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Introduction: Obstructive sleep apnea syndrome, manifested by tissue hypoxia, is causally linked with the development of metabolic diseases such as Type 2 diabetes. Although there is convincing epidemiological evidence, molecular mechanisms mediating the adverse metabolic effects remain unclear. Hypoxia may play an important role and modulate metabolic pathways in young adipocytes including the utilization of glucose and acetate or the activation of the reverse tricarboxylic acid cycle (rTCA) leading to increase de novo lipogenesis and excessive fat accumulation. The aim of this study was to investigate the impact of long-term hypoxia on important pathways of de novo lipogenesis in mouse early and late adipocytes. Hypothesis: Hypoxia affects the utilization of carbon sources for de novo lipogenesis differently in early and late adipocytes. Methods: Mouse 3T3-L1 cells were differentiated into adipocytes for 7 days - early adipocytes (EA) or 14 days - late adipocytes (LA). The cells were cultured in gas-permeable cultureware allowing exposure to sustained oxygen levels of 21% O2 or 4% O2. [13C-5]-glutamine (2.5mM) was added to culture media for 7 and 14 days to assess 13C incorporation to newly synthesized lipids via rTCA and [13C-1]-glutamine (2.5mM) was added to media for 24h to assess 13C incorporation to rTCA metabolites. The 13C incorporation studies were analyzed via gas chromatography-mass spectrometry. The contribution of glucose and acetate to de novo lipogenesis was assessed using [14C]-glucose and [14C]-acetate (both 0.2 μCi) provided in culture media for 2h at the end of experiments. Subsequently, radioactivity in extracted lipids was measured via scintillation counter. Statistical significance was assessed by 2-way ANOVA followed by Tukey's test. Data are presented as means ± SD, N=9. Data Hypoxia had no effect on lipid accumulation in EA, lipid accumulation in LA was increased by 134,41% vs control. The 13C incorporation to lipids was increased in EA by 42,2% vs control and by 13,33% vs LA. The 13C incorporation in citrate was increased by 8,71%, in malate by 9,58% in EA vs control, in LA the incorporation remained unchanged. The [14C]-glucose incorporation to lipids was elevated in EA vs control by 209,98% and EA vs LA by 60,02%. The [14C]-acetate incorporation to lipids was increased in EA by 198,43% vs control and decreased by 45,13% vs LA. Differences are statistically significant (p 14C-glucose incorporation. In LA the rTCA and 14C-glucose incorporation were reduced to the control level and the contribution of acetate was increased. Conclusion: Hypoxia modified metabolic pathways in maturating adipocytes leading to increased de novo lipogenesis and thus hypertrophic mature adipocytes. Project was supported by Grant Agency of the Charles University project GAUK 294822 and by grant AZV project NU21-01-00259 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Aims/Hypothesis: Beta-cell failure plays a fundamental role in type 2 diabetes mellitus (T2DM) development. It has been shown that the beta-cells are among the most sensitive to hypoxia. We aimed to analyze whether decrease in pancreatic perfusion relates to 1/decline in beta-cell function and 2/visceral fat accumulation in patients with T2DM. Methods: Fifteen women with T2DM on metformin therapy alone and fifteen women of comparable age and BMI without prediabetes/diabetes were cross-sectionally examined: clinical and anthropometric examination, fast sampled intravenous glucose tolerance test (FSIVGTT), dynamic contrast-enhanced magnetic resonance imaging to assess pancreatic perfusion (area under the curve of postcontrast saturation, AUCTSIC), and visceral adiposity (VAT, calculated from transverse sections at the level L2–L5 vertebrae). Results: Pancreatic blood perfusion (AUCTSIC) did not differ between groups (p = 0.273), but it negatively correlated with BMI (r = −0.434, p = 0.017), WHR (r = −0.411, p = 0.024), and VAT (r = −0.436, p = 0.016) in both groups. Moreover, AUCTSIC in the head of the pancreas negatively correlated with the level of fasting glycemia (r = −0.401, p = 0.028) and HOMA-IR (r = −0.376, p = 0.041). Discussion/Conclusion: We showed that decreased pancreatic perfusion did not relate to beta-cell dysfunction in early stages of T2DM development, but it was related to VAT, insulin resistance, and higher fasting glycemia. Furthermore, lower pancreatic perfusion was related to VAT, insulin resistance, and higher fasting glycemia.

