive response to microenvironment stress.

Cellular Adaptation Takes Advantage of Atavistic Regression Programs during Carcinogenesis.

Adaptation of cancer cells to extreme microenvironmental conditions (i.e., hypoxia, high acidity, and reduced nutrient availability) contributes to cancer resilience. Furthermore, neoplastic transformation can be envisioned as an extreme adaptive response to tissue damage or chronic injury. The recent Systemic-Evolutionary Theory of the Origin of Cancer (SETOC) hypothesizes that cancer cells "revert" to "primitive" characteristics either ontogenically (embryo-like) or phylogenetically (single-celled organisms). This regression may confer robustness and maintain the disordered state of the tissue, which is a hallmark of malignancy. Changes in cancer cell metabolism during adaptation may also be the consequence of altered microenvironmental conditions, often resulting in a shift toward lactic acid fermentation. However, the mechanisms underlying the robust adaptive capacity of cancer cells remain largely unknown. In recent years, cancer cells' metabolic flexibility has received increasing attention among researchers. Here, we focus on how changes in the microenvironment can affect cancer cell energy production and drug sensitivity. Indeed, changes in the cellular microenvironment may lead to a "shift" toward "atavistic" biologic features, such as the switch from oxidative phosphorylation (OXPHOS) to lactic acid fermentation, which can also sustain drug resistance. Finally, we point out new integrative metabolism-based pharmacological approaches and potential biomarkers for early detection.

Silicon in action: Between iron scarcity and excess copper.

Essential micronutrients belonging to the transition metals, such as Fe and Cu, are indispensable for plant growth and stress tolerance; however, when present in excess, they can become potentially dangerous producers of reactive oxygen species. Therefore, their homeostases must be strictly regulated. Both microelement deficiencies and elevated concentrations of heavy metals in the soil are global problems that reduce the nutritional value of crops and seriously affect human health. Silicon, a beneficial element known for its protective properties, has been reported to alleviate the symptoms of Cu toxicity and Fe deficiency stress in plants; however, we are still far from a comprehensive understanding of the underlying molecular mechanisms. Although Si-mediated mitigation of these stresses has been clearly demonstrated for some species, the effects of Si vary depending on plant species, growing conditions and experimental design. In this review, the proposed mechanistic models explaining the effect of Si are summarized and discussed. Iron and copper compete for the common metal transporters and share the same transport routes, hence, inadequate concentration of one element leads to disturbances of another. Silicon is reported to beneficially influence not only the distribution of the element supplied below or above the optimal concentration, but also the distribution of other microelements, as well as their molar ratios. The influence of Si on Cu immobilization and retention in the root, as well as Si-induced Fe remobilization from the source to the sink organs are of vital importance. The changes in cellular Cu and Fe localization are considered to play a crucial role in restoring homeostasis of these microelements. Silicon has been shown to stimulate the accumulation of metal chelators involved in both the mobilization of deficient elements and scavenging excess heavy metals. Research into the mechanisms of the ameliorative effects of Si is valuable for reducing mineral stress in plants and improving the nutritional value of crops. This review aims to provide a thorough and critical overview of the current state of knowledge in this field and to discuss discrepancies in the observed effects of Si and different views on its mode of action.

Anti-inflammatory properties of an aldehydes-enriched fraction of grapefruit essential oil.

