Life Under Hypoxia Lowers Blood Glucose Independently of Effects on Appetite and Body Weight in Mice

Blood glucose and the prevalence of diabetes are lower in mountain than lowland dwellers, which could among other factors be due to reduced oxygen availability. To investigate metabolic adaptations to life under hypoxia, male mice on high fat diet (HFD) were continuously maintained at 10% O2. At variance to preceding studies, the protocol was designed to dissect direct metabolic effects from such mediated indirectly via hypoxia-induced reductions in appetite and weight gain. This was achieved by two separate control groups on normal air, one with free access to HFD, and one fed restrictedly in order to obtain a weight curve matching that of hypoxia-exposed mice. Comparable body weight in restrictedly fed and hypoxic mice was achieved by similar reductions in calorie intake (−22%) and was associated with parallel effects on body composition as well as on circulating insulin, leptin, FGF-21, and adiponectin. Whereas the effects of hypoxia on the above parameters could thus be attributed entirely to blunted weight gain, hypoxia improved glucose homeostasis in part independently of body weight (fasted blood glucose, mmol/l: freely fed control, 10.2 ± 0.7; weight-matched control, 8.0 ± 0.3; hypoxia, 6.8 ± 0.2; p < 0.007 each; AUC in the glucose tolerance test, mol/l*min: freely fed control, 2.54 ± 0.15; weight-matched control, 1.86 ± 0.08; hypoxia, 1.67 ± 0.05; p < 0.05 each). Although counterintuitive to lowering of glycemia, insulin sensitivity appeared to be impaired in animals adapted to hypoxia: In the insulin tolerance test, hypoxia-treated mice started off with lower glycaemia than their weight-matched controls (initial blood glucose, mmol/l: freely fed control, 11.5 ± 0.7; weight-matched control, 9.4 ± 0.3; hypoxia, 8.1 ± 0.2; p < 0.02 each), but showed a weaker response to insulin (final blood glucose, mmol/l: freely fed control, 7.0 ± 0.3; weight-matched control, 4.5 ± 0.2; hypoxia, 5.5 ± 0.3; p < 0.01 each). Furthermore, hypoxia weight-independently reduced hepatic steatosis as normalized to total body fat, suggesting a shift in the relative distribution of triglycerides from liver to fat (mg/g liver triglycerides per g total fat mass: freely fed control, 10.3 ± 0.6; weight-matched control, 5.6 ± 0.3; hypoxia, 4.0 ± 0.2; p < 0.0004 each). The results show that exposure of HFD-fed mice to continuous hypoxia leads to a unique metabolic phenotype characterized by improved glucose homeostasis along with evidence for impaired rather than enhanced insulin sensitivity

Acute mountain sickness.

Acute mountain sickness (AMS) is a clinical syndrome occurring in otherwise healthy normal individuals who ascend rapidly to high altitude. Symptoms develop over a period ofa few hours or days. The usual symptoms include headache, anorexia, nausea, vomiting, lethargy, unsteadiness of gait, undue dyspnoea on moderate exertion and interrupted sleep. AMS is unrelated to physical fitness, sex or age except that young children over two years of age are unduly susceptible. One of the striking features ofAMS is the wide variation in individual susceptibility which is to some extent consistent. Some subjects never experience symptoms at any altitude while others have repeated attacks on ascending to quite modest altitudes. Rapid ascent to altitudes of 2500 to 3000m will produce symptoms in some subjects while after ascent over 23 days to 5000m most subjects will be affected, some to a marked degree. In general, the more rapid the ascent, the higher the altitude reached and the greater the physical exertion involved, the more severe AMS will be. Ifthe subjects stay at the altitude reached there is a tendency for acclimatization to occur and symptoms to remit over 1-7 days

Male life history of a harlequin toad population in French Guiana

Harlequin toads (Atelopus spp.) constitute one of the most threatened amphibian clades worldwide, yet much of their life history remains poorly understood. These anurans are strongly associated with stream environments, which are used for reproduction and occupied by males throughout the year, while only visited by females during the reproduction season. We studied a population of the Atelopus flavescens complex in French Guiana. We describe male population den- sity, habitat use, site fidelity and movement, as well as home range behaviour – all prior to the arrival of females. We also present further natural history observations such as nocturnal resting sites and anecdotal observations of females. Our findings suggest that in this lowland population of Atelopus, males maintain territories for a relatively long time compared to other species. Within them, they acoustically compete for females, which they attempt to clasp for amplexus when they arrive later in the season on their way to the breeding sites.publishe