Iron (Fe) treatment is one of the most commonly used methods to restore eutrophic lakes and reservoirs. The Fe-based coagulants dosage results in an almost immediate improvement in water quality at a relatively low cost. However, the effects of the application of coagulants are not always predictable, and the scale of the risks is not fully understood. The dosage of coagulants changes the chemical and physical properties of water, thereby affecting aquatic biocenoses. In this study, several laboratory experiments were conducted to evaluate the effects of Fe-based coagulant dosage on two bivalves species: Anodonta anatina and Unio tumidus. Their ability to efficiently filter water and reduce seston makes them a key component of aquatic ecosystems in terms of maintaining proper ecological health and stable functioning. Behavioral response, biochemical parameters, and body chemistry changes in mussels exposed to different doses of coagulant were surveyed. A dose-dependent reduction in filtration activity of both species was observed. As early as 10 g Fe m

Recenzja książki: Bondecka-Krzykowska I., Brzeziński K.M., Bulińska-Stangrecka H., i in., Przedmioty wirtualne, P. Stacewicz, B. Skowron (red.), Oficyna Wydawnicza Politechniki Warszawskiej, Warszawa 2019, ss. 135.

Background: Exposure to intermittent hypoxia (IH) may play a role in the development of metabolic impairments in the context of obstructive sleep apnea syndrome, probably by elevated plasma levels ...

The glycemic response to ingested glucose for the treatment of hypoglycemia following exercise in type 1 diabetes patients has never been studied. Therefore, we aimed to characterize glucose dynamics during a standardized bout of hypoglycemia-inducing exercise and the subsequent hypoglycemia treatment with the oral ingestion of glucose. Ten male patients with type 1 diabetes performed a standardized bout of cycling exercise using an electrically braked ergometer at a target heart rate (THR) of 50% of the individual heart rate reserve, determined using the Karvonen equation. Exercise was terminated when hypoglycemia was reached, followed by immediate hypoglycemia treatment with the oral ingestion of 20 g of glucose. Arterialized blood glucose (ABG) levels were monitored at 5 min intervals during exercise and for 60 min during recovery. During exercise, ABG decreased at a mean rate of 0.11 ± 0.03 mmol/L·min−1 (minimum: 0.07, maximum: 0.17 mmol/L·min−1). During recovery, ABG increased at a mean rate of 0.13 ± 0.05 mmol/L·min−1 (minimum: 0.06, maximum: 0.19 mmol/L·min−1). Moreover, 20 g of glucose maintained recovery from hypoglycemia throughout the 60 min postexercise observation window.

Mitochondrial substrate flux is a distinguishing characteristic of each cell type, and changes in its components such as transporters, channels, or enzymes are involved in the pathogenesis of several diseases. Mitochondrial substrate flux can be studied using intact cells, permeabilized cells, or isolated mitochondria. Investigating intact cells encounters several problems due to simultaneous oxidation of different substrates. Besides, several cell types contain internal stores of different substrates that complicate results interpretation. Methods such as mitochondrial isolation or using permeabilizing agents are not easily reproducible. Isolating pure mitochondria with intact membranes in sufficient amounts from small samples is problematic. Using non-selective permeabilizers causes various degrees of unavoidable mitochondrial membrane damage. Recombinant perfringolysin O (rPFO) was offered as a more appropriate permeabilizer, thanks to its ability to selectively permeabilize plasma membrane without affecting mitochondrial integrity. When used in combination with microplate respirometry, it allows testing the flux of several mitochondrial substrates with enough replicates within one experiment while using a minimal number of cells. In this work, the protocol describes a method to compare mitochondrial substrate flux of two different cellular phenotypes or genotypes and can be customized to test various mitochondrial substrates or inhibitors.

