Hørsholm, Denmark
Hørsholm, Denmark
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Mace M.L.,Copenhagen University | Gravesen E.,Copenhagen University | Nordholm A.,Copenhagen University | Hofman-Bang J.,Copenhagen University | And 3 more authors.
Kidney International | Year: 2017

Fibroblast growth factor 23 (FGF23) secreted by osteocytes is a circulating factor essential for phosphate homeostasis. High plasma FGF23 levels are associated with cardiovascular complications and mortality. Increases of plasma FGF23 in uremia antedate high levels of phosphate, suggesting a disrupted feedback regulatory loop or an extra-skeletal source of this phosphatonin. Since induction of FGF23 expression in injured organs has been reported we decided to examine the regulation of FGF23 gene and protein expressions in the kidney and whether kidney-derived FGF23 contributes to the high plasma levels of FGF23 in uremia. FGF23 mRNA was not detected in normal kidneys, but was clearly demonstrated in injured kidneys, already after four hours in obstructive nephropathy and at 8 weeks in the remnant kidney of 5/6 nephrectomized rats. No renal extraction was found in uremic rats in contrast to normal rats. Removal of the remnant kidney had no effect on plasma FGF23 levels. Well-known regulators of FGF23 expression in bone, such as parathyroid hormone, calcitriol, and inhibition of the FGF receptor by PD173074, had no impact on kidney expression of FGF23. Thus, the only direct contribution of the injured kidney to circulating FGF23 levels in uremia appears to be reduced renal extraction of bone-derived FGF23. Kidney-derived FGF23 does not generate high plasma FGF23 levels in uremia and is regulated differently than the corresponding regulation of FGF23 gene expression in bone. © 2017 International Society of Nephrology.

Paulsen S.J.,Gubra | Larsen L.K.,Vipergen Aps | Hansen G.,Gubra | Chelur S.,Aurigene Discovery Technologies Ltd. | And 2 more authors.
PLoS ONE | Year: 2014

Stimulation of the G protein coupled receptor GPR120 has been shown to have anti-inflammatory and insulin-sensitizing effects, to promote glucagon like peptide-1 (GLP-1) secretion, and to play a key role in sensing dietary fat and control energy balance. In a search for differentially expressed genes potentially involved in food intake and body-weight regulation we identified GPR120 to be differentially regulated in the intestine of selectively bred diet induced obese (DIO) and diet resistant (DR) rats. Subsequently we investigated the effect of GPR120 receptor stimulation with the long chain fatty acid alpha linolenic acid (ALA) on GLP-1 secretion in rats. Independent of diet (high or low fat), GPR120 expression showed a two-fold increase in the intestine of DIO compared to DR rats. In situ hybridization revealed a broad expression of GPR120 in the gut mucosa in both intestinal epithelial and endocrine cells. Using double in situ hybridization GPR120 mRNA did not appear to be enriched in preproglucagon expressing L-cells. In line with the anatomical data, ALA administration did not increase circulating GLP-1 levels. Our data shows a widespread expression of GPR120 in the gut epithelium and can not confirm a major role for GPR120 in the regulation of GLP-1 secretion. The broad expression of GPR120 in the gut epithelium supports reports indicating a putative role of GPR120 as a sensor of dietary fat. © 2014 Paulsen et al.

Dyrby T.B.,Copenhagen University | Dyrby T.B.,Technical University of Denmark | Baare W.F.,Copenhagen University | Baare W.F.,Center for Integrated Molecular Brain Imaging | And 5 more authors.
Human Brain Mapping | Year: 2011

