Intermittent hypoxia-induced glucose intolerance is abolished by α-adrenergic blockade or adrenal medullectomy

Obstructive sleep apnea causes intermittent hypoxia (IH) during sleep and is associated with dysregulation of glucose metabolism. We developed a novel model of clinically realistic IH in mice to test the hypothesis that IH causes hyperglycemia, glucose intolerance, and insulin resistance via activation of the sympathetic nervous system. Mice were exposed to acute hypoxia of graded severity (21, 14, 10, and 7% O2) or to IH of graded frequency [oxygen desaturation index (ODI) of 0, 15, 30, or 60, SpO2nadir 80%] for 30 min to measure levels of glucose fatty acids, glycerol, insulin, and lactate. Glucose tolerance tests and insulin tolerance tests were then performed under each hypoxia condition. Next, we examined these outcomes in mice that were administered phentolamine (α-adrenergic blockade) or propranolol (β-adrenergic blockade) or that underwent adrenal medullectomy before IH exposure. In all experiments, mice were maintained in a thermoneutral environment. Sustained and IH induced hyperglycemia, glucose intolerance, and insulin resistance in a dose-dependent fashion. Only severe hypoxia (7% O2) increased lactate, and only frequent IH (ODI 60) increased plasma fatty acids. Phentolamine or adrenal medullectomy both prevented IH-induced hyperglycemia and glucose intolerance. IH inhibited glucose-stimulated insulin secretion, and phentolamine prevented the inhibition. Propranolol had no effect on glucose metabolism but abolished IH-induced lipolysis. IH-induced insulin resistance was not affected by any intervention. Acutely hypoxia causes hyperglycemia, glucose intolerance, and insulin resistance in a dose-dependent manner. During IH, circulating catecholamines act upon α-adrenoreceptors to cause hyperglycemia and glucose intolerance.

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Biofabricated Fatty Acids-Capped Silver Nanoparticles as Potential Antibacterial, Antifungal, Antibiofilm and Anticancer Agents

Pharmaceuticals ◽

10.3390/ph14020139 ◽

2021 ◽

Vol 14 (2) ◽

pp. 139

Author(s):

Mohammad Azam Ansari ◽

Sarah Mousa Maadi Asiri ◽

Mohammad A. Alzohairy ◽

Mohammad N. Alomary ◽

Ahmad Almatroudi ◽

...

Keyword(s):

Fatty Acids ◽

Silver Nanoparticles ◽

Anticancer Agents ◽

Sem Analysis ◽

Dependent Manner ◽

Anticancer Activities ◽

Anticancer Efficacy ◽

Hct 116 ◽

Hct 116 Cells ◽

Dose Dependent

The current study demonstrates the synthesis of fatty acids (FAs) capped silver nanoparticles (AgNPs) using aqueous poly-herbal drug Liv52 extract (PLE) as a reducing, dispersing and stabilizing agent. The NPs were characterized by various techniques and used to investigate their potent antibacterial, antibiofilm, antifungal and anticancer activities. GC-MS analysis of PLE shows a total of 37 peaks for a variety of bio-actives compounds. Amongst them, n-hexadecanoic acid (21.95%), linoleic acid (20.45%), oleic acid (18.01%) and stearic acid (13.99%) were found predominately and most likely acted as reducing, stabilizing and encapsulation FAs in LIV-AgNPs formation. FTIR analysis of LIV-AgNPs shows some other functional bio-actives like proteins, sugars and alkenes in the soft PLE corona. The zone of inhibition was 10.0 ± 2.2–18.5 ± 1.0 mm, 10.5 ± 2.5–22.5 ± 1.5 mm and 13.7 ± 1.0–16.5 ± 1.2 against P. aeruginosa, S. aureus and C. albicans, respectively. LIV-AgNPs inhibit biofilm formation in a dose-dependent manner i.e., 54.4 ± 3.1%—10.12 ± 2.3% (S. aureus), 72.7 ± 2.2%–23.3 ± 5.2% (P. aeruginosa) and 85.4 ± 3.3%–25.6 ± 2.2% (C. albicans), and SEM analysis of treated planktonic cells and their biofilm biomass validated the fitness of LIV-AgNPs in future nanoantibiotics. In addition, as prepared FAs rich PLE capped AgNPs have also exhibited significant (p < 0.05 *) antiproliferative activity against cultured HCT-116 cells. Overall, this is a very first demonstration on employment of FAs rich PLE for the synthesis of highly dispersible, stable and uniform sized AgNPs and their antibacterial, antifungal, antibiofilm and anticancer efficacy.