Recenzja książki: Michał Heller, Ważniejsze niż Wszechświat, Copernicus Center Press, Kraków 2018, ss. 128.

Recenzja książki: Adam Adamandy Kochański, Gottfried Wilhelm Leibniz, Korespondencja Adama Adamandego Kochańskiego i Gottfrieda Wilhelma Leibniza z lat 1670-1698, D. Sieńko (tłum.), wyd. Muzeum Pałacu Króla Jana III w Wilanowie, Warszawa 2019, ss. 256.

Aims: The aims of the study were to assess the degree of knowledge and adherence to the recommended safe practice for driving and the risk of road traffic accidents among people with diabetes mellitus in Armenia. Methods: A total of 628 respondents, including 200 drivers, out of 641 consecutive attendees at six diabetes clinics, participated in the survey. A modified British questionnaire on driving and diabetes was used to obtain the relevant data. The information from all 103 drivers treated with insulin and 73 taking sulfonylureas was reviewed. Results: The study revealed that of 176 insulin and sulfonylurea-treated drivers, 161 (91.5%) had never received any advice about safe driving practices. Among the drivers, 156 (88.6%) never measured their blood glucose before, or during driving. The survey revealed that 86 (51.2%) of 168 patients had a history of at least one motor vehicle accident within the previous 5 years. The average road traffic accident rate per person/year was 0.21. Conclusions: The study revealed a lack of knowledge among drivers with diabetes treated with insulin or sulfonylureas concerning recommended safe practices for driving. This was associated with significant hypoglycemia while driving and an elevated rate of road traffic accidents.

Obstructive sleep apnea syndrome, characterized by repetitive episodes of tissue hypoxia, is associated with several metabolic impairments. Role of fatty acids and lipids attracts attention in its pathogenesis for their metabolic effects. Parallelly, hypoxia-induced activation of reverse tricarboxylic acid cycle (rTCA) with reductive glutamine metabolism provides precursor molecules for de novo lipogenesis. Gas-permeable cultureware was used to culture L6-myotubes in chronic hypoxia (12%, 4% and 1% O2) with 13C labelled glutamine and inhibitors of glutamine uptake or rTCA-mediated lipogenesis. We investigated changes in lipidomic profile, 13C appearance in rTCA-related metabolites, gene and protein expression of rTCA-related proteins and glutamine transporters, glucose uptake and lactate production. Lipid content increased by 308% at 1% O2, predominantly composed of saturated fatty acids, while triacylglyceroles containing unsaturated fatty acids and membrane lipids (phosphatidylcholines, phosphatidylethanolamines, phosphatidylinositol) decreased by 20-70%. rTCA labelling of malate, citrate and 2-hydroxyglutarate increased by 4.7-fold, 2.2-fold and 1.9-fold in 1% O2, respectively. ATP-dependent citrate lyase inhibition in 1% O2 decreased lipid amount by 23% and increased intensity of triacylglyceroles containing unsaturated fatty acids by 56-80%. Lactate production increased with hypoxia. Glucose uptake dropped by 75% with progression of hypoxia from 4% to 1% O2. Protein expression remained unchanged. Altogether, hypoxia modified cell metabolism leading to lipid composition alteration and rTCA activation.