Chronic inflammation is linked to the development of numerous diseases and is accompanied by increased cytokine secretion. Macrophages provide a first line of defense against pathogens that under inflammatory stimuli release pro-inflammatory cytokines. The essential oil (EO) fractions obtained from Citrus spp. rich in different compounds have gained the attention of both researchers and users during the last decades. In particular, grapefruit (Citrus paradisi) peel is rich in phenolics and flavonoids with several health benefits, including anti-inflammatory actions. Additionally, its EO consists of a large number of compounds such as monoterpenes, sesquiterpenes, alcohols, aldehydes, esters, and oxides. Among the methods for encapsulating EOs, spray-drying is the main one. In the present study, we aimed to determine the in vitro anti-inflammatory activity of EO from C. paradisi (grapefruit essential oil [GEO]) (whole and fractions) in a lipopolysaccharide (LPS)-induced inflammation model. Results indicate that Fr-GEO and Fr-GEO_SD exert protective effects against LPS-induced inflammation by decreasing gene expression and levels of pro-inflammatory cytokines as IL-6 and TNF-α. Monoterpenes as the most common components, as well as aldehydes and sesquiterpenes, might be responsible for such effects, although a synergistic action is not excluded. Furthermore, a higher percent of aldehydes is linked to improved olfactory properties. Our findings support the anti-inflammatory effects of selected Fr-GEO with a great potential for the development of new nutraceuticals and/or functional food for the treatment of inflammatory-associated diseases. PRACTICAL APPLICATION: The findings of this study support the anti-inflammatory effects of selected Fr-GEO with a great potential for the development of new nutraceuticals and/or functional food for the treatment of inflammatory-associated diseases.

Daily Use of Extra Virgin Olive Oil with High Oleocanthal Concentration Reduced Body Weight, Waist Circumference, Alanine Transaminase, Inflammatory Cytokines and Hepatic Steatosis in Subjects with the Metabolic Syndrome: A 2-Month Intervention Study.

Extra virgin olive oil (EVOO) intake is associated with reduced cardiovascular risk, and its phenolic compound oleocanthal (OC) has anti-oxidant and anti-inflammatory properties. The cardiometabolic effects of EVOO with a high OC concentration have not been fully elucidated. We administered EVOO with a high OC concentration daily to 23 subjects with the metabolic syndrome (MetS) and hepatic steatosis (15 men and 8 women, age: 60 ± 11 years) for 2 months. Anthropometric data, metabolic parameters, hepatic steatosis (by fatty liver index, FLI), abdominal fat distribution (by ultrasound), and pro- and anti-inflammatory cytokines were assessed before and after the intervention. EVOO supplementation was associated with a reduction in body weight, waist circumference, body mass index (BMI), alanine transaminase and FLI, as well as interleukin (IL)-6, IL-17A, tumor necrosis factor-α and IL-1B, while IL-10 increased. Maximum subcutaneous fat thickness (SFT max) also increased, with a concomitant decrease in the ratio of visceral fat layer thickness/SFT max. Correlation analysis revealed positive associations between changes in body weight and BMI and those in SFT max, along with an inverse association between changes in IL-6 and those in SFT max. In conclusion, ingestion of EVOO with a high OC concentration had beneficial effects on metabolic parameters, inflammatory cytokines and abdominal fat distribution in MetS subjects with hepatic steatosis, a category of patients at high cardiometabolic risk.

Cardiovascular outcomes trials with incretin-based medications: a critical review of data available on GLP-1 receptor agonists and DPP-4 inhibitors.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors are so called "incretin-based therapies" (IBTs) that represent innovative therapeutic approaches and are commonly used in clinical practice for the treatment of type 2 diabetes mellitus (T2DM). The cardiovascular outcome trials (CVOTs) have provided useful information that has helped to shape changes in clinical practice guidelines for the management of T2DM. At the same time, the mechanisms that may explain the nonglycemic and cardiovascular (CV) benefits of these medications are still being explored. A summary of the main findings from CVOTs performed to-date with particular emphasis on various outcomes and inconsistencies observed in the trials is provided. Overall, available data is favourable to the early deployment of GLP-1RAs in clinical practice, fully in line with recommendations from international scientific guidelines, and based on their effects on glucose metabolism parameters, body weight reduction and CV outcomes. Evidence further suggest that the CV benefits of GLP-1RAs may not be a class effect, with GLP-1 analogues having a greater benefit rather than exendin-based agents.

The efficacy and safety of dipeptidyl peptidase-4 inhibitors compared to other oral glucose-lowering medications in the treatment of type 2 diabetes.

INTRODUCTION: The dipeptidyl peptidase-4 inhibitors (DPP-4is), which belong to the class of incretin-based medications, are recommended as second or third-line therapies in guidelines for the management of type 2 diabetes mellitus. They have a favorable drug tolerability and safety profile compared to other glucose-lowering agents. OBJECTIVE: This review discusses data concerning the use of DPP-4is and their cardiovascular profile, and gives an updated comparison with the other oral glucose-lowering medications with regards to safety and efficacy. Currently available original studies, abstracts, reviews articles, systematic reviews and meta-analyses were included in the review. DISCUSSION: DPP4is are moderately efficient in decreasing the HbA1c by an average of 0.5% as monotherapy, and 1.0% in combination therapy with other drugs. They have a good tolerability and safety profile compared to other glucose-lowering drugs. However, there are possible risks pertaining to acute pancreatitis and pancreatic cancer. CONCLUSION: Cardiovascular outcome trials thus far have proven the cardiovascular safety for ischemic events in patients treated with sitagliptin, saxagliptin, alogliptin, linagliptin and vildagliptin. Data showing increased rate of hospitalisation in the case of saxagliptin did not seem to be a class effect.

COMPUTED TOMOGRAPHY SCAN FOR DIAGNOSIS OF OSTEOARTHRITIS: RARE LOCALIZATION IN THE SHOULDER IN A TWELVE-YEAR-OLD BOY.

Acute osteomyelitis is pyogenic infection of the bone and bone marrow. We report a case of successful diagnosis and treatment in a 12-year-old boy with right shoulder joint osteoarthritis. On admission, he was febrile (39.0 ºC) with pain in his right shoulder. Laboratory and biochemistry findings were as follows: leukocytes 10.9x109/L; hemoglobin 122 g/l; fibrinogen 34.7; C-reactive protein 56.8. No changes were observed using conventional radiography. Computed tomography (CT) scan was conducted on the right limb using LightSpeed 16 slices in native and contrast series. The area of interest was shown on axial section, less dense fluid within the joint cavity with a thickened capsule and joint soft tissue swelling around the joint. On bone structures, CT morphological changes were not observed. After deterioration of the condition despite antibiotic therapy, surgery had to be performed. The purulent content was removed by surgery. Prolonged antibiotic therapy and rehabilitation led to improvement of the condition. At two-month follow-up, ultrasonography and CT scan showed that there were no pathologic changes, while magnetic resonance imaging showed minimal tissue fibrosis that did no require surgical treatment.

Silicon and Iron Differently Alleviate Copper Toxicity in Cucumber Leaves.

Copper (Cu) toxicity in plants may lead to iron (Fe), zinc (Zn) and manganese (Mn) deficiencies. Here, we investigated the effect of Si and Fe supply on the concentrations of micronutrients and metal-chelating amino acids nicotianamine (NA) and histidine (His) in leaves of cucumber plants exposed to Cu in excess. Cucumber (Cucumis sativus L.) was treated with 10 µM Cu, and additional 100 µM Fe or/and 1.5 mM Si for five days. High Cu and decreased Zn, Fe and Mn concentrations were found in Cu treatment. Additional Fe supply had a more pronounced effect in decreasing Cu accumulation and improving the molar ratio between micronutrients as compared to the Si supply. However, the simultaneous supply of Fe and Si was the most effective treatment in alleviation of Cu-induced deficiency of Fe, Zn and Mn. Additional Fe supply increased the His but not NA concentration, while Si supply significantly increased both NA and His whereby the NA:Cu and His:Cu molar ratios exceeded the control values indicating that Si recruits Cu-chelation to achieve Cu tolerance. In conclusion, Si-mediated alleviation of Cu toxicity was directed toward Cu tolerance while Fe-alleviative effect was due to a dramatic decrease in Cu accumulation.

Gut Microbiota, Obesity and Bariatric Surgery: Current Knowledge and Future Perspectives.

BACKGROUND: There is an urgent need for a better understanding and management of obesity and obesity- associated diseases. It is known that obesity is associated with structural and functional changes in the microbiome. METHODS: The purpose of this review is to present current evidence from animal and human studies, demonstrating the effects and the potential efficacy of microbiota modulation in improving obesity and associated metabolic dysfunctions. RESULTS: This review discusses possible mechanisms linking gut microbiota dysbiosis and obesity, since there is a dual interaction between the two of them. Furthermore, comments on bariatric surgery, as a favourable model to understand the underlying metabolic and inflammatory effects, as well as its association with changes in the composition of the gut microbiota, are included. Also, a possible impact of anti-obesity drugs and the novel antidiabetic drugs on the gut microbiota has been briefly discussed. CONCLUSION: More research is needed to better understand here discussed the association between microbiota modulation and obesity. It is expected that research in this field, in the following years, will lead to a personalized therapeutic approach considering the patient's microbiome, and also give rise to the discovery of new drugs and/or the combination therapies for the management of obesity and obesity-related co-morbidities.

Silicon Alleviates Iron Deficiency in Barley by Enhancing Expression of Strategy II Genes and Metal Redistribution.

The beneficial effects of silicon (Si) have been shown on plants using reduction-based strategy for iron (Fe) acquisition. Here we investigated the influence of Si on Fe deficiency stress alleviation in barley (Hordeum vulgare), a crop plant which uses the chelation-based strategy for Fe acquisition. Analyses of chlorophyll content, ROS accumulation, antioxidative status, concentrations of Fe and other micronutrients, along with the expression of Strategy II genes were studied in response to Si supply. Si successfully ameliorated Fe deficiency in barley, diminishing chlorophyll and biomass loss, and improving the activity of antioxidative enzymes, resulting in lowered reactive oxidative species accumulation in the youngest leaves. Alleviation of Fe deficiency stress correlated well with the Si-induced increase of Fe content in the youngest leaves, while it was decreased in root. Moreover, Si nutrition lowered accumulation of other micronutrients in the youngest leaves of Fe deprived plants, by retaining them in the root. On the transcriptional level, Si led to an expedient increase in the expression of genes involved in Strategy II Fe acquisition in roots at the early stage of Fe deficiency stress, while decreasing their expression in a prolonged stress response. Expression of Strategy II genes was remarkably upregulated in the leaves of Si supplied plants. This study broadens the perspective of mechanisms of Si action, providing evidence for ameliorative effects of Si on Strategy II plants, including its influence on accumulation and distribution of microelements, as well as on the expression of the Strategy II genes.

"Velcro-type" crackles predict specific radiologic features of fibrotic interstitial lung disease.

BACKGROUND: "Velcro-type" crackles on chest auscultation are considered a typical acoustic finding of Fibrotic Interstitial Lung Disease (FILD), however whether they may have a role in the early detection of these disorders has been unknown. This study investigated how "Velcro-type" crackles correlate with the presence of distinct patterns of FILD and individual radiologic features of pulmonary fibrosis on High Resolution Computed Tomography (HRCT). METHODS: Lung sounds were digitally recorded from subjects immediately prior to undergoing clinically indicated chest HRCT. Audio files were independently assessed by two chest physicians and both full volume and single HRCT sections corresponding to the recording sites were extracted. The relationships between audible "Velcro-type" crackles and radiologic HRCT patterns and individual features of pulmonary fibrosis were investigated using multivariate regression models. RESULTS: 148 subjects were enrolled: bilateral "Velcro-type" crackles predicted the presence of FILD at HRCT (OR 13.46, 95% CI 5.85-30.96, p < 0.001) and most strongly the Usual Interstitial Pneumonia (UIP) pattern (OR 19.8, 95% CI 5.28-74.25, p < 0.001). Extent of isolated reticulation (OR 2.04, 95% CI 1.62-2.57, p < 0.001), honeycombing (OR 1.88, 95% CI 1.24-2.83, < 0.01), ground glass opacities (OR 1.74, 95% CI 1.29-2.32, p < 0.001) and traction bronchiectasis (OR 1.55, 95% CI 1.03-2.32, p < 0.05) were all independently associated with the presence of "Velcro-type" crackles. CONCLUSIONS: "Velcro-type" crackles predict the presence of FILD and directly correlate with the extent of distinct radiologic features of pulmonary fibrosis. Such evidence provides grounds for further investigation of lung sounds as an early identification tool in FILD.

GLP-1 receptor agonists and reduction of cardiometabolic risk: Potential underlying mechanisms.

