| 1. |
- Figueiredo, Bryanne Silva, et al.
(författare)
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Coadministration of sitagliptin or metformin has no major impact on the adverse metabolic outcomes induced by dexamethasone treatment in rats
- 2021
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Ingår i: Life Sciences. - : Elsevier. - 0024-3205 .- 1879-0631. ; 286
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Tidskriftsartikel (refereegranskat)abstract
- Aims: Glucocorticoids (GC) in excess cause glucose intolerance and dyslipidemia due to their diabetogenic actions. Conceptually, antidiabetic drugs should attenuate these side effects. Thus, we evaluated whether the coadministration of metformin or sitagliptin (or both) with dexamethasone could attenuate GC-induced adverse effects on metabolism. Materials and methods: Adult male rats were treated for 5 consecutive days with dexamethasone (1 mg/kg, body mass (bm), intraperitoneally). Additional groups were coadministered with metformin (300 mg/kg, bm, by oral gavage (og)) or sitagliptin (20 mg/kg, bm, og) or with both compounds in combination. The day after the last treatments, rats were submitted to glucose tolerance tests, pyruvate tolerance test, and euthanized for biometric, biochemical, morphologic, and molecular analyses. Key findings: Dexamethasone treatment resulted in reduced body mass and food intake, increased blood glucose and plasma insulin, dyslipidemia, glucose intolerance, pyruvate intolerance, and increased hepatic content of glycogen and fat. Sitagliptin coadministration improved glucose tolerance compared with the control group, an effect paralleled with higher levels of active GLP-1 during an oral GTT. Overall, sitagliptin or metformin coadministration did not prevent any of the dexamethasone-induced metabolic disturbances. Significance: Coadministration of sitagliptin or metformin result in no major improvement of glucose and lipid metabolism altered by dexamethasone treatment in male adult rats.
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| 2. |
- Fransson, Liselotte, et al.
(författare)
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β-cell adaptation in a mouse model of glucocorticoid-induced metabolic syndrome
- 2013
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Ingår i: Journal of Endocrinology. - : Bioscientifica. - 0022-0795 .- 1479-6805. ; 219:3, s. 231-241
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Tidskriftsartikel (refereegranskat)abstract
- Glucocorticoids (GCs) are stress hormones primarily responsible for mobilizing glucose to the circulation. Due to this effect, insulin resistance and glucose intolerance are concerns in patients with endogenous overproduction of GCs and in patients prescribed GC-based therapy. In addition, hypercortisolemic conditions share many characteristics with the metabolic syndrome. This study reports on a thorough characterization, in terms of glucose control and lipid handling, of a mouse model where corticosterone is given via the drinking water. C57BL/6J mice were treated with corticosterone (100 or 25 μg/ml) or vehicle in their drinking water for 5 weeks after which they were subjected to insulin or glucose tolerance tests. GC-treated mice displayed increased food intake, body weight gain, and central fat deposit accumulations. In addition, the GC treatment led to dyslipidemia as well as accumulation of ectopic fat in the liver and skeletal muscle, having a substantial negative effect on insulin sensitivity. Also glucose intolerance and hypertension, both part of the metabolic syndrome, were evident in the GC-treated mice. However, the observed effects of corticosterone were reversed after drug removal. Furthermore, this study reveals insights into β-cell adaptation to the GC-induced insulin resistance. Increased pancreatic islet volume due to cell proliferation, increased insulin secretion capacity, and increased islet chaperone expression were found in GC-treated animals. This model mimics the human metabolic syndrome. It could be a valuable model for studying the complex mechanisms behind the development of the metabolic syndrome and type 2 diabetes, as well as the multifaceted relations between GC excess and disease.
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| 3. |
- Frye, Maike, et al.
(författare)
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EphrinB2-EphB4 signalling provides Rho-mediated homeostatic control of lymphatic endothelial cell junction integrity
- 2020
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Ingår i: eLIFE. - : eLife Sciences Publications, Ltd. - 2050-084X. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Endothelial integrity is vital for homeostasis and adjusted to tissue demands. Although fluid uptake by lymphatic capillaries is a critical attribute of the lymphatic vasculature, the barrier function of collecting lymphatic vessels is also important by ensuring efficient fluid drainage as well as lymph node delivery of antigens and immune cells. Here, we identified the transmembrane ligand EphrinB2 and its receptor EphB4 as critical homeostatic regulators of collecting lymphatic vessel integrity. Conditional gene deletion in mice revealed that EphrinB2/EphB4 signalling is dispensable for blood endothelial barrier function, but required for stabilization of lymphatic endothelial cell (LEC) junctions in different organs of juvenile and adult mice. Studies in primary human LECs further showed that basal EphrinB2/EphB4 signalling controls junctional localisation of the tight junction protein CLDN5 and junction stability via Rac1/Rho-mediated regulation of cytoskeletal contractility. EphrinB2/EphB4 signalling therefore provides a potential therapeutic target to selectively modulate lymphatic vessel permeability and function.