Objective . The strongest locus which associated with type 2 diabetes (T2D) by the common variant rs7903146 is the transcription factor 7-like 2 gene ( TCF7L2 ). We aimed to quantify the interaction of diet/lifestyle interventions and the genetic effect of TCF7L2 rs7903146 on glycemic traits, body weight, or waist circumference in overweight or obese adults in several randomized controlled trials (RCTs). Methods . From October 2016 to May 2018, a large collaborative analysis was performed by pooling individual-participant data from 7 RCTs. These RCTs reported changes in glycemic control and adiposity of the variant rs7903146 after dietary/lifestyle-related interventions in overweight or obese adults. Gene treatment interaction models which used the genetic effect encoded by the allele dose and common covariates were applicable to individual participant data in all studies. Results . In the joint analysis, a total of 7 eligible RCTs were included ( n = 4,114 ). Importantly, we observed a significant effect modification of diet/lifestyle-related interventions on the TCF7L2 variant rs7903146 and changes in fasting glucose. Compared with the control group, diet/lifestyle interventions were related to lower fasting glucose by -3.06 (95% CI, -5.77 to -0.36) mg/dL (test for heterogeneity and overall effect: I 2 = 45.1 % , p < 0.05 ; z = 2.20 , p = 0.028 ) per one copy of the TCF7L2 T risk allele. Furthermore, regardless of genetic risk, diet/lifestyle interventions were associated with lower waist circumference. However, there was no significant change for diet/lifestyle interventions in other glycemic control and adiposity traits per one copy of TCF7L2 risk allele. Conclusions . Our findings suggest that carrying the TCF7L2 T risk allele may have a modestly greater benefit for specific diet/lifestyle interventions to improve the control of fasting glucose in overweight or obese adults.

In this paper, we describe a new statistical approach to estimate blood glucose concentration along time during endurance sports based on measurements of glucose concentration in subcutaneous interstitial tissue. The final goal is the monitoring of glucose concentration in blood to maximize performance in endurance sports. Blood glucose concentration control during and after aerobic physical activity could also be useful to reduce the risk of hypoglycemia in type 1 diabetes mellitus subjects. By means of a low invasive technology known as "continuous glucose monitoring", glucose concentration in subcutaneous interstitial tissue can now be measured every five minutes. However, it can be expressed as function of blood glucose concentration along time by means of a convolution integral equation. In the training phase of the proposed approach, based on measurements of glucose concentration in both artery and subcutaneous interstitial tissue during physical activity, the parameters of the convolution kernel are estimated. Then, given a new subject performing aerobic physical activity, a deconvolution problem is solved to estimate glucose concentration in blood from continuous glucose monitoring measurements

Performing hypoxia-reoxygenation cycles in cell culture with a cycle duration accurately reflecting what occurs in obstructive sleep apnea (OSA) patients is a difficult but crucial technical challenge. Our goal was to develop a novel device to expose multiple cell culture dishes to intermittent hypoxia (IH) cycles relevant to OSA with limited gas consumption. With gas flows as low as 200 ml/min, our combination of plate holders with gas-permeable cultureware generates rapid normoxia-hypoxia cycles. Cycles alternating 1 min at 20% O2 followed by 1 min at 2% O2 resulted in Po2 values ranging from 124 to 44 mmHg. Extending hypoxic and normoxic phases to 10 min allowed Po2 variations from 120 to 25 mmHg. The volume of culture medium or the presence of cells only modestly affected the Po2 variations. In contrast, the nadir of the hypoxia phase increased when measured at different heights above the membrane. We validated the physiological relevance of this model by showing that hypoxia inducible factor-1α expression was significantly increased by IH exposure in human aortic endothelial cells, murine breast carcinoma (4T1) cells as well as in a blood-brain barrier model (2.5-, 1.5-, and 6-fold increases, respectively). In conclusion, we have established a new device to perform rapid intermittent hypoxia cycles in cell cultures, with minimal gas consumption and the possibility to expose several culture dishes simultaneously. This device will allow functional studies of the consequences of IH and deciphering of the molecular biology of IH at the cellular level using oxygen cycles that are clinically relevant to OSA.