Diffusion tensor (DT) imaging and related multifiber reconstruction algorithms allow the study of in vivo microstructure and, by means of tractography, structural connectivity. Although reconstruction algorithms are promising imaging tools, high-quality diffusion-weighted imaging (DWI) datasets for verification and validation of postprocessing and analysis methods are lacking. Clinical in vivo DWI is limited by, for example, physiological noise and low signal-to-noise ratio. Here, we performed a series of DWI measurements on postmortem pig brains, which resemble the human brain in neuroanatomical complexity, to establish an ex vivo imaging pipeline for generating high-quality DWI datasets. Perfusion fixation ensured that tissue characteristics were comparable to in vivo conditions. There were three main results: (i) heat conduction and unstable tissue mechanics accounted for time-varying artefacts in the DWI dataset, which were present for up to 15 h after positioning brain tissue in the scanner; (ii) using fitted DT, q-ball, and persistent angular structure magnetic resonance imaging algorithms, any b-value between ∼2,000 and ∼8,000 s/mm2, with an optimal value around 4,000 s/mm2, allowed for consistent reconstruction of fiber directions; (iii) diffusivity measures in the postmortem brain tissue were stable over a 3-year period. On the basis of these results, we established an optimized ex vivo pipeline for high-quality and high-resolution DWI. The pipeline produces DWI data sets with a high level of tissue structure detail showing for example two parallel horizontal rims in the cerebral cortex and multiple rims in the hippocampus. We conclude that high-quality ex vivo DWI can be used to validate fiber reconstruction algorithms and to complement histological studies. © 2010 Wiley-Liss, Inc.

Jelsing J.,Gubra | Eibye-Jacobsen D.,Natural History Museum of Denmark
Journal of Morphology | Year: 2010

The nuchal organs of annelid Laonice bahusiensis (Spionidae) from northern Europe have been studied using scanning and transmission electron microscopy. L. bahusiensis is the first spionid species in which extensively developed, continuous nuchal organs are described. The nuchal organs of this genus are the longest known among polychaete annelids. They consist of paired double bands extending from the prostomium on a mid-dorsal caruncle for about 24-30 setigers. Their microanatomy corresponds to the general structural plan of nuchal organs: there are ciliated supporting cells and bipolar sensory cells with sensory cilia traversing an olfactory chamber. The organs are overlaid by a secondary paving-stone-like cover and innervated by one pair of longitudinally elongated nuchal nerves. These findings clearly favor the hypothesis that the paired, extensively developed ciliated structures found in some Spionidae are homologous with the prostomial nuchal organs characteristic of polychaete annelids. © 2009 Wiley-Liss, Inc.

Sharkovska Y.,Charité - Medical University of Berlin | Reichetzeder C.,Institute of Pharmacology | Reichetzeder C.,University of Potsdam | Alter M.,Institute of Pharmacology | And 5 more authors.
Journal of Hypertension | Year: 2014

Background: Despite the beneficial effects of type 4 dipeptidyl peptidase (DPP-4) inhibitors on glucose levels, its effects on diabetic nephropathy remain unclear. Method: This study examined the long-term renoprotective effects of DPP-4 inhibitor linagliptin in db/ db mice, a model of type 2 diabetes. Results were compared with the known beneficial effects of reninangiotensin system blockade by enalapril. Ten-week-old male diabetic db/db mice were treated for 3 months with either vehicle (n=10), 3mg linagliptin/kg per day (n=8), or 20mg enalapril/kg per day (n=10). Heterozygous db/m mice treated with vehicle served as healthy controls (n=8). Results: Neither linagliptin nor enalapril had significant effects on the parameters of glucose metabolism or blood pressure in diabetic db/db mice. However, linagliptin treatment reduced albuminuria and attenuated kidney injury. In addition, expression of podocyte marker podocalyxin was normalized. We also analysed DPP-4 expression by immunofluorescence in human kidney biopsies and detected upregulation of DPP-4 in the glomeruli of patients with diabetic nephropathy, suggesting that our findings might be of relevance for human kidney disease as well. Conclusion: Treatment with DPP-4 inhibitor linagliptin delays the progression of diabetic nephropathy damage in a glucose-independent and blood-pressure-independent manner. The observed effects may be because of the attenuation of podocyte injury and inhibition of myofibroblast transformation. © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Hansen C.F.,Gubra | Hansen C.F.,Copenhagen University | Bueter M.,University of Zürich | Theis N.,University of Zürich | And 5 more authors.
PLoS ONE | Year: 2013