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| 4. |
- Frye, Maike, et al.
(författare)
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Matrix stiffness controls lymphatic vessel formation through regulation of a GATA2-dependent transcriptional program
- 2018
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Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Tissue and vessel wall stiffening alters endothelial cell properties and contributes to vascular dysfunction. However, whether extracellular matrix (ECM) stiffness impacts vascular development is not known. Here we show that matrix stiffness controls lymphatic vascular morphogenesis. Atomic force microscopy measurements in mouse embryos reveal that venous lymphatic endothelial cell (LEC) progenitors experience a decrease in substrate stiffness upon migration out of the cardinal vein, which induces a GATA2-dependent transcriptional program required to form the first lymphatic vessels. Transcriptome analysis shows that LECs grown on a soft matrix exhibit increased GATA2 expression and a GATA2-dependent upregulation of genes involved in cell migration and lymphangiogenesis, including VEGFR3. Analyses of mouse models demonstrate a cell-autonomous function of GATA2 in regulating LEC responsiveness to VEGF-C and in controlling LEC migration and sprouting in vivo. Our study thus uncovers a mechanism by which ECM stiffness dictates the migratory behavior of LECs during early lymphatic development.
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| 5. |
- Hernández-Fisac, Inés, et al.
(författare)
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Oxo-4-methylpentanoic acid directs the metabolism of GABA into the Krebs cycle in rat pancreatic islets
- 2006
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Ingår i: Biochemical Journal. - 0264-6021 .- 1470-8728. ; 400:1, s. 81-89
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Tidskriftsartikel (refereegranskat)abstract
- OMP (oxo-4-methylpentanoic acid) stimulates by itself a biphasic secretion of insulin whereas L-leucine requires the presence of L-glutamine. L-Glutamine is predominantly converted into GABA (gamma-aminobutyric acid) in rat islets and L-leucine seems to promote its metabolism in the 'GABA shunt' [Fernandez-Pascual, Mukala-Nsengu-Tshibangu, Martin del Rio and Tamarit-Rodriguez (2004) Biochem. J. 379,721-729]. In the present study, we have investigated how 10mM OMP affects L-glutamine metabolism to uncover possible differences with L-leucine that might help to elucidate whether they share a common mechanism of stimulation of insulin secretion. In contrast with L-leucine, OMP alone stimulated a biphasic insulin secretion in rat perifused islets and decreased the islet content of GABA without modifying its extracellular release irrespective of the concentration of L-glutamine in the medium. GABA was transaminated to L-leucine whose intracellular concentration did not change because it was efficiently transported out of the islet cells. The L-[U-C-14]-Glutamine (at 0.5 and 10.0 mM) conversion to (CO2)-C-14 was enhanced by 10 mM OMP within 30% and 70% respectively. Gabaculine (250 mu M), a GABA transaminase inhibitor, suppressed OMP-induced oxygen consumption but not L-leucineor glucose-stimulated respiration. It also suppressed the OMP-induced decrease in islet GABA content and the OMP-induced increase in insulin release. These results support the view that OMP promotes islet metabolism in the 'GABA shunt' generating 2-oxo-glutarate, in the branched-chain a-amino acid transaminase reaction, which would in turn trigger GABA deamination by GABA transaminase. OMP, but not L-leucine, suppressed islet semialdehyde succinic acid reductase activity and this might shift the metabolic flux of the 'GABA shunt' from gamma-hydroxybutyrate to succinic acid production.
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| 6. |
- Hult, Malin, et al.
(författare)
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Short-term glucocorticoid treatment increases insulin secretion in islets derived from lean mice through multiple pathways and mechanisms
- 2009
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Ingår i: Molecular and Cellular Endocrinology. - : Elsevier BV. - 0303-7207 .- 1872-8057. ; 301:1-2, s. 109-116
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Tidskriftsartikel (refereegranskat)abstract
- Chronic exposure to elevated levels of glucocorticoids leads to metabolic dysfunctions with hyperglycemia and insulin resistance. Long-term treatment with glucocorticoids induces severe impairment of glucose-stimulated insulin secretion. We analyzed the effects of short-, and medium-term (2-120h) treatment with 50-200nM glucocorticoids on primary pancreatic islet cultures derived from lean C57BL/6J mice. In contrast to animal models of insulin resistance, beta-cells from lean mice respond with an increased glucose-stimulated insulin secretion, with a peak effect around 18-24h of treatment. Analyses of the insulin secretion response reveal that early and late phase responses are dissociated upon glucocorticoid treatment. Whereas late phase responses return to basal levels after long treatment, early phase responses remain increased over several days. Increased insulin secretion is also obtained by incubation with the inactive glucocorticoid dehydrocorticosterone, pointing to an important role of the enzyme 11beta-hydroxysteroid dehydrogenase type 1 in mediating glucocorticoid effects in beta-cells. Transcript profiling revealed differential regulation of genes involved in mediation of signal transduction, insulin secretion, stress and inflammatory responses. The results show that short- to medium-term glucocorticoid treatment of pancreatic islets derived from lean mice leads to an increased insulin release and may constitute an important parameter in changing towards a pro-diabetic phenotype.
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| 7. |
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| 8. |
- Mansouri, Shiva, et al.
(författare)
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GalR3 activation promotes adult neural stem cell survival in response to a diabetic milieu
- 2013
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Ingår i: Journal of Neurochemistry. - : Wiley. - 0022-3042 .- 1471-4159. ; 127:2, s. 209-220
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Tidskriftsartikel (refereegranskat)abstract
- Type 2 diabetes impairs adult neurogenesis which could play a role in the CNS complications of this serious disease. The goal of this study was to determine the potential role of galanin in protecting adult neural stem cells (NSCs) from glucolipotoxicity and to analyze whether apoptosis and the unfolded protein response were involved in the galanin-mediated effect. We also studied the regulation of galanin and its receptor subtypes under diabetes in NSCs in vitro and in the subventricular zone (SVZ) in vivo. The viability of mouse SVZ-derived NSCs and the involvement of apoptosis (Bcl-2, cleaved caspase-3) and unfolded protein response [C/EBP homologous protein (CHOP) Glucose-regulated protein 78/immunoglobulin heavy-chain binding protein (GRP78/BiP), spliced X-box binding protein 1 (XBP1), c-Jun N-terminal kinases (JNK) phosphorylation] were assessed in the presence of glucolipotoxic conditions after 24h. The effect of diabetes on the regulation of galanin and its receptor subtypes was assessed on NSCs in vitro and in SVZ tissues isolated from normal and type 2 diabetes ob/ob mice. We show increased NSC viability following galanin receptor (GalR)3 activation. This protective effect correlated with decreased apoptosis and CHOP levels. We also report how galanin and its receptors are regulated by diabetes in vitro and in vivo. This study shows GalR3-mediated neuroprotection, supporting a potential future therapeutic development, based on GalR3 activation, for the treatment of brain disorders.
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| 9. |
- Martinez-Corral, Ines, et al.
(författare)
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Blockade of VEGF-C signaling inhibits lymphatic malformations driven by oncogenic PIK3CA mutation
- 2020
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Lymphatic malformations (LMs) are debilitating vascular anomalies presenting with large cysts (macrocystic) or lesions that infiltrate tissues (microcystic). Cellular mechanisms underlying LM pathology are poorly understood. Here we show that the somatic PIK3CA(H1047R) mutation, resulting in constitutive activation of the p110 alpha PI3K, underlies both macrocystic and microcystic LMs in human. Using a mouse model of PIK3CA(H1047R)-driven LM, we demonstrate that both types of malformations arise due to lymphatic endothelial cell (LEC)-autonomous defects, with the developmental timing of p110 alpha activation determining the LM subtype. In the postnatal vasculature, PIK3CA(H1047R) promotes LEC migration and lymphatic hypersprouting, leading to microcystic LMs that grow progressively in a vascular endothelial growth factor C (VEGF-C)-dependent manner. Combined inhibition of VEGF-C and the PI3K downstream target mTOR using Rapamycin, but neither treatment alone, promotes regression of lesions. The best therapeutic outcome for LM is thus achieved by co-inhibition of the upstream VEGF-C/VEGFR3 and the downstream PI3K/mTOR pathways. Lymphatic malformation (LM) is a debilitating often incurable vascular disease. Using a mouse model of LM driven by a disease-causative PIK3CA mutation, the authors show that vascular growth is dependent on the upstream lymphangiogenic VEGF-C signalling, permitting effective therapeutic intervention.
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| 10. |
- Ortsäter, Henrik, et al.
(författare)
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An inducible Cldn11-CreERT2 mouse line for selective targeting of lymphatic valves
- 2021
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Ingår i: Genesis. - : Wiley. - 1526-954X .- 1526-968X. ; 59:7-8
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Tidskriftsartikel (refereegranskat)abstract
- Luminal valves of collecting lymphatic vessels are critical for maintaining unidirectional flow of lymph and their dysfunction underlies several forms of primary lymphedema. Here, we report on the generation of a transgenic mouse expressing the tamoxifen inducible CreERT2 under the control of Cldn11 promoter that allows, for the first time, selective and temporally controlled targeting of lymphatic valve endothelial cells. We show that within the vasculature CLDN11 is specifically expressed in lymphatic valves but is not required for their development as mice with a global loss of Cldn11 display normal valves in the mesentery. Tamoxifen treated Cldn11-CreERT2 mice also carrying a fluorescent Cre-reporter displayed reporter protein expression selectively in lymphatic valves and, to a lower degree, in venous valves. Analysis of developing vasculature further showed that Cldn11-CreERT2-mediated recombination is induced during valve leaflet formation, and efficient labeling of valve endothelial cells was observed in mature valves. The Cldn11-CreERT2 mouse thus provides a valuable tool for functional studies of valves.
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