Background/Aims: Branched chain amino acids (BCAAs) are known to exert an insulinotropic effect. Whether this effect is mediated by incretins (glucagon like peptide 1 [GLP-1] or glucose-dependent insulinotropic peptide [GIP]) is not known. The aim of this study was to show whether an equivalent dose of BCAA elicits a greater insulin and incretin response when administered orally than intravenously (IV). Methods: Eighteen healthy, male subjects participated in 3 tests: IV application of BCAA solution, oral ingestion of BCAA and placebo in an equivalent dose (30.7 ± 1.1 g). Glucose, insulin, C-peptide, glucagon, GLP-1, GIP, valine, leucine and isoleucine concentrations were measured. Results: Rise in serum BCAA was achieved in both BCAA tests, with incremental areas under the curve (iAUC) being 2.1 times greater for IV BCAA compared with those of the oral BCAA test (p < 0.0001). Oral and IV BCAA induced comparable insulin response greater than placebo (240 min insulin iAUC: oral 3,411 ± 577 vs. IV 2,361 ± 384 vs. placebo 961.2 ± 175 pmol/L, p = 0.0006). Oral BCAA induced higher GLP-1 (p < 0.0001) and GIP response (p < 0.0001) compared with the IV or placebo. Glucose levels declined significantly (p < 0.001) in the same pattern during both BCAA tests with no change in the placebo group. Conclusions: An equivalent dose of BCAA elicited a comparable insulin and greater incretin response when administered orally and not when administered through IV. We conclude that insulinotropic effects of BCAA are partially incretin dependent.

Saturated fatty acids (FAs) induce apoptosis in the human pancreatic NES2Y β-cell line while unsaturated FAs have nearly no detrimental effect. Moreover, unsaturated FAs are capable of inhibiting the pro-apoptotic effect of saturated FAs. Hypoxia is also known to have deleterious effects on β-cells function and viability. In the present study, we have tested the modulatory effect of hypoxia on the effect of FAs on the growth and viability of the human pancreatic NES2Y β-cells. This study represents the first study testing hypoxia effect on effects of FAs in pancreatic β-cells as well as in other cell types. We showed that hypoxia increased the pro-apoptotic effect of saturated stearic acid (SA). Endoplasmic reticulum stress signaling seemed to be involved while redistribution of FA transporters fatty acid translocase/cluster of differentiation 36 (FAT/CD36) and fatty acid-binding protein (FABP) do not seem to be involved in this effect. Hypoxia also strongly decreased the protective effect of unsaturated oleic acid (OA) against the pro-apoptotic effect of SA. Thus, in the presence of hypoxia, OA was unable to save SA-treated β-cells from apoptosis induction. Hypoxia itself had only a weak detrimental effect on NES2Y cells. Our data suggest that hypoxia could represent an important factor in pancreatic β-cell death induced and regulated by FAs and thus in the development of type 2 diabetes mellitus.

Background Obstructive sleep apnea (OSA) is highly prevalent in patients with Type 2 diabetes mellitus representing an additional risk factor for already increased cardiovascular mortality. As cardiovascular diseases are the main cause of death in this population, there is a need to identify patients with moderate to severe OSA indicated for treatment. We aimed to evaluate the performance of the Berlin, STOP, and STOP-Bang screening questionnaires in a population of patients with Type 2 diabetes mellitus. Methods 294 consecutive patients with Type 2 diabetes mellitus filled in the questionnaires and underwent overnight home sleep monitoring using a type IV sleep monitor. Results Severe, moderate, and mild OSA was found in 31 (10%), 61 (21%), and 121 (41%) patients, respectively. The questionnaires showed a similar sensitivity and specificity for AHI ≥ 15: 0.69 and 0.50 for Berlin, 0.65 and 0.49 for STOP, and 0.59 and 0.68 for STOP-Bang. However, the performance of the STOP-Bang questionnaire was different in men vs. women, sensitivity being 0.74 vs. 0.29 (p Conclusions Even the best-performing Berlin questionnaire failed to identify 31% of patients with moderate to severe OSA as being at high risk of OSA, thus preventing them from receiving a correct diagnosis and treatment. Considering that patients with Type 2 diabetes mellitus are at high risk of cardiovascular mortality and also have a high prevalence of moderate to severe OSA, we find screening based on the questionnaires suboptimal and suggest that OSA screening should be performed using home sleep monitoring devices.