Background and Aims:Roux-en-Y gastric bypass (RYGB) leads to a rapid remission of type 2 diabetes mellitus (T2DM), but the underlying mode of action remains incompletely understood. L-cell derived gut hormones such as glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) are thought to play a central role in the anti-diabetic effects of RYGB; therefore, an improved understanding of intestinal endocrine L-cell adaptability is considered pivotal.Methods:The full rostrocaudal extension of the gut was analyzed in rats after RYGB and in sham-operated controls ad libitum fed or food restricted to match the body weight of RYGB rats. Total number of L-cells, as well as regional numbers, densities and mucosa volumes were quantified using stereological methods. Preproglucagon and PYY mRNA transcripts were quantified by qPCR to reflect the total and relative hormone production capacity of the L-cells.Results:RYGB surgery induced hypertrophy of the gut mucosa in the food exposed regions of the small intestine coupled with a doubling in the total number of L-cells. No changes in L-cell density were observed in any region regardless of surgery or food restriction. The total gene expression capacity of the entire gut revealed a near 200% increase in both PYY and preproglucagon mRNA levels in RYGB rats associated with both increased L-cell number as well as region-specific increased transcription per cell.Conclusions:Collectively, these findings indicate that RYGB in rats is associated with gut hypertrophy, an increase in L-cell number, but not density, and increased PYY and preproglucagon gene expression. This could explain the enhanced gut hormone dynamics seen after RYGB. © 2013 Hansen et al.

A. Koehler J.,Mount Sinai Hospital | Baggio L.L.,Mount Sinai Hospital | Cao X.,Mount Sinai Hospital | Abdulla T.,Mount Sinai Hospital | And 5 more authors.
Diabetes | Year: 2015

Glucagon-like peptide-1 (GLP-1) controls glucose homeostasis by regulating secretion of insulin and glucagon through a single GLP-1 receptor (GLP-1R). GLP-1R agonists also increase pancreatic weight in some preclinical studies through poorly understood mechanisms. Here we demonstrate that the increase in pancreatic weight following activation of GLP-1R signaling in mice reflects an increase in acinar cell mass, without changes in ductal compartments or β-cell mass. GLP-1R agonists did not increase pancreatic DNA content or the number of Ki67+ cells in the exocrine compartment; however, pancreatic protein content was increased in mice treated with exendin-4 or liraglutide. The increased pancreatic mass and protein content was independent of cholecystokinin receptors, associated with a rapid increase in S6 phosphorylation, and mediated through the GLP-1R. Rapamycin abrogated the GLP-1R-dependent increase in pancreatic mass but had no effect on the robust induction of Reg3α and Reg3β gene expression. Mass spectrometry analysis identified GLP- 1R-dependent upregulation of Reg family members, as well as proteins important for translation and export, including Fam129a, eIF4a1, Wars, and Dmbt1. Hence, pharmacological GLP-1R activation induces protein synthesis, leading to increased pancreatic mass, independent of changes in DNA content or cell proliferation in mice. © 2015 by the American Diabetes Association.

Hansen H.H.,Gubra | Jelsing J.,Gubra | Hansen C.F.,Gubra | Hansen G.,Gubra | And 4 more authors.
The Journal of pharmacology and experimental therapeutics | Year: 2014

