Gender Differences in the Context of Obstructive Sleep Apnea and Metabolic Diseases

Funding: The author FM is funded by the Portuguese Foundation for Science and Technology with contract reference CEECIND/04266/2017.The relationship between obstructive sleep apnea (OSA) and endocrine and metabolic disease is unequivocal. OSA, which is characterized by intermittent hypoxia and sleep fragmentation, leads to and exacerbates obesity, metabolic syndrome, and type 2 diabetes (T2D) as well as endocrine disturbances, such as hypothyroidism and Cushing syndrome, among others. However, this relationship is bidirectional with endocrine and metabolic diseases being considered major risk factors for the development of OSA. For example, polycystic ovary syndrome (PCOS), one of the most common endocrine disorders in women of reproductive age, is significantly associated with OSA in adult patients. Several factors have been postulated to contribute to or be critical in the genesis of dysmetabolic states in OSA including the increase in sympathetic activation, the deregulation of the hypothalamus-pituitary axis, the generation of reactive oxygen species (ROS), insulin resistance, alteration in adipokines levels, and inflammation of the adipose tissue. However, probably the alterations in the hypothalamus-pituitary axis and the altered secretion of hormones from the peripheral endocrine glands could play a major role in the gender differences in the link between OSA-dysmetabolism. In fact, normal sleep is also different between men and women due to the physiologic differences between genders, with sex hormones such as progesterone, androgens, and estrogens, being also connected with breathing pathologies. Moreover, it is very well known that OSA is more prevalent among men than women, however the prevalence in women increases after menopause. At the same time, the step-rise in obesity and its comorbidities goes along with mounting evidence of clinically important sex and gender differences. Metabolic and cardiovascular diseases, seen as a men's illness for decades, presently are more common in women than in men and obesity has a higher association with insulin-resistance-related risk factors in women than in men. In this way, in the present manuscript, we will review the major findings on the overall mechanisms that connect OSA and dysmetabolism giving special attention to the specific regulation of this relationship in each gender. We will also detail the gender-specific effects of hormone replacement therapies on metabolic control and sleep apnea.publishersversionpublishe

Impact of Diet Composition on Insulin Resistance

Funding: FO Martins is supported by Portuguese Science and Technology Foundation (CEECIND/04266/2017).Insulin resistance is a complex condition in which the body does not respond adequately to insulin, a hormone secreted by the pancreas with an essential role in the regulation of blood sugar levels [...].publishersversionpublishe

An enzymatic route to a benzocarbazole framework using bacterial CotA laccase

The CotA laccase-catalysed oxidation of the meta, para-disubstituted arylamine 2,4-diaminophenyldiamine delivers, under mild reaction conditions, a benzocarbazole derivative (1) (74% yield), a key structural motif of a diverse range of applications. This work extends the scope of aromatic frameworks obtained using these enzymes and represents a new efficient and clean method to construct in one step C-C and C-N bonds

Trick or Treat?

Funding Information: Funding: AC and FOM were supported by grants and contracts from the Portuguese Foundation for Science and Technology, PD/BD/136863/2018 and CEECIND/04266/2017, respectively.Accumulating evidence suggests the existence of a strong link between metabolic syndrome and neurodegeneration. Indeed, epidemiologic studies have described solid associations between metabolic syndrome and neurodegeneration, whereas animal models contributed for the clarification of the mechanistic underlying the complex relationships between these conditions, having the development of an insulin resistance state a pivotal role in this relationship. Herein, we review in a concise manner the association between metabolic syndrome and neurodegeneration. We start by providing concepts regarding the role of insulin and insulin signaling pathways as well as the pathophysiological mechanisms that are in the genesis of metabolic diseases. Then, we focus on the role of insulin in the brain, with special attention to its function in the regulation of brain glucose metabolism, feeding, and cognition. Moreover, we extensively report on the association between neurodegeneration and metabolic diseases, with a particular emphasis on the evidence observed in animal models of dysmetabolism induced by hypercaloric diets. We also debate on strategies to prevent and/or delay neurodegeneration through the normalization of whole-body glucose homeostasis, particularly via the modulation of the carotid bodies, organs known to be key in connecting the periphery with the brain.publishersversionpublishe

Dysmetabolism and Sleep Fragmentation in Obstructive Sleep Apnea Patients Run Independently of High Caffeine Consumption