In-vitro investigation of the effects of hypoxia is limited by physical laws of gas diffusion and cellular O2 consumption, making prolonged exposures to stable O2 concentrations impossible. Using a gas-permeable cultureware, chronic effects of mild and severe hypoxia on triglyceride accumulation, lipid droplet size distribution, spontaneous lipolysis and gene expression of adipocyte-specific markers were assessed. 3T3-L1 cells were differentiated under 20%, 4% or 1% O2 using a gas-permeable cultureware. Triglyceride accumulation, expression of genes characteristic for advanced adipocyte differentiation and involvement of key lipogenesis enzymes were assessed after exposures. Lipogenesis increased by 375% under mild hypoxia, but dropped by 43% in severe hypoxia. Mild, but not severe, hypoxia increased formation of large lipid droplets 6.4 fold and strongly induced gene expression of adipocyte-specific markers. Spontaneous lipolysis increased by 488% in mild, but only by 135% in severe hypoxia. Inhibition of ATP-dependent citrate lyase suppressed hypoxia-induced lipogenesis by 81% and 85%. Activation of HIF inhibited lipogenesis by 59%. Mild, but not severe, hypoxia stimulates lipolysis and promotes adipocyte differentiation, probably through excess of acetyl-CoA originating from tricarboxylic acid cycle independently of HIF activation.

Metabolic impairments associated with obstructive sleep apnea syndrome (OSA) are linked to tissue hypoxia, however, the explanatory molecular and endocrine mechanisms remain unknown. Using gas-permeable cultureware, we studied the chronic effects of mild and severe hypoxia on free fatty acid (FFA) uptake, storage, and oxidation in L6 myotubes under 20, 4, or 1% O2. Additionally, the impact of metformin and the peroxisome proliferator-activated receptor (PPAR) β/δ agonist, called GW501516, were investigated. Exposure to mild and severe hypoxia reduced FFA uptake by 37 and 32%, respectively, while metformin treatment increased FFA uptake by 39% under mild hypoxia. GW501516 reduced FFA uptake under all conditions. Protein expressions of CD36 (cluster of differentiation 36) and SCL27A4 (solute carrier family 27 fatty acid transporter, member 4) were reduced by 17 and 23% under severe hypoxia. Gene expression of UCP2 (uncoupling protein 2) was reduced by severe hypoxia by 81%. Metformin increased CD36 protein levels by 28% under control conditions and SCL27A4 levels by 56% under mild hypoxia. Intracellular lipids were reduced by mild hypoxia by 18%, while in controls only, metformin administration further reduced intracellular lipids (20% O2) by 36%. Finally, palmitate oxidation was reduced by severe hypoxia, while metformin treatment reduced non-mitochondrial O2 consumption, palmitate oxidation, and proton leak at all O2 levels. Hypoxia directly reduced FFA uptake and intracellular lipids uptake in myotubes, at least partially, due to the reduction in CD36 transporters. Metformin, but not GW501516, can increase FFA uptake and SCL27A4 expression under mild hypoxia. Described effects might contribute to elevated plasma FFA levels and metabolic derangements in OSA.

Background: The transcription factor 7-like 2 gene (TCF7L2) is the strongest locus associated by the variant rs7903146 with type 2 diabetes (T2D) identified to date. Whether diet/lifestyle intervention modifies genetic effect of TCF7L2 variant on glucose homeostasis and adiposity is still controversial. Objective: To quantify the modification effects of the diet/lifestyle interventions on genetic association of TCF7L2 variant rs7903146 with glycemic control and adiposity changes in randomized controlled trials (RCTs). Design A large collaborative analysis of individual-participant data from seven RCTs. Setting RCTs conducted in adults reporting changes in glycemic traits, body weight, or waist circumference by TCF7L2 rs7903146 after dietary/lifestyle-based interventions. Gene-treatment interaction models were fitted to individual participant data from all studies, using allele dose coding for genetic effects and a common set of covariates. Results: We included seven eligible RCTs for the joint analysis (n=4,114 participants). Overall, a significant interaction between TCF7L2 rs7903146 and diet/lifestyle interventions on decrease in fasting glucose was observed. Compared with control, diet/lifestyle interventions reduced fasting glucose by -0.17 (95% CI, -0.32 to -0.02) mmol/L (test for heterogeneity: I2=45.1%, p