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Association between sleep disordered breathing in early pregnancy and glucose metabolism

SLEEP ◽

10.1093/sleep/zsab281 ◽

2022 ◽

Author(s):

Laura Sanapo ◽

Margaret H Bublitz ◽

Alice Bai ◽

Niharika Mehta ◽

Geralyn M Messerlian ◽

...

Keyword(s):

Insulin Resistance ◽

Obstructive Sleep Apnea ◽

Sleep Apnea ◽

Glucose Metabolism ◽

Early Pregnancy ◽

Airway Pressure ◽

Sleep Disordered Breathing ◽

Positive Airway Pressure ◽

Obstructive Sleep ◽

Respiratory Event

Abstract Study Objectives To examine the association between maternal sleep disordered breathing (SDB) and glucose metabolism in early gestation. Methods Women with body mass index (BMI) ≥27 kg/m2 and singleton pregnancies underwent in-home sleep study (HSAT) and homeostatic model assessment (HOMA) in early pregnancy. Insulin resistance (HOMA-IR) and β-cell function (HOMA %B) were derived. Exclusion criteria included pregestational diabetes, use of continuous positive airway pressure and chronic steroid therapy. We performed linear regression analyses to evaluate the association between continuous measures of SDB (respiratory event index (REI), and oxygen desaturation index (ODI)) and glucose metabolism parameters (HOMA-IR and HOMA %B). Analyses were adjusted for a set of a priori selected variables which included gestational age, maternal age, BMI, ethnicity, race, and parity. Results One hundred and ninety-two pregnant women with median (interquartile range) BMI of 35.14 (8.30) kg/m2 underwent HSAT and HOMA assessment at 11.14 (3) and 15.35 (4.14) gestational weeks, respectively. REI and ODI, as continuous values, were associated with HOMA-IR after adjusting for covariates. OSA (obstructive sleep apnea) diagnosis (REI > 5 events per hour) was not associated with HOMA-IR after adjusting for BMI (p ≥ 0.05). None of the parameters were associated with HOMA %B (p > 0.07). Conclusions SDB and insulin resistance are associated in early pregnancy, with a dose response association between respiratory event index severity and insulin resistance. Further studies are needed to establish if pregnant women with overweight and obesity may benefit from early SDB screening to improve glucose metabolic outcome. Clinical trials: NCT02412696, Positive Airway Pressure, Sleep Apnea, and the Placenta (PAP-SAP) https://clinicaltrials.gov/ct2/show/NCT02412696?term=Bourjeily&draw=2&rank=2 and NCT02917876, Predictors of De-novo Development of Obstructive Sleep Apnea in Pregnancy (Predictors) https://clinicaltrials.gov/ct2/show/NCT02917876?term=Bourjeily&draw=2&rank=1

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Short-term intermittent hypoxia enhances sympathetic responses to continuous hypoxia in humans

Journal of Applied Physiology ◽

10.1152/japplphysiol.00036.2007 ◽

2007 ◽

Vol 103 (3) ◽

pp. 835-842 ◽

Cited By ~ 28

Author(s):

Urs A. Leuenberger ◽

Cynthia S. Hogeman ◽

Sadeq Quraishi ◽

Latoya Linton-Frazier ◽

Kristen S. Gray

Keyword(s):