Male life history of a harlequin toad population in French Guiana

Harlequin toads (Atelopus spp.) constitute one of the most threatened amphibian clades worldwide, yet much of their life history remains poorly understood. These anurans are strongly associated with stream environments, which are used for reproduction and occupied by males throughout the year, while only visited by females during the reproduction season. We studied a population of the Atelopus flavescens complex in French Guiana. We describe male population density, habitat use, site fidelity and movement, as well as home range behaviour – all prior to the arrival of females. We also present further natural history observations such as nocturnal resting sites and anecdotal observations of females. Our findings suggest that in this lowland population of Atelopus, males maintain territories for a relatively long time compared to other species. Within them, they acoustically compete for females, which they attempt to clasp for amplexus when they arrive later in the season on their way to the breeding sites

Life Under Hypoxia Lowers Blood Glucose Independently of Effects on Appetite and Body Weight in Mice

Blood glucose and the prevalence of diabetes are lower in mountain than lowland dwellers, which could among other factors be due to reduced oxygen availability. To investigate metabolic adaptations to life under hypoxia, male mice on high fat diet (HFD) were continuously maintained at 10% O2. At variance to preceding studies, the protocol was designed to dissect direct metabolic effects from such mediated indirectly via hypoxia-induced reductions in appetite and weight gain. This was achieved by two separate control groups on normal air, one with free access to HFD, and one fed restrictedly in order to obtain a weight curve matching that of hypoxia-exposed mice. Comparable body weight in restrictedly fed and hypoxic mice was achieved by similar reductions in calorie intake (22%) and was associated with parallel effects on body composition as well as on circulating insulin, leptin, FGF-21, and adiponectin. Whereas the effects of hypoxia on the above parameters could thus be attributed entirely to blunted weight gain, hypoxia improved glucose homeostasis in part independently of body weight (fasted blood glucose, mmol/l: freely fed control, 10.2 0.7; weight-matched control, 8.0 0.3; hypoxia, 6.8 0.2; p < 0.007 each; AUC in the glucose tolerance test, mol/l*min: freely fed control, 2.54 0.15; weight-matched control, 1.86 0.08; hypoxia, 1.67 0.05; p < 0.05 each). Although counterintuitive to lowering of glycemia, insulin sensitivity appeared to be impaired in animals adapted to hypoxia: In the insulin tolerance test, hypoxia-treated mice started off with lower glycaemia than their weight-matched controls (initial blood glucose, mmol/l: freely fed control, 11.5 0.7; weight-matched control, 9.4 0.3; hypoxia, 8.1 0.2; p < 0.02 each), but showed a weaker response to insulin (final blood glucose, mmol/l: freely fed control, 7.0 0.3; weight-matched control, 4.5 0.2; hypoxia, 5.5 0.3; p < 0.01 each). Furthermore, hypoxia weight-independently reduced hepatic steatosis as normalized to total body fat, suggesting a shift in the relative distribution of triglycerides from liver to fat (mg/g liver triglycerides per g total fat mass: freely fed control, 10.3 0.6; weight-matched control, 5.6 0.3; hypoxia, 4.0 0.2; p < 0.0004 each). The results show that exposure of HFD-fed mice to continuous hypoxia leads to a unique metabolic phenotype characterized by improved glucose homeostasis along with evidence for impaired rather than enhanced insulin sensitivity.(VLID)470109

Emodin : a compound with putative antidiabetic potential, deteriorates glucose tolerance in rodents

Emodin is found in remedies from Traditional Chinese Medicine. Since antihyperglycaemic action was observed in rodents, non-scientific sources advertise emodin intake as a natural cure for diabetes. Emodin was admixed to high fat-food of obese mice at two doses (2 and 5 g/kg; daily emodin uptake 103 and 229 mg/kg). Comparison was made to ad libitum fed and to food restricted control groups, the latter showing the same weight gain as the corresponding emodin-treated groups. Emodin blunted food intake by 6% and 20% for the low and high dose, which was accompanied by proportionate reductions in weight gain. Emodin reduced blood glucose relative to freely feeding controls, but comparison to weight-matched controls unmasked deterioration, rather than improvement, of basal glycaemia (mmol/l: fed ad libitum, 9.5±0.4; low emodin, 9.4±0.3, weight-matched, 8.2±0.3; high emodin, 7.2±0.4, weight-matched, 6.1±0.3; P<0.01, emodin vs weight-matched) and glucose tolerance (area under the curve, min*mol/l: fed ad libitum, 2.01±0.08; low emodin, 1.97±0.12, weight-matched, 1.75±0.03; high emodin, 1.89±0.07, weight-matched, 1.65±0.05; P<0.0002, emodin vs weight-matched). An insulin tolerance test suggested insulin desensitisation by prolonged emodin treatment. Furthermore, a single oral emodin dose did not affect glucose tolerance in obese mice, whereas intravenous injection in rats suggested a potential of emodin to acutely impair insulin release. Our results show that the antihyperglycaemic action of emodin as well as associated biochemical alterations could be the mere consequences of a spoilt appetite. Published claims of antidiabetic potential via other mechanisms evoke the danger of misuse of natural remedies by diabetic patients