Hyperglycemia is suggested to be one of the drivers of the proinflammatory state observed in obese and diabetic patients.The objectives of the study was to investigate whether sc abdominal adipose tissue (scAT) could be one of the important sources of proinflammatory cytokines released in response to short-term hyperglycemia and whether this secretion capacity could be influenced by weight loss.Output of cytokines and proteins of acute phase from scAT in response to a 3-hours hyperglycemic clamp was evaluated in nine obese women in vivo using Fick's principle. Moreover, the output of cytokines was analyzed during a multiphase dietary intervention consisting of 1 month on a very low-calorie diet and subsequent 5-month weight-stabilization phase.The levels of cytokines and proteins of acute phase [IL-6, IL-8, IL-1 receptor antagonist (IL-1Ra), TNF-α, monocyte chemoattractant protein-1 (MCP-1), serum amyloid A, and C-reactive protein] in arterial and venous plasma were measured during each dietary phase. The insulin sensitivity of scAT in respect to the antilipolytic effect of insulin during the clamp was assessed.Hyperglycemia increased the output of cytokines IL-6, MCP-1, and IL-1Ra from scAT. This effect had a tendency to be reduced after weight loss. The output of other proinflammatory substances from scAT into circulation was not detected. The diet-induced weight loss was associated with the improvement of antilipolytic insulin sensitivity in scAT.The results suggest that short-term hyperglycemia induces an increase of the output of cytokines IL-6, IL-1Ra, and MCP-1 from adipose tissue, and this deleterious hyperglycemia effect may be attenuated by the diet-induced weight reduction. This lowered responsiveness of the inflammation-related system may be an important feature of the weight reduction-induced improvement of the metabolic status of obese prediabetic individuals.

Oxygen administration inhibits spontaneous and ANP-stimulated lipolysis in adipose tissue in severe COPD http://ow.ly/ZVg53022Yah

Performing hypoxia-reoxygenation cycles in cell culture with a cycle duration accurately reflecting what occurs in obstructive sleep apnea (OSA) patients is a difficult but crucial technical challenge. Our goal was to develop a novel device to expose multiple cell culture dishes to intermittent hypoxia (IH) cycles relevant to OSA with limited gas consumption. With gas flows as low as 200 ml/min, our combination of plate holders with gas-permeable cultureware generates rapid normoxia-hypoxia cycles. Cycles alternating 1 min at 20% O

Objectives Obstructive sleep apnea is associated with insulin resistance, glucose intolerance, and type 2 diabetes mellitus. Although several studies have suggested that intermittent hypoxia in obstructive sleep apnea may induce abnormalities in glucose homeostasis, it remains to be determined whether these abnormalities improve after discontinuation of the exposure. The objective of this study was to delineate the effects of intermittent hypoxia on glucose homeostasis, beta cell function, and liver glucose metabolism and to investigate whether the impairments improve after the hypoxic exposure is discontinued. Interventions C57BL6/J mice were exposed to 14 days of intermittent hypoxia, 14 days of intermittent air, or 7 days of intermittent hypoxia followed by 7 days of intermittent air (recovery paradigm). Glucose and insulin tolerance tests were performed to estimate whole-body insulin sensitivity and calculate measures of beta cell function. Oxidative stress in pancreatic tissue and glucose output from isolated hepatocytes were also assessed. Results Intermittent hypoxia increased fasting glucose levels and worsened glucose tolerance by 67% and 27%, respectively. Furthermore, intermittent hypoxia exposure was associated with impairments in insulin sensitivity and beta cell function, an increase in liver glycogen, higher hepatocyte glucose output, and an increase in oxidative stress in the pancreas. While fasting glucose levels and hepatic glucose output normalized after discontinuation of the hypoxic exposure, glucose intolerance, insulin resistance, and impairments in beta cell function persisted. Conclusions Intermittent hypoxia induces insulin resistance, impairs beta cell function, enhances hepatocyte glucose output, and increases oxidative stress in the pancreas. Cessation of the hypoxic exposure does not fully reverse the observed changes in glucose metabolism.