Blood Pressure ◽

Sleep Apnea ◽

Sympathetic Activity ◽

Intermittent Hypoxia ◽

Muscle Sympathetic Nerve Activity ◽

Acute Hypoxia ◽

Short Term ◽

Healthy Humans ◽

Obstructive Sleep ◽

Normal Humans

Short-term intermittent hypoxia leads to sustained sympathetic activation and a small increase in blood pressure in healthy humans. Because obstructive sleep apnea, a condition associated with intermittent hypoxia, is accompanied by elevated sympathetic activity and enhanced sympathetic chemoreflex responses to acute hypoxia, we sought to determine whether intermittent hypoxia also enhances chemoreflex activity in healthy humans. To this end, we measured the responses of muscle sympathetic nerve activity (MSNA, peroneal microneurography) to arterial chemoreflex stimulation and deactivation before and following exposure to a paradigm of repetitive hypoxic apnea (20 s/min for 30 min; O2 saturation nadir 81.4 ± 0.9%). Compared with baseline, repetitive hypoxic apnea increased MSNA from 113 ± 11 to 159 ± 21 units/min ( P = 0.001) and mean blood pressure from 92.1 ± 2.9 to 95.5 ± 2.9 mmHg ( P = 0.01; n = 19). Furthermore, compared with before, following intermittent hypoxia the MSNA (units/min) responses to acute hypoxia [fraction of inspired O2 (FiO2) 0.1, for 5 min] were enhanced (pre- vs. post-intermittent hypoxia: +16 ± 4 vs. +49 ± 10%; P = 0.02; n = 11), whereas the responses to hyperoxia (FiO2 0.5, for 5 min) were not changed significantly ( P = NS; n = 8). Thus 30 min of intermittent hypoxia is capable of increasing sympathetic activity and sensitizing the sympathetic reflex responses to hypoxia in normal humans. Enhanced sympathetic chemoreflex activity induced by intermittent hypoxia may contribute to altered neurocirculatory control and adverse cardiovascular consequences in sleep apnea.

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Adrenaline Stimulation of Phospholipid Metabolism in Adipocyte Ghosts

Australian Journal of Biological Sciences ◽

10.1071/bi9870405 ◽

1987 ◽

Vol 40 (4) ◽

pp. 405

Author(s):

David Mann ◽

Audrey M Bersten

Keyword(s):

Fatty Acids ◽

Arachidonic Acid ◽

Linoleic Acid ◽

Adenylate Cyclase ◽

Phospholipid Metabolism ◽

Dependent Manner ◽

Long Chain Fatty Acids ◽

Membrane Phospholipids ◽

Dose Dependent ◽

Stimulation Of

The incorporation of long-chain fatty acids into phospholipids has been detected in adipocyte ghosts that were incubated with [1_14 C] stearic, [1_14 C] linoleic or [l_14C] arachidonic acid. Adrenaline and adenosine activated this incorporation within 15 s of exposure of the ghosts to the hormones and the response was dose dependent. Maximum incorporation of labelled linoleic acid occurred at 10-5 M adrenaline and 10-7 M adenosine. The a-agonist phenylephrine and the ~-agonist isoproterenol were also shown to stimulate the incorporation of fatty acid in a dose dependent manner. Phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine and phosphatidylinositol were each labelled preferentially with linoleic or arachidonic acid. p-Bromophenacylbromide, quinacrine and centrophenoxine inhibited the adrenaline-stimulated incorporation of fatty acids into ghost membrane phospholipids, and p-bromophenacylbromide also reduced the activation of adenylate cyclase by adrenaline. NaF, an activator of adenylate cyclase, like adrenaline, stimulated the incorporation of linoleic acid into ghost membrane phospholipids.

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Hypoxia-induced PD-L1/PD-1 crosstalk impairs T-cell function in sleep apnoea

European Respiratory Journal ◽

10.1183/13993003.00833-2017 ◽

2017 ◽

Vol 50 (4) ◽

pp. 1700833 ◽

Cited By ~ 34

Author(s):

Carolina Cubillos-Zapata ◽

Jose Avendaño-Ortiz ◽

Enrique Hernandez-Jimenez ◽

Victor Toledano ◽

Jose Casas-Martin ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Intermittent Hypoxia ◽

Cell Activation ◽

Cell Function ◽

Sleep Apnoea ◽

Orphan Receptor ◽

Dependent Manner ◽

Obstructive Sleep

Obstructive sleep apnoea (OSA) is associated with higher cancer incidence, tumour aggressiveness and cancer mortality, as well as greater severity of infections, which have been attributed to an immune deregulation. We studied the expression of programmed cell death (PD)-1 receptor and its ligand (PD-L1) on immune cells from patients with OSA, and its consequences on immune-suppressing activity. We report that PD-L1 was overexpressed on monocytes and PD-1 was overexpressed on CD8+ T-cells in a severity-dependent manner. PD-L1 and PD-1 overexpression were induced in both the human in vitro and murine models of intermittent hypoxia, as well as by hypoxia-inducible factor-1α transfection. PD-L1/PD-1 crosstalk suppressed T-cell proliferation and activation of autologous T-lymphocytes and impaired the cytotoxic activity of CD8+ T-cells. In addition, monocytes from patients with OSA exhibited high levels of retinoic acid related orphan receptor, which might explain the differentiation of myeloid-derived suppressor cells. Intermittent hypoxia upregulated the PD-L1/PD-1 crosstalk in patients with OSA, resulting in a reduction in CD8+ T-cell activation and cytotoxicity, providing biological plausibility to the increased incidence and aggressiveness of cancer and the higher risk of infections described in these patients.

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Abstract 653: Muscle Ring Finger-1 (MuRF1) Expression Shifts Cardiomyocyte Substrate Utilization from Fatty Acids to Glucose

Circulation ◽

10.1161/circ.116.suppl_16.ii_120-c ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Monte S Willis ◽

Jon Schisler ◽

Holly McDonough ◽

Cam Patterson

Keyword(s):

Fatty Acids ◽

Fatty Acid ◽

Fatty Acid Oxidation ◽

Glucose Oxidation ◽

Relative Proportion ◽

Substrate Utilization ◽

Acid Oxidation ◽

Protective Mechanism ◽

Dependent Manner ◽

Dose Dependent

Previous work has suggested that MuRF1, a cardiac-specific protein, regulates metabolism by its interactions with proteins that regulate ATP transport, glycolysis, and the electron transport chain. We recently identified that MuRF1 is cardioprotective in ischemia reperfusion injury. In the current study, we investigated the effects of MuRF1 expression on metabolic substrate utilization and found that MuRF1 shifts substrate utilization from fatty acids to glucose in a dose-dependent manner. Isolated neonatal ventricular cardiomyocytes were treated with an adenovirus expressing MuRF1 (Ad.MuRF1) or GFP (Ad.GFP) at a range of 0–25 MOI (Multiplicity Of Infection). 14C-Oleate or 14C-glucose were added to cells for 1 hour and 14C-CO2 release was determined using the CO2-trapping method. Trapped 14CO2 and acid soluble metabolites were used to calculate total fatty acid oxidation. Cardiomyocytes treated with 5–25 MOI Ad.MuRF1 demonstrated a dose dependent decrease in fatty acid oxidation of 10.5 +/− 2.3(5 MOI), 8.5 +/− 1.9 (10 MOI), 6.6 +/− 1.6 (15 MOI), and 5.1 +/− 1.3 (25 MOI) nmol oleate/mg protein/h. Compared with control cardiomyocytes treated with 5–25 MOI Ad.GFP (average of 5–25 MOI=13.5 +/− 0.7 nmol oleate/mg protein/h), this represents a 22.2%– 62.2% decrease in fatty acid oxidation. Inversely, glucose oxidation increased with increasing MuRF1 expression. Cardiomyocytes infected with 25 MOI Ad.MuRF1 oxidized 184% more glucose (28.9 +/− 4.6 nmol glucose/mg protein/h) compared to control cells treated with 25 MOI Ad.GFP (15.7 +/− 1.3 nmol glucose/mg protein/h). Increasing MuRF1 expression resulted in no net gain or loss of calculated ATP production (1699 +/− 157 vs. 1480 +/− 188 nmol ATP/mg protein/h). The co-utilization of glucose and fatty acids as substrates for the production of ATP allows the heart to adapt to both environmental stress and disease. Increasing the relative proportion of glucose oxidation in relationship to fatty acids is a known protective mechanism during cardiac stress, and may represent one mechanism by which MuRF1 is cardioprotective.

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Hyperinsulinemia, But Not Other Factors Associated with Insulin Resistance, Acutely Enhances Colorectal Epithelial Proliferation in Vivo

Endocrinology ◽

10.1210/en.2005-1012 ◽

2006 ◽

Vol 147 (4) ◽

pp. 1830-1837 ◽

Cited By ~ 86

Author(s):

Thien T. Tran ◽

Dinaz Naigamwalla ◽

Andrei I. Oprescu ◽

Loretta Lam ◽

Gail McKeown-Eyssen ◽

...

Keyword(s):

Insulin Resistance ◽

Epithelial Cells ◽

Dependent Manner ◽

Epithelial Proliferation ◽

Euglycemic Clamp ◽

The Individual ◽

Dose Dependent ◽

Circulating Levels

The similarity in risk factors for insulin resistance and colorectal cancer (CRC) led to the hypothesis that markers of insulin resistance, such as elevated circulating levels of insulin, glucose, fatty acids, and triglycerides, are energy sources and growth factors in the development of CRC. The objective was thus to examine the individual and combined effects of these circulating factors on colorectal epithelial proliferation in vivo. Rats were fasted overnight, randomized to six groups, infused iv with insulin, glucose, and/or Intralipid for 10 h, and assessed for 5-bromo-2-deoxyuridine labeling of replicating DNA in colorectal epithelial cells. Intravenous infusion of insulin, during a 10-h euglycemic clamp, increased colorectal epithelial proliferation in a dose-dependent manner. The addition of hyperglycemia to hyperinsulinemia did not further increase proliferation. Intralipid infusion alone did not affect proliferation; however, the combination of insulin, glucose, and Intralipid infusion resulted in greater hyperinsulinemia than the infusion of insulin alone and further increased proliferation. Insulin infusion during a 10-h euglycemic clamp decreased total IGF-I levels and did not affect insulin sensitivity. These results provide evidence for an acute role of insulin, at levels observed in insulin resistance, in the proliferation of colorectal epithelial cells in vivo.

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Effects of acute intermittent hypoxia on glucose metabolism in awake healthy volunteers

Journal of Applied Physiology ◽

10.1152/japplphysiol.91523.2008 ◽

2009 ◽

Vol 106 (5) ◽

pp. 1538-1544 ◽

Cited By ~ 198

Author(s):

Mariam Louis ◽

Naresh M. Punjabi

Keyword(s):

Obstructive Sleep Apnea ◽

Insulin Secretion ◽

Sleep Apnea ◽

Insulin Sensitivity ◽

Glucose Metabolism ◽

Healthy Volunteers ◽

Intermittent Hypoxia ◽

Metabolic Dysfunction ◽

Glucose Effectiveness ◽

Obstructive Sleep

Accumulating evidence suggests that obstructive sleep apnea is associated with alterations in glucose metabolism. Although the pathophysiology of metabolic dysfunction in obstructive sleep apnea is not well understood, studies of murine models indicate that intermittent hypoxemia has an important contribution. However, corroborating data on the metabolic effects of intermittent hypoxia on glucose metabolism in humans are not available. Thus the primary aim of this study was to characterize the acute effects of intermittent hypoxia on glucose metabolism. Thirteen healthy volunteers were subjected to 5 h of intermittent hypoxia or normoxia during wakefulness in a randomized order on two separate days. The intravenous glucose tolerance test (IVGTT) was used to assess insulin-dependent and insulin-independent measures of glucose disposal. The IVGTT data were analyzed using the minimal model to determine insulin sensitivity (SI) and glucose effectiveness (SG). Drops in oxyhemoglobin saturation were induced during wakefulness at an average rate of 24.3 events/h. Compared with the normoxia condition, intermittent hypoxia was associated with a decrease in SI [4.1 vs. 3.4 (mU/l)−1·min−1; P = 0.0179] and SG (1.9 vs. 1.3 min−1×10−2, P = 0.0065). Despite worsening insulin sensitivity with intermittent hypoxia, pancreatic insulin secretion was comparable between the two conditions. Heart rate variability analysis showed the intermittent hypoxia was associated with a shift in sympathovagal balance toward an increase in sympathetic nervous system activity. The average R-R interval on the electrocardiogram was 919.0 ms during the normoxia condition and 874.4 ms during the intermittent hypoxia condition ( P < 0.04). Serum cortisol levels after intermittent hypoxia and normoxia were similar. Hypoxic stress in obstructive sleep apnea may increase the predisposition for metabolic dysfunction by impairing insulin sensitivity, glucose effectiveness, and insulin secretion.

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Intermittent Hypoxia Disrupts Glucose Homeostasis in Liver Cells in an Insulin-Dependent and Independent Manner

Cellular Physiology and Biochemistry ◽

10.1159/000490169 ◽

2018 ◽

Vol 47 (3) ◽

pp. 1042-1050 ◽

Cited By ~ 6

Author(s):

Chen Juan Gu ◽

Hua Hua Yi ◽

Jing Feng ◽

Zhi Guo Zhang ◽

Jun Zhou ◽

...

Keyword(s):

Glucose Homeostasis ◽

Insulin Signaling ◽

Intermittent Hypoxia ◽

Quantitative Polymerase Chain Reaction ◽

Liver Cells ◽

Dependent Manner ◽

Independent Manner ◽

Obstructive Sleep ◽

Gsk 3Β ◽

Glucose Output

Background/Aims: Obstructive sleep apnea is associated with diabetes and insulin resistance, but the underlying mechanisms remain unclear. The purpose of the current study was to determine the molecular effects of intermittent hypoxia (IH) on hepatic insulin signaling and glucose homeostasis, and whether c-Jun NH2-terminal-kinase (JNK) contributed to metabolic responses to IH in liver cells. Methods: The human HepG2 cells and rat FAO cells were exposed to 10, 30, 120, 240 or 360 cycles of IH (1% O2 for 60 s followed by 21% O2 for 60s, 7.5 cycles per hour) or normoxia as a control. In a subgroup, we exposed cells to 360 cycles of IH with the JNK inhibitor SP600125. After IH exposure, cell glycogen content and glucose output were measured using colorimetric assay kits. Canonical insulin signaling and gluconeogenic genes were measured by western blot and quantitative polymerase chain reaction. Results: IH decreased insulin-stimulated protein kinase B (AKT)/glycogen synthase kinase-3β (GSK-3β) phosphorylation in a time-dependent manner, while inhibiting forkhead box protein O1 (FOXO1) expression and phosphoenolpyruvate carboxykinase (PEPCK) transcription independent of insulin signaling. JNK inhibitor SP600125 partially restored AKT/ GSK-3β phosphorylation and glycogen synthesis, but did not affect other IH-induced glucose metabolic changes. Conclusion: IH in vitro impaired insulin signal transduction in liver cells as assessed by inhibited AKT/GSK-3β phosphorylation via JNK activation. IH inhibited FOXO1 and gluconeogenesis in an insulin-independent manner.

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Unsaturated fatty acids and cyclooxygenase inhibitors: effects on pial arterioles

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1982.242.4.h629 ◽

1982 ◽

Vol 242 (4) ◽

pp. H629-H632

Author(s):

W. I. Rosenblum

Keyword(s):

Fatty Acids ◽

Unsaturated Fatty Acids ◽

Eicosatrienoic Acid ◽

Inhibitory Effect ◽

Cyclooxygenase Inhibitors ◽

Dependent Manner ◽

Double Bonds ◽

Pial Arterioles ◽

Dose Dependent

Cerebral surface arterioles of the mouse were constricted in a dose-dependent manner by three different unsaturated fatty acids each with one of its double bonds in the n-6 position: arachidonate, linoleic, and 11,14,17-eicosatrienoic acid (ETA) in doses of 10-200 micrograms/ml. The constriction was transient, and its magnitude was significantly reduced by pretreatment of the mice with intraperitoneal injections of indomethacin (5 mg/kg), aspirin (100 mg/kg), or sodium 2-amino-3-(4 chlorobenzyl)-phenylacetate (AHR-6293, 100 mg/kg). The inhibitory effect of these cyclooxygenase inhibitors suggests that this enzyme is involved in the response to these fatty acids and is in keeping with suggestions in the literature stating that such unsaturated fatty acids may interact with cyclooxygenase even when they cannot form prostaglandin (PG) endoperoxides, The PG endoperoxide formed by arachidonate or the analogous hydroperoxy compounds formed by linoleic or 11,14,17 ETA, may then alter cerebrovascular tone by production of reactive, O2-containing species. Alternate explanations for the data are also proposed.

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