A Comparative Study on the Experimentally Derived Electron Densities of three Protease Inhibitor Model Compounds

In order to contribute to a rational design of optimised protease inhibitors which can covalently block the nucleophilic amino acids of the proteases' active sites, we have chosen three model compounds (aziridine , oxirane and acceptor-substituted olefin ) for the examination of their electron-density distribution. Therefore, high-resolution low temperature (9, 27 and 100 K) X-ray diffraction experiments on single-crystals were carried out with synchrotron and conventional X-radiation. It could be shown by the analysis of the electron density using mainly Bader's Theory of Atoms in Molecules, Volkov's EPMM method for interaction energies, electrostatic potentials and Gatti's Source Function that aziridine is most suitable for drug design in this field. A regioselective nucleophilic attack at carbon atom C1 could be predicted and even hints about the reaction's stereoselectivity could be obtained. Moreover, the comparison between two data sets of aziridine (conventional X-ray source vs. synchrotron radiation) gave an estimate concerning the reproducibility of the quantitative results

The Electron Localizability Indicator from X-Ray Diffraction Data - A First Application to a Series of Epoxide Derivatives

No longer hidden! An extension of the capabilities of the X‐ray diffraction experiment is introduced. Locations of electron pairs within a molecule can be measured and made visible (see figure). This is demonstrated on a series of epoxides, for which ring strain, crystal, and substituent effects can be quantified. Comparison with experimental and theoretical electron‐density analyses shows the advantages of the new method

Differential expression of CD8 defines phenotypically distinct cytotoxic T cells in cancer and multiple sclerosis

Abstract Background Cytotoxic T lymphocytes take on a leading role in many immune‐related diseases. They function as key effector immune cells fighting cancer cells, but they are also considerably involved in autoimmune diseases. Common to both situations, CD8+ T cells need to adapt their metabolism and effector function to the harsh and nutrient‐deprived conditions of the disease‐associated microenvironment. Methods We used an in vitro starvation as well as rapamycin treatment protocol mimicking nutrient deprivation to generate CD8Low versus CD8High T cells and performed FACS‐Sorting followed by transcriptomic profiling of the cytotoxic T cell subsets. Prominent markers identified in the CD8Low versus the CD8High T cells were then used to investigate the presence of these cell subsets in immune‐related human diseases. Employing cancer tissue microarrays and PhenOptics multispectral imaging as well as flow cytometry, we studied these CD8+ T cell subsets in cancer and relapsing‐remitting multiple sclerosis patients. Results Starvation induced a decreased expression of CD8, yielding a CD8Low T cell subpopulation with an altered transcriptomic signature and reduced effector function. CD8Low T cell showed enhanced ST2L and IL6ST (CD130) expression compared to CD8High T cells which expressed elevated KLRD1 (CD94) and granzyme B levels within the tumour microenvironment (TME). Spatial analysis revealed the presence of CD8High T cells in close proximity to tumour cells, while the CD8Low T cells resided at the tumour boundaries. Importantly, the number of tumour‐infiltrating CD8Low T lymphocytes correlated with a poor prognosis as well as with enhanced cancer progression in human mammary carcinoma. We also found a reduced frequency of CD8Low T lymphocytes in a cohort of relapse (disease active) multiple sclerosis patients compared to healthy subjects during immune cell starvation in vitro. Conclusions In summary, our data show that functionally distinct cytotoxic T lymphocytes can be identified based on their expression of CD8. Indicating a more general role in CD8 T cell immunity, these cells may play opposing roles in the TME, and also in the pathophysiology of autoimmune diseases such as multiple sclerosis