| 1. |
- Dixen, Karen, et al.
(författare)
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ERR gamma Enhances UCP1 Expression and Fatty Acid Oxidation in Brown Adipocytes
- 2013
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Ingår i: Obesity. - : Wiley. - 1930-7381 .- 1930-739X. ; 21:3, s. 516-524
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Estrogen-related receptors (ERRs) are important regulators of energy metabolism. Here we investigated the hypothesis that ERR gamma impacts on differentiation and function of brown adipocytes. Design and Methods: We characterize the expression of ERR gamma in adipose tissues and cell models and investigate the effects of modulating ERR? activity on UCP1 gene expression and metabolic features of brown and white adipocytes. Results: ERR gamma was preferentially expressed in brown compared to white fat depots, and ERR gamma was induced during cold-induced browning of subcutaneous white adipose tissue and brown adipogenesis. Overexpression of ERR gamma positively regulated uncoupling protein 1 (UCP1) expression levels during brown adipogenesis. This ERR gamma-induced augmentation of UCP1 expression was independent of the presence of peroxisome proliferator-activated receptor coactivator-1 (PGC-1 alpha) but was associated with increased rates of fatty acid oxidation in adrenergically stimulated cells. ERR? did not influence mitochondrial biogenesis, and its reduced expression in white adipocytes could not explain their low expression level of UCP1. Conclusions: Through its augmenting effect on expression of UCP1, ERR gamma may physiologically be involved in increasing the potential for energy expenditure in brown adipocytes, a function that is becoming of therapeutic interest.
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| 2. |
- Beck, Astrid L, et al.
(författare)
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Cotinine concentrations in maternal serum and amniotic fluid during pregnancy and risk of testicular germ cell cancer in the offspring : A prospective nested case-control study
- 2024
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Ingår i: International Journal of Cancer. - 0020-7136. ; 154:1, s. 71-80
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Tidskriftsartikel (refereegranskat)abstract
- Maternal smoking in pregnancy may increase the risk of testicular germ cell cancer (TGCC) in offspring, but current evidence remains inconclusive. We performed a nested case-control study using cotinine measurements in maternal serum and amniotic fluid as a biomarker for tobacco exposure during pregnancy. A total of 654 males with maternal serum (n = 359, ncases/controls = 71/288) and/or amniotic fluid (n = 295, ncases/controls = 66/229) samples were included. Data on TGCC diagnoses and relevant covariates were derived from nationwide Danish health registries. Cotinine was quantified by liquid chromatography tandem mass spectrometry. An adapted cox regression model estimated the risk of TGCC considering active and inactive tobacco use defined according to cotinine concentrations of <, ≥15 ng/ml. Overall, the concentrations of cotinine were comparable in maternal serum and amniotic fluid (medianserum/amniotic fluid : 2.1/2.6 ng/ml). A strong statistically significant correlation was detected in 14 paired samples (Spearman rho: 0.85). Based on maternal serum cotinine concentrations, exposure to active tobacco use was not associated with risk of TGCC in offspring (HR 0.88, 95% CI 0.51; 1.52). Similarly, based on amniotic fluid cotinine concentrations, exposure to active tobacco use was not associated with risk of TGCC (HR 1.11, 95% CI 0.64; 1.95). However, different risks were observed for seminomas and nonseminomas in both matrices, but none were statistically significant. Our findings did not provide convincing evidence supporting that exposure to tobacco during pregnancy is associated with TGCC.
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| 3. |
- Himmelmann, Anders, et al.