Type 2 diabetes mellitus (T2DM) is a metabolic condition with an elevated impact on cardiovascular (CV) risk. The innovative therapeutic approaches for T2DM - incretin-based therapies (IBTs), including glucagon-like peptide 1 (GLP-1) receptor agonists, have become popular and more widely used in recent years. The available scientific data from clinical studies and clinical practice highlights their beyond glucose-lowering effects, which is achieved without any increase in hypoglycaemia. The former effects include reduction in body weight, lipids, blood pressure, inflammatory markers, oxidative stress, endothelial dysfunction, and subclinical atherosclerosis, thus reducing and potentially preventing CV events. In fact, the introduction of IBTs is one of the key moments in the history of diabetes research and treatment. Such therapeutic strategies allow customization of antidiabetic treatment to each patient's need and therefore obtain better metabolic control with reduced CV risk. The aim of the present paper is to provide a comprehensive overview of the effects of GLP-1RA on various cardiometabolic markers and overall CV risk, with particular attention on recent CV outcome studies and potential mechanisms. In particular, the effects of liraglutide on formation and progression of atherosclerotic plaque and mechanisms explaining its cardioprotective effects are highlighted.

Natural approaches in metabolic syndrome management.

Metabolic syndrome (MetS) is characterized as a group of cardiometabolic risk factors that raise the risk for heart disease and other health problems, such as diabetes mellitus and stroke. Treatment strategies include pharmacologic interventions and supplementary (or "alternative") treatments. Nutraceuticals are derived from food sources (isolated nutrients, dietary supplements and herbal products) that are purported to provide health benefits, in addition to providing basic nutritional value. Nutraceuticals are claimed to prevent chronic diseases, improve health, delay the aging process, increase life expectancy, and support the structure and function of the body. The study of the beneficial effects of nutraceuticals in patients with MetS, including product standardization, duration of supplementation and definition of optimal dosing, could help better define appropriate treatment. This review focuses on widely marketed nutraceuticals (namely polyphenols, omega-3 fatty acids, macroelements and vitamins) with clinically demonstrated effects on more than one component of MetS.

Lifestyle recommendations for the prevention and management of metabolic syndrome: an international panel recommendation.

The importance of metabolic syndrome (MetS) lies in its associated risk of cardiovascular disease and type 2 diabetes, as well as other harmful conditions such as nonalcoholic fatty liver disease. In this report, the available scientific evidence on the associations between lifestyle changes and MetS and its components is reviewed to derive recommendations for MetS prevention and management. Weight loss through an energy-restricted diet together with increased energy expenditure through physical activity contribute to the prevention and treatment of MetS. A Mediterranean-type diet, with or without energy restriction, is an effective treatment component. This dietary pattern should be built upon an increased intake of unsaturated fat, primarily from olive oil, and emphasize the consumption of legumes, cereals (whole grains), fruits, vegetables, nuts, fish, and low-fat dairy products, as well as moderate consumption of alcohol. Other dietary patterns (Dietary Approaches to Stop Hypertension, new Nordic, and vegetarian diets) have also been proposed as alternatives for preventing MetS. Quitting smoking and reducing intake of sugar-sweetened beverages and meat and meat products are mandatory. Nevertheless, there are inconsistencies and gaps in the evidence, and additional research is needed to define the most appropriate therapies for MetS. In conclusion, a healthy lifestyle is critical to prevent or delay the onset of MetS in susceptible individuals and to prevent cardiovascular disease and type 2 diabetes in those with existing MetS. The recommendations provided in this article should help patients and clinicians understand and implement the most effective approaches for lifestyle change to prevent MetS and improve cardiometabolic health.

The dissociation of the Hsp60/pro-Caspase-3 complex by bis(pyridyl)oxadiazole copper complex (CubipyOXA) leads to cell death in NCI-H292 cancer cells.