Funding Information: This research was funded by the Portuguese Science and Technology Foundation (FCT) with the grant number CEECIND/04266/2017. Acknowledgments: The authors would like to thank Eunice Silva for technical support. Funding Information: Funding: This research was funded by the Portuguese Science and Technology Foundation (FCT) with the grant number CEECIND/04266/2017.Daytime hypersomnolence, the prime feature of obstructive sleep apnea (OSA), frequently leads to high coffee consumption. Nevertheless, some clinicians ask for patients’ caffeine avoidance. Caffeinated drinks are sometimes associated with more severe OSA. However, these effects are not consensual. Here we investigated the effect of caffeine consumption on sleep architecture and apnea/hypopnea index in OSA. Also, the impact of caffeine on variables related with dysmetabolism, dyslipidemia, and sympathetic nervous system (SNS) dysfunction were investigated. A total of 65 patients diagnosed with OSA and 32 without OSA were included after given written informed consent. Polysomnographic studies were performed. Blood was collected to quantify caffeine and its metabolites in plasma and biochemical parameters. 24 h urine samples were collected for catecholamines measurement. Statistical analyses were performed by SPSS: (1) non-parametric Mann-Whitney test to compare variables between controls and OSA; (2) multivariate logistic regression testing the effect of caffeine on sets of variables in the 2 groups; and (3) Spearmans’ correlation between caffeine levels and comorbidities in patients with OSA. As expected OSA development is associated with dyslipidemia, dysmetabolism, SNS dysfunction, and sleep fragmentation. There was also a significant increase in plasma caffeine levels in the OSA group. However, the higher consumption of caffeine by OSA patients do not alter any of these associations. These results showed that there is no apparent rationale for caffeine avoidance in chronic consumers with OSA.publishersversionpublishe

Disposition of [U-2H7]glucose into hepatic glycogen in rat and in seabass

The stimulation of hepatic glycogenesis is a ubiquitous response to a glucose challenge and quantifying its contribution to glucose uptake informs its role in restoring euglycemia. Glycogenesis can be quantified with labeled water provided that exchange of glucose-6-phosphate hydrogen 2 (G6P-H2) and body water via glucose-6-phosphate isomerase, and exchange of positions 4, 5 and 6 hydrogens (G6P-H456) via transaldolase, are known. These exchanges were quantified in 24-h fasted rats (Rattus norvegicus; n=6) and 21-day fasted seabass (Dicentrarchus labrax; n = 8) by administration of a glucose load (2000 mg·kg−1) enriched with [U-2H7]glucose and by quantifying hepatic glycogen 2H-enrichments after 2 h (rats) and 48 h (seabass). Direct pathway contributions of the glucose load to glycogenesis were also estimated. G6P-H2 and body water exchange was 61 ± 1% for rat and 47 ± 3% for seabass. Transaldolase-mediated exchange of G6P-H456 was 5 ± 1% for rat and 10 ± 1% for seabass. Conversion of the glucose load to hepatic glycogen was significant in seabass (249 ± 54 mg·kg−1) but negligible in rats (12 ± 1 mg·kg−1). Preload plasma glucose levels were similar for seabass and rats (3.3 ± 0.7 and 4.4 ± 0.1 mmol·L−1, respectively) but post-load plasma glucose was significantly higher in seabass compared to rats (14.6 ± 1.8 versus 5.8 ± 0.3 mmol·L−1, p b 0.01). In conclusion, G6P-H2 and body water exchange is incomplete for both species and has to be accounted for in estimating hepatic glycogen synthesis and direct pathway activities with labeled water tracers. Transaldolase-mediated exchange is insignificant. Hepatic direct pathway glycogenesis plays a prominent role in seabass glucose load disposal, but a negligible role in the rat.The authors acknowledge the financial support from Fundação para a Ciência e a Tecnologia (FCT) in the form of a Ph.D. Fellowship to F.O.M.: SFRH/ BD/51194/2010, and Research Grants to J.G.J.: PTDC/EBB-BIO/ 098111/2008 & PTDC/SAU-MET/111398/2009. The NMR spectrometer is part of the National NMR Network and was purchased in the framework of the National Programme for Scientific re-equipment, contract REDE/1517/RMN/2005, with funds from POCI 2010 (FEDER) and FCT

Knockout of insulin-degrading enzyme leads to mice testicular morphological changes and impaired sperm quality

Insulin-degrading enzyme (IDE) is a zinc metalloprotease responsible for degrading and inactivating several bioactive peptides, including insulin. Individuals without this enzyme or with a loss-of-function mutation in the gene that codifies it, present hyperinsulinemia. In addition, impairment of IDE-mediated insulin clearance is associated with the development of metabolic diseases, namely prediabetes. Although insulin regulates male fertility, the role of IDE on male reproductive function remains unknown. We proposed to study the influence of IDE in the reproductive potential of males. As insulin mediates key events for the normal occurrence of spermatogenesis, we hypothesized that IDE functioning might be linked with sperm quality. We used C57BL/6N mice that were divided in three groups according to its genotype: wild type (WT), heterozygous and knockout (KO) male mice for Ide. Spermatozoa were collected from the cauda of epididymis and sperm parameters were evaluated. Testicular tissue morphology was assessed through hematoxylin and eosin stain. Mitochondrial complex protein levels and lipid peroxidation were also evaluated in the testicular tissue. Our results show that KO mice present a 50% decrease in testes weight compared to WT mice as well as a decrease in seminiferous tubules diameter. Moreover, KO mice present impaired sperm quality, namely a decrease in both sperm viability and morphology. These results provide evidence that IDE plays an important role in determining the reproductive potential of males.publishe