(författare)
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The impact of smoking on inhaled insulin
- 2003
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Ingår i: Diabetes Care. - : American Diabetes Association. - 0149-5992 .- 1935-5548. ; 26:3, s. 677-682
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: This study, one of the first to address issues of pulmonary insulin delivery in smokers, compared pharmacokinetics of inhaled insulin delivered via the AERx insulin Diabetes Management System (iDMS) in nondiabetic cigarette smokers and nonsmokers.RESEARCH DESIGN AND METHODS: In this randomized two-period crossover efficacy and safety trial in 27 nondiabetic smokers and 16 nonsmokers (18 men/25 women, mean age 28 years, mean BMI 23.0 kg/m(2)), subjects received single doses of inhaled insulin (33.8 IU) following overnight fasting on consecutive dosing days. On one dosing day, smokers smoked three cigarettes immediately before insulin administration ("acute smoking"); on the other dosing day, smokers had not smoked since midnight ("nonacute smoking"). After inhalation, 6-h serum insulin and serum glucose profiles were determined.RESULTS: Pharmacokinetic results for evaluable subjects were derived from serum insulin profiles. The amount of insulin absorbed during the first 6 h after dosing (area under the exogenous serum insulin curve from 0 to 6 h [AUC((0-6 h))]) was significantly greater in smokers (63.2 vs. 40.0 mU l(-1) x h(-1), P = 0.0017); peak concentration was both higher and earlier in the smokers (maximal serum concentration of insulin [C(max)] 42.0 vs. 13.9 mU/l, P < 0.0001; time to maximal serum concentration of insulin [t(max)] 31.5 vs. 53.9 min, P = 0.0003). The estimated intrasubject variability of AUC((0-6 h)) was 13.7 and 16.5% for nonsmokers and smokers, respectively. No safety issues arose.CONCLUSIONS: Absorption of inhaled insulin via the AERx iDMS was significantly greater in smokers, with a higher AUC((0-6 h)) and C(max) and a shorter t(max). Intrasubject variability of AUC((0-6 h)) was low and similar in nonsmokers and smokers. These data prompt more extensive investigation of inhaled insulin in diabetic smokers.
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| 4. |
- Isidor, Marie S., et al.
(författare)
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An siRNA-based method for efficient silencing of gene expression in mature brown adipocytes
- 2016
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Ingår i: Adipocyte. - : Informa UK Limited. - 2162-3945 .- 2162-397X. ; 5:2, s. 175-185
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Tidskriftsartikel (refereegranskat)abstract
- Brown adipose tissue is a promising therapeutic target for opposing obesity, glucose intolerance and insulin resistance. The ability to modulate gene expression in mature brown adipocytes is important to understand brown adipocyte function and delineate novel regulatory mechanisms of non-shivering thermogenesis. The aim of this study was to optimize a lipofection-based small interfering RNA (siRNA) transfection protocol for efficient silencing of gene expression in mature brown adipocytes. We determined that a critical parameter was to deliver the siRNA to mature adipocytes by reverse transfection, i.e. transfection of non-adherent cells. Using this protocol, we effectively knocked down both high-and low-abundance transcripts in a model of mature brown adipocytes (WT-1) as well as in primary mature mouse brown adipocytes. A functional consequence of the knockdown was confirmed by an attenuated increase in uncoupled respiration (thermogenesis) in response to beta-adrenergic stimulation of mature WT-1 brown adipocytes transfected with uncoupling protein 1 siRNA. Efficient gene silencing was also obtained in various mouse and human white adipocyte models (3T3-L1, primary mouse white adipocytes, hMADS) with the ability to undergo browning. In summary, we report an easy and versatile reverse siRNA transfection protocol to achieve specific silencing of gene expression in various models of mature brown and browning-competent white adipocytes, including primary cells.
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| 5. |
- Petersen, Astrid H., et al.
(författare)
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The effect of exercise on the absorption of inhaled human insulin via the AERx insulin diabetes management system in people with type 1 diabetes
- 2007
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Ingår i: Diabetes Care. - : American Diabetes Association. - 1935-5548 .- 0149-5992. ; 30:10, s. 2571-2576
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE - This study investigated the effect of moderate exercise on the absorption of inhaled insulin via the AERx insulin diabetes management system (iDMS). RESEARCH DESIGN AND METHODS - in this randomized, open-label, four-period crossover, glucose clamp study 23 nonsmoking subjects with type I diabetes received a dose of 0.19 units/kg inhaled human insulin followed in random order by either 1) no exercise (NOEX group) or 30 min exercise starting, 2) 30 min after dosing (EX30), 3) 120 min after dosing (EX120), or 4) 240 min after dosing (EX240). RESULTS - Exercise changed the shape of the free plasma insulin curves, but compared with the NOEX group the area under the curve for free plasma insulin (AUC(ins)) for the first 2 h after the start of exercise was unchanged for EX30 and EX240, while it was 15% decreased for EX120 (P < 0.01). The overall insulin absorption during 6 and 10 h after dosing was 13% decreased for EX30 (P < 0.005), 11% decreased for EX120 (P < 0.01), and unchanged for EX240. Exercise.), while the time to C-max was 22 min did not influence the maximum insulin concentration (C-max) earlier for EX30 (P = 0.04). The AUC for the glucose infusion rate (AUC(GIR)) for 2 h after the start of exercise increased by 58% for EX30, 45% for EX120, and 71% for EX240 (all P < 0.02) compared with the NOEX group. CONCLUSIONS - Thirty minutes of moderate exercise led to unchanged or decreased absorption of inhaled insulin via AERx iDMS and faster C-max for early exercise. Thus, patients using AERx iDMS can adjust insulin dose as usual independent of time of exercise, but they should be aware of the faster effect if exercising early after dosing.