Cell survival and proliferation are central to carcinogenesis, involving various mechanisms among which those that impede apoptosis are important. In this, the role of the molecular chaperone Hsp60 is unclear since it has been reported that it can be both, pro- or anti-apoptotic. A solution to this riddle is crucial to the development of anti-cancer therapies targeting Hsp60. We addressed this question using a tumor cell line, NCI-H292, and [Cu(3,5-bis(2'-pyridyl)-1,2,4-oxadiazole)2(H2O)2](ClO4)2, CubipyOXA, a copper-containing compound with cytotoxic properties. We treated cells with various doses of the compound and measured cell viability; apoptosis indicators; and levels of Hsp60, pro-Caspase-3 (pC3), Caspase-3 (C3), and complex Hsp60/pC3, with complementary methods. The quantitative dose-response curves of the levels of Hsp60, activated C3, inactivated pC3, Hsp60/pC3 complex and indicators of cell apoptosis, and cell death, all coincided to show that CubipyOXA has pro-apoptotic activity and promotes cell death. The curves also indicate that the pro-apoptotic effects of CubipyOXA could likely be due to a lowering of Hsp60 levels and to its blocking the formation of the Hsp60/pC3 complex and/or its dissociating the complex when already formed, thus, interfering with the anti-apoptotic action of Hsp60. These findings shed some light on how a tumor cell may avert apoptosis using Hsp60 and point to the anti-cancer potential of drugs, such as CubipyOXA, which interfere with Hsp60/pC3 complex formation, and thus allow the apoptotic cascade to proceed. In view of these findings it becomes clear that the novel compound CubipyOXA should be considered a potential, high-efficiency antitumor agent deserving further testing.

Incretins, Pregnancy, and Gestational Diabetes.

The number of pregnant women affected by gestational diabetes mellitus (GDM) is increasing among Caucasians, and East Asians. GDM also increases the risk for later advent of type 2 diabetes mellitus (T2DM), obesity, and cardiovascular disease in both women and their offspring. The underlying mechanism of GDM is not fully elucidated. Incretins such as glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), have been suggested to have a role in maternal metabolism and weight as well as fetal growth. These hormones might be implicated in mechanisms that compensate for the increment in glycemia and insulin resistance seen during pregnancy, while other factors, such as heredity, environment and lifestyle, but also different race/ethnic background might also lead to the comorbid health problems. Some studies indicate that pregnancy is associated with a diminished GLP-1 response which is more prominently evident in women with GDM and normalizes after delivery. Postprandial GIP level seems to be unaffected by pregnancy, despite its increased level in GDM. On the other hand, the reduced incretin effect observed in GDM may represent a risk factor for obesity, T2DM and metabolic disorders even in the offspring of these women. Further investigations are needed to establish the exact role of incretins in pregnancy and gestational glucose intolerance.

Low- and high-density lipoprotein subclasses in subjects with nonalcoholic fatty liver disease.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is associated with increased cardiometabolic risk. Although dyslipidemia represents a key factor in this disease, its impact on serum levels of distinct lipoprotein subfractions is largely unknown. OBJECTIVE: To assess the full low-density lipoprotein (LDL) and high-density lipoprotein (HDL) profiles in patients with NAFLD. METHODS: Seven LDL and 10 HDL subfractions were assessed by gel electrophoresis (Lipoprint, Quantimetrix Corporation, USA) in men with biopsy proven NAFLD (simple steatosis [n = 17, age, 34 ± 7 years] and nonalcoholic steatohepatitis [NASH; n = 24, age, 32 ± 6 years]). Exclusion criteria included robust alcohol consumption, infection with hepatitis B or C virus, body mass index ≥ 40 kg/m(2), diabetes mellitus, and hypertension. RESULTS: Compared with simple steatosis, NASH patients had similar body mass index, homeostasis model assessment of insulin resistance index and plasma lipids, with increased levels of both aspartate aminotransferase and alanine transaminase. NASH subjects had lower levels of larger LDL1 (10 ± 4 vs 13 ± 4%, P = .010) and increased smaller LDL3 and LDL4 particles (9 ± 5 vs 5 ± 5%, P = .017 and 3 ± 3 vs 1 ± 2%, P = .012, respectively). No changes were found in the HDL subclass profile. By multiple regression analysis, we found that NASH was associated only with increased levels of LDL3 (P = .0470). CONCLUSIONS: The increased levels of small, dense LDL3 and LDL4 in NASH may help to at least partly explain the increased risk for atherosclerosis and cardiovascular diseases in these patients.