Primary Effects on Skeletal Muscle

The present study was supported by the Portuguese Society of Diabetes. JS was supported by a PhD Grant from the Portuguese Foundation for Science and Technology, PD/BD/105890/2014.Epidemiological studies showed that chronic caffeine intake decreased the risk of type 2 diabetes. Previously, we described that chronic caffeine intake prevents and reverses insulin resistance induced by hypercaloric diets and aging, in rats. Caffeine has several cellular mechanisms of action, being the antagonism of adenosine receptors the only attained with human coffee consumption. Here, we investigated the subtypes of adenosine receptors involved on the effects of chronic caffeine intake on insulin sensitivity and the mechanisms and sex differences behind this effect. Experiments were performed in male and female Wistar rats fed either a chow or high-sucrose (HSu) diet (35% of sucrose in drinking water) during 28 days, to induce insulin resistance. In the last 15 days of diet the animals were submitted to DPCPX (A1 antagonist, 0.4 mg/kg), SCH58261 (A2A antagonist, 0.5 mg/kg), or MRS1754 (A2B antagonist, 9.5 μg/kg) administration. Insulin sensitivity, fasting glycaemia, blood pressure, catecholamines, and fat depots were assessed. Expression of A1, A2A, A2B adenosine receptors and protein involved in insulin signaling pathways were evaluated in the liver, skeletal muscle, and visceral adipose tissue. UCP1 expression was measured in adipose tissue. Paradoxically, SCH58261 and MRS1754 decreased insulin sensitivity in control animals, whereas they both improved insulin response in HSu diet animals. DPCPX did not alter significantly insulin sensitivity in control or HSu animals, but reversed the increase in total and visceral fat induced by the HSu diet. In skeletal muscle, A1, A2A, and A2B adenosine receptor expression were increased in HSu group, an effect that was restored by SCH58261 and MRS1754. In the liver, A1, A2A expression was increased in HSu group, while A2B expression was decreased, being this last effect reversed by administration of MRS1754. In adipose tissue, A1 and A2A block upregulated the expression of these receptors. A2 adenosine antagonists restored impaired insulin signaling in the skeletal muscle of HSu rats, but did not affect liver or adipose insulin signaling. Our results show that adenosine receptors exert opposite effects on insulin sensitivity, in control and insulin resistant states and strongly suggest that A2 adenosine receptors in the skeletal muscle are the majors responsible for whole-body insulin sensitivity.publishersversionpublishe

Pyrazole or tris(pyrazolyl)ethanol oxo-vanadium(IV) complexes as homogeneous or supported catalysts for oxidation of cyclohexane under mild conditions

The oxovanadium(IV) complexes [VO(acac)(2)(Hpz)].HC(pz)(3) 1.HC(pz)(3) (acac= acetylacetonate, Hpz = pyrazole, pz = pyrazoly1) and [VOCl2{HOCH2C(pz)(3)}] 2 were obtained from reaction of [VO(acac)(2)] with hydrotris(1-pyrazolyl)methane or of VCl(3)with 2,2,2-tris(1-pyrazolyl)ethanol. The compounds were characterized by elemental analysis, IR, Far-IR and EPR spectroscopies, FAB or ESI mass-spectrometry and, for 1, by single crystal X-ray diffraction analysis. 1 and 2 exhibit catalytic activity for the oxidation of cyclohexane to the cyclohexanol and cyclohexanone mixture in homogeneous system (TONS up to 1100) under mild conditions (NCMe, 24h, room temperature) using benzoyl peroxide (BPO), tert-butyl hydroperoxide (TBHP), m-chloroperoxybenzoic acid (mCPBA), hydrogen peroxide or the urea-hydrogen peroxide adduct (UHP) as oxidants. 1 and 2 were also immobilized on a polydimethylsiloxane membrane (1-PDMS or 2-PDMS) and the systems acted as supported catalysts for the cyclohexane oxidation using the above oxidants (TONs up to 620). The best results were obtained with mCPBA or BP0 as oxidant. The effects of various parameters, such as the amount of catalyst, nitric acid, reaction time, type of oxidant and oxidant-to-catalyst molar ratio, were investigated, for both homogeneous and supported systems. (C) 2012 Elsevier B.V. All rights reserved