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| 6. |
- Petersen, Astrid H., et al.
(författare)
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The effect of terbutaline on the absorption of pulmonary administered insulin in subjects with asthma
- 2010
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Ingår i: British Journal of Clinical Pharmacology. - : Wiley. - 1365-2125 .- 0306-5251. ; 69:3, s. 271-278
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Tidskriftsartikel (refereegranskat)abstract
- center dot People with mild and moderate asthma have been shown to absorb less inhaled insulin than healthy subjects. center dot In people with moderate asthma, the administration of a bronchodilator before inhalation of insulin has been shown to lead to increased uptake of inhaled insulin compared with no prior administration of bronchodilator. WHAT THIS STUDY ADDS center dot This study is the first to show that in people with asthma, reduction of bronchoconstriction leads to increased absorption of inhaled insulin. center dot This study illustrates that due to the effect of terbutaline on glucose metabolism, the effect of insulin on plasma glucose is complex when terbutaline is administered concomitantly. AIM To investigate the effect of prior administration of a bronchodilator on the absorption of inhaled insulin in people with asthma treated with inhaled corticosteroids. METHODS A single-centre, randomized, open-label, two-period cross-over trial was carried out in 41 nondiabetic subjects with asthma treated with inhaled steroids, with reversible bronchoconstriction (Rev+; n = 25) or without reversible bronchoconstriction (Rev-; n = 16). A dose of 0.10 U kg-1 inhaled human insulin was administered on each dosing day with or without prior administration of the bronchodilator terbutaline (in random order). RESULTS Prior administration of terbutaline led to a 44% increase in absorption of insulin over 6 h for the Rev+ group compared with no prior administration of bronchodilator [ratio (95% confidence interval) 1.44 (1.13, 1.82), P = 0.004], whereas no effect was seen for the Rev- or the whole group. The maximum insulin concentration (C-max) increased by 34% for the Rev+ group (P = 0.018) and 17% for the whole group (P = 0.046), whereas no significant effect of prior terbutaline administration was seen for Rev-. The time to C-max was not significantly different for the Rev+ group, whereas it was approximately 30% longer after bronchodilator administration for the Rev- group (P = 0.044) and the whole group (P = 0.032). CONCLUSIONS In people with asthma and reversible bronchoconstriction, the administration of a bronchodilator prior to administration of inhaled insulin led to increased absorption of insulin, whereas no effect on insulin absorption in subjects without significant reversibility could be detected.
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| 7. |
- Petersen, Astrid H, et al.
(författare)
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The impact of large tidal volume ventilation on the absorption of inhaled insulin in rabbits.
- 2007
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Ingår i: European Journal of Pharmaceutical Sciences. - : Elsevier BV. - 1879-0720 .- 0928-0987. ; 30:3-4, s. 351-357
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Tidskriftsartikel (refereegranskat)abstract
- Previous studies have shown that ventilation patterns affect absorption of inhaled compounds. Thus, the aim of this study was to investigate the effect of large tidal volume ventilation (LTVV) on the absorption of inhaled insulin in rabbits. Mechanically ventilated rabbits were given human insulin via a nebuliser system, and plasma insulin was measured for the following 120 min. Ventilation was adjusted to (1) normal tidal volume ventilation (NTVV) for the entire period after dosing (NTVV group), to (2) LTVV for the entire period after dosing (LTVV group), to (3) NTVV except for 15 min LTVV immediately after dosing (Early LTVV group), or to (4) NTVV except for 15 min LTVV starting at 60 min after dosing (late LTVV group). Insulin absorption (AUC(ins(0-120min))) was increased by 149% for the LTVV group compared to NTVV group (p < 0.01) with increased maximal insulin concentration (106%, p = 0.03). The Early LTVV group showed a changed absorption profile. For the late LTVV group an increase in insulin levels was observed after the LTVV period (not significant compared to the NTVV group). These data could potentially have implications for patients using inhaled insulin in situations where a change in breathing pattern is seen, such as exercise.
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