The shorter life expectancy of patients with type 2 diabetes caused by cardiovascular and cerebrovascular diseases compels clinicians to make a systematic effort to address traditional cardiovascular risk factors, such as dyslipidemia, hypertension, hyperglycemia, obesity, and smoking. However, another major cardiovascular risk factor substantially influencing the quality and length of life – obstructive sleep apnea syndrome (OSA) – is frequently overlooked. OSA is characterized by a repetitive upper airway obstruction during sleep leading to intermittent hypoxemia and sleep fragmentation. Numerous epidemiological studies have proved that untreated OSA represents an independent risk factor significantly increasing all cause as well as cardiovascular, cerebrovascular, and cancer mortality (1–7). The importance of OSA is underscored by its considerable prevalence ranging from 5 to 10% in the general population and is even higher in the population of type 2 diabetes patients where a prevalence of ~70% was reported (8–10). Furthermore, ~90% of all subjects suffering from moderate or severe OSA remain undiagnosed (11).

Obstructive sleep apnea (OSA) is associated with insulin resistance, glucose intolerance, and type 2 diabetes. Causal mechanisms mediating this association are not well defined; however, augmented lipolysis in adipose might be involved. Here, we investigated the effect of acipimox treatment (lipolysis inhibitor) on glucose tolerance and insulin sensitivity in mice exposed to intermittent hypoxia (IH). C57BL6/J mice were exposed for 14 days to IH or control conditions. IH was created by decreasing the fraction of inspired oxygen from 20.9 to 6.5%, 60 times/h. Control exposure was air (fraction of inspired oxygen, 20.9%) delivered at an identical flow rate. Acipimox was provided in drinking water (0.5 g/ml) during exposures. After exposures, intraperitoneal insulin (0.5 IU/kg) and glucose (1 g/kg) tolerance tests were performed, and primary adipocytes were isolated for lipolysis experiments. IH elevated fasting glucose by 51% and worsened glucose tolerance and insulin sensitivity by 33 and 102%, respectively. In parallel, IH increased spontaneous lipolysis by 264%, and reduced epididymal fat mass by 15% and adipocyte size by 8%. Acipimox treatment prevented IH-induced lipolysis and increased epididymal fat mass and adipocyte size by 19 and 10%, respectively. Acipimox fully prevented IH-induced impairments in fasting glycemia, glucose tolerance, and insulin sensitivity. For all reported results, P less than 0.05 was considered significant. Augmented lipolysis contributes to insulin resistance and glucose intolerance observed in mice exposed to IH. Acipimox treatment ameliorated the metabolic consequences of IH and might represent a novel treatment option for patients with obstructive sleep apnea.

Methyltriphenylphosphonium (TPMP) salts have been widely used to measure the mitochondrial membrane potential and the triphenylphosphonium (TPP+) moiety has been attached to many bioactive compounds including antioxidants to target them into mitochondria thanks to their high affinity to accumulate in the mitochondrial matrix. The adverse effects of these compounds on cellular metabolism have been insufficiently studied and are still poorly understood. Micromolar concentrations of TPMP cause a progressive inhibition of cellular respiration in adherent cells without a marked effect on mitochondrial coupling. In permeabilized cells the inhibition was limited to NADH-linked respiration. We found a mixed inhibition of the Krebs cycle enzyme 2-oxoglutarate dehydrogenase complex (OGDHC) with an estimated IC50 3.93 [3.70-4.17] mM, which is pharmacologically plausible since it corresponds to micromolar extracellular concentrations. Increasing the lipophilic character of the used TPP+ compound further potentiates the inhibition of OGDHC activity. This effect of TPMP on the Krebs cycle ought to be taken into account when interpreting observations on cells and mitochondria in the presence of TPP+ derivatives. Compounds based on or similar to TPP+ derivatives may also be used to alter OGDHC activity for experimental or therapeutic purposes.