Type 2 diabetes is characterized by impaired β-cell function associated with progressive reduction of insulin secretion and β-cell mass. Evidently, there is an unmet need for treatments with greater sustainability in β-cell protection and antidiabetic efficacy. Through an insulin and β cell-independent mechanism, empagliflozin, a specific sodium glucose cotransporter type 2 (SGLT-2) inhibitor, may potentially provide longer efficacy. This study compared the antidiabetic durability of empagliflozin treatment (10 mg/kg p.o.) against glibenclamide (3 mg/kg p.o.) and liraglutide (0.2 mg/kg s.c.) on deficient glucose homeostasis and β-cell function in Zucker diabetic fatty (ZDF) rats. Empagliflozin and liraglutide led to marked improvements in fed glucose and hemoglobin A1c levels, as well as impeding a progressive decline in insulin levels. In contrast, glibenclamide was ineffective. Whereas the effects of liraglutide were less pronounced at week 8 of treatment compared with week 4, those of empagliflozin remained stable throughout the study period. Similarly, empagliflozin improved glucose tolerance and preserved insulin secretion after both 4 and 8 weeks of treatment. These effects were reflected by less reduction in β-cell mass with empagliflozin or liraglutide at week 4, whereas only empagliflozin showed β-cell sparing effects also at week 8. Although this study cannot be used to dissociate the absolute antidiabetic efficacy among the different mechanisms of drug action, the study demonstrates that empagliflozin exerts a more sustained improvement of glucose homeostasis and β-cell protection in the ZDF rat. In comparison with other type 2 diabetic treatments, SGLT-2 inhibitors may through insulin-independent pathways thus enhance durability of β-cell protection and antidiabetic efficacy. Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.

Hansen H.H.,Gubra | Hansen G.,Gubra | Paulsen S.,Gubra | Vrang N.,Gubra | And 3 more authors.
European Journal of Pharmacology | Year: 2014

Linagliptin is a dipeptidyl peptidase (DPP)-IV inhibitor approved for the treatment of type 2 diabetes. DPP-IV inhibitors are considered weight neutral, suggesting that elevation of endogenous incretin levels is not sufficient to promote weight loss per se. Here we evaluated the effect of linagliptin in combination with subcutaneous treatment of GLP-1(7-36) on body weight regulation in diet-induced obese (DIO) rats. Linagliptin administered perorally (1.5 mg/kg, b.i.d.), but not subcutaneously (0.5 mg/kg, b.i.d.), evoked a very modest body weight loss (2.2%) after 28 days of treatment. GLP-1 (0.5 mg/kg, s.c.) treatment alone induced a body weight loss of 4.1%. In contrast, combined linagliptin (1.5 mg/kg, p.o., or 0.5 mg/kg, s.c.) and GLP-1 (0.5 mg/kg) treatment evoked a marked anorectic response with both routes of linagliptin administration being equally effective on final body weight loss (7.5-8.0%). In comparison, liraglutide monotherapy (0.2 mg/kg, s.c., b.i.d.) reduced body weight by 10.1%. Interestingly, the weight lowering effect of combined linagliptin and GLP-1 treatment was associated with a marked increase in chow preference, being more pronounced as compared to liraglutide treatment. In addition, linagliptin and GLP-1 co-treatment, but not liraglutide, specifically increased prepro-dynorphin mRNA levels in the caudate-putamen, an effect not obtained with administration of the compounds individually. In conclusion, co-treatment with linagliptin and GLP-1 synergistically reduces body weight in obese rats. The anti-obesity effect was caused by appetite suppression with a concomitant change in diet preference, which may potentially be associated with increased dynorphin activity in forebrain regions involved in reward anticipation and habit learning. © 2014 Elsevier B.V.

Paulsen S.J.,Gubra
Methods in Molecular Biology | Year: 2011

Laser capture microdissection (LCM) provides an efficient and precise method for the sampling of single cells or subgroups of cells in heterogeneous tissues such as the brain. We have recently applied LCM coupled with microarray analysis for the examination of gene expression in the hypothalamic arcuate nucleus of free fed versus fasted rats. We successfully used QPCR analysis to validate our findings and to confirm the regulation of several known neuropeptides. We show that the combination of LCM and QPCR analysis provides a reliable, fast, and efficient alternative to semiquantitative in situ hybridization analysis of gene expression. © 2011 Springer Science+Business Media, LLC.

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