| 1. |
- Efe, C., et al.
(author)
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Validation of Risk Scoring Systems in Ursodeoxycholic Acid-Treated Patients With Primary Biliary Cholangitis
- 2019
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In: American Journal of Gastroenterology. - : Ovid Technologies (Wolters Kluwer Health). - 0002-9270 .- 1572-0241. ; 114:7, s. 1101-1108
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Journal article (peer-reviewed)abstract
- INTRODUCTION: Risk stratification based on biochemical variables is a useful tool for monitoring ursodeoxycholic acid (UDCA)-treated patients with primary biliary cholangitis (PBC). Several UDCA response criteria and scoring systems have been proposed for risk prediction in PBC, but these have not been validated in large external cohorts. METHODS: We performed a study on data of 1746 UDCA-treated patients with PBC from 25 centers in Europe, United States, and Canada. The prognostic performance of the risk scoring systems (GLOBE and UK-PBC) and the UDCA response criteria (Barcelona, Paris I, Paris II, Rotterdam, and Toronto) were evaluated. We regarded cirrhosis-related complications (ascites, variceal bleeding, and/or hepatic encephalopathy) as clinical end points. RESULTS: A total of 171 patients reached a clinical end point during a median 7 years (range 1-16 years) of follow-up. The 5-, 10- and 15-year adverse outcome-free survivals were 95%, 85%, and 77%. The GLOBE and UK-PBC scores predicted cirrhosis-related complications better than the UDCA response criteria. The hazard ratio (HR) for a 1 standard deviation increase was HR 5.05 (95% confidence interval (CI): 4.43-5.74, P < 0.001) for the GLOBE score and HR 3.39 (95% CI: 3.10-3.72, P < 0.001) for the UK-PBC score. Overall, the GLOBE and UK-PBC risk scores showed similar and excellent prognostic performance (C-statistic, 0.93; 95% CI: 0.91%-95% vs 0.94; 95% CI: 0.91%-0.96%). DISCUSSION: In our international, multicenter PBC cohort, the GLOBE and UK-PBC risk scoring systems were good predictors of future cirrhosis-related complications.
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| 2. |
- Zhang, Q., et al.
(author)
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Na+ current properties in islet alpha- and beta-cells reflect cell-specific Scn3a and Scn9a expression
- 2014
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In: Journal of Physiology-London. - : Wiley. - 0022-3751 .- 1469-7793. ; 592:21, s. 4677-4696
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Journal article (peer-reviewed)abstract
- - and -cells express both Na(v)1.3 and Na(v)1.7 Na+ channels but in different relative amounts. The differential expression explains the different properties of Na+ currents in - and -cells. Na(v)1.3 is the functionally important Na+ channel subunit in both - and -cells. Islet Na(v)1.7 channels are locked in an inactive state due to an islet cell-specific factor. Mouse pancreatic - and -cells are equipped with voltage-gated Na+ currents that inactivate over widely different membrane potentials (half-maximal inactivation (V-0.5) at -100mV and -50mV in - and -cells, respectively). Single-cell PCR analyses show that both - and -cells have Na(v)1.3 (Scn3) and Na(v)1.7 (Scn9a) subunits, but their relative proportions differ: -cells principally express Na(v)1.7 and -cells Na(v)1.3. In -cells, genetically ablating Scn3a reduces the Na+ current by 80%. In -cells, knockout of Scn9a lowers the Na+ current by >85%, unveiling a small Scn3a-dependent component. Glucagon and insulin secretion are inhibited in Scn3a(-/-) islets but unaffected in Scn9a-deficient islets. Thus, Na(v)1.3 is the functionally important Na+ channel subunit in both - and -cells because Na(v)1.7 is largely inactive at physiological membrane potentials due to its unusually negative voltage dependence of inactivation. Interestingly, the Na(v)1.7 sequence in brain and islets is identical and yet the V-0.5 for inactivation is >30mV more negative in -cells. This may indicate the presence of an intracellular factor that modulates the voltage dependence of inactivation.
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| 3. |
- Denwood, G., et al.
(author)
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Glucose stimulates somatostatin secretion in pancreatic delta-cells by cAMP-dependent intracellular Ca-2+ release
- 2019
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In: Journal of General Physiology. - : Rockefeller University Press. - 0022-1295 .- 1540-7748. ; 151:9, s. 1094-1115
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Journal article (peer-reviewed)abstract
- Somatostatin secretion from pancreatic islet delta-cells is stimulated by elevated glucose levels, but the underlying mechanisms have only partially been elucidated. Here we show that glucose-induced somatostatin secretion (GISS) involves both membrane potential-dependent and -independent pathways. Although glucose-induced electrical activity triggers somatostatin release, the sugar also stimulates GISS via a cAMP-dependent stimulation of CICR and exocytosis of somatostatin. The latter effect is more quantitatively important and in mouse islets depolarized by 70 mM extracellular K+, increasing glucose from 1 mM to 20 mM produced an similar to 3.5-fold stimulation of somatostatin secretion, an effect that was mimicked by the application of the adenylyl cyclase activator forskolin. Inhibiting cAMP-dependent pathways with PKI or ESI-05, which inhibit PKA and exchange protein directly activated by cAMP 2 (Epac2), respectively, reduced glucose/forskolin-induced somatostatin secretion. Ryanodine produced a similar effect that was not additive to that of the PKA or Epac2 inhibitors. Intracellular application of cAMP produced a concentration-dependent stimulation of somatostatin exocytosis and elevation of cytoplasmic Ca2+ ([Ca2+](i)). Both effects were inhibited by ESI-05 and thapsigargin (an inhibitor of SERCA). By contrast, inhibition of PKA suppressed delta-cell exocytosis without affecting [Ca2+](i) . Simultaneous recordings of electrical activity and [Ca2+](i) in delta-cells expressing the genetically encoded Ca2+ indicator GCaMP3 revealed that the majority of glucose-induced [Ca2+](i) spikes did not correlate with delta-cell electrical activity but instead reflected Cat' release from the ER. These spontaneous [Ca2+](i) spikes are resistant to PKI but sensitive to ESI-05 or thapsigargin. We propose that cAMP links an increase in plasma glucose to stimulation of somatostatin secretion by promoting CICR, thus evoking exocytosis of somatostatin-containing secretory vesicles in the delta-cell.
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| 4. |
- Efe, C., et al.
(author)
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Extrahepatic autoimmune diseases in primary biliary cholangitis: Prevalence and significance for clinical presentation and disease outcome
- 2021
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In: Journal of Gastroenterology and Hepatology. - : Wiley. - 0815-9319 .- 1440-1746. ; 36:4, s. 936-942
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Journal article (peer-reviewed)abstract
- Background and Aim The prevalence and clinical significance of extrahepatic autoimmune diseases (EHAIDs) have not been evaluated in a large cohort of primary biliary cholangitis (PBC). Methods The medical records of 1554 patients with PBC from 20 international centers were retrospectively reviewed. Development of decompensated cirrhosis (ascites, variceal bleeding, and/or hepatic encephalopathy) and hepatocellular carcinoma were considered clinical endpoints. Results A total of 35 different EHAIDs were diagnosed in 440 (28.3%) patients with PBC. Patients with EHAIDs were more often female (92.5%vs86.1%,P < 0.001) and seropositive for anti-mitochondrial antibodies (88%vs84%,P = 0.05) and antinuclear antibodies and/or smooth muscle antibodies (53.8%vs43.6%,P = 0.005). At presentation, patients with EHAIDs had significantly lower levels of alkaline phosphatase (1.76vs1.98 x upper limit of normal [ULN],P = 0.006), aspartate aminotransferase (1.29vs1.50 x ULN,P < 0.001), and total bilirubin (0.53vs0.58 x ULN,P = 0.002). Patients with EHAIDs and without EHAIDs had similar rates of GLOBE high-risk status (12.3%vs16.1%,P = 0.07) and Paris II response (71.4%vs69.4%,P = 0.59). Overall, event-free survival was not different in patients with and without EHAIDs (90.8%vs90.7%,P = 0.53, log rank). Coexistence of each autoimmune thyroid diseases (10.6%), Sjogren disease (8.3%), systemic sclerosis (2.9%), rheumatoid arthritis (2.7%), systemic lupus erythematosus (1.7%), celiac disease (1.7%), psoriasis (1.5%), and inflammatory bowel diseases (1.3%) did not influence the outcome. Conclusions Our study confirms that EHAIDs are frequently diagnosed in patients with PBC. The presence of EHAIDs may influence the clinical phenotype of PBC at presentation but has no impact on PBC outcome.
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| 9. |
- Tarasov, A. I., et al.
(author)
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Monitoring real-time hormone release kinetics: Via high-content 3-D imaging of compensatory endocytosis
- 2018
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In: Lab on a Chip. - : Royal Society of Chemistry (RSC). - 1473-0197 .- 1473-0189. ; 18:18, s. 2838-2848
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Journal article (peer-reviewed)abstract
- High-content real-time imaging of hormone secretion in tissues or cell populations is a challenging task, which is unlikely to be resolved directly, despite immense translational value. We approach this problem indirectly, using compensatory endocytosis, a process that closely follows exocytosis in the cell, as a surrogate read-out for secretion. The tissue is immobilized in an open-air perifusion chamber and imaged using a two-photon microscope. A fluorescent polar tracer, perifused through the experimental circuit, gets trapped into the cells via endocytosis, and is quantified using a feature-detection algorithm. The signal of the tracer that accumulates into the endocytotic system reliably reflects stimulated exocytosis, which is demonstrated via co-imaging of the latter using existing reporters. A high signal-to-noise ratio and compatibility with multisensor imaging affords the real-time quantification of the secretion at the tissue/population level, whereas the cumulative nature of the signal allows imprinting of the “secretory history” within each cell. The technology works for several cell types, reflects disease progression and can be used for human tissue.
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| 12. |
- Barg, Sebastian, et al.
(author)
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The stimulatory action of tolbutamide on Ca2+-dependent exocytosis in pancreatic beta cells is mediated by a 65-kDa mdr-like P-glycoprotein
- 1999
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In: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 96:10, s. 5539-5544
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Journal article (peer-reviewed)abstract
- Intracellular application of the sulfonylurea tolbutamide during whole-cell patch-clamp recordings stimulated exocytosis >5-fold when applied at a cytoplasmic Ca2+ concentration of 0.17 microM. This effect was not detectable in the complete absence of cytoplasmic Ca2+ and when exocytosis was elicited by guanosine 5'-O-(3-thiotriphosphate) (GTPgammaS). The stimulatory action could be antagonized by the sulfonamide diazoxide, by the Cl--channel blocker 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS), by intracellular application of the antibody JSB1 [originally raised against a 170-kDa multidrug resistance (mdr) protein], and by tamoxifen (an inhibitor of the mdr- and volume-regulated Cl- channels). Immunocytochemistry and Western blot analyses revealed that JSB1 recognizes a 65-kDa protein in the secretory granules. This protein exhibited no detectable binding of sulfonylureas and is distinct from the 140-kDa sulfonylurea high-affinity sulfonylurea receptors also present in the granules. We conclude that (i) tolbutamide stimulates Ca2+-dependent exocytosis secondary to its binding to a 140-kDa high-affinity sulfonylurea receptor in the secretory granules; and (ii) a granular 65-kDa mdr-like protein mediates the action. The processes thus initiated culminate in the activation of a granular Cl- conductance. We speculate that the activation of granular Cl- fluxes promotes exocytosis (possibly by providing the energy required for membrane fusion) by inducing water uptake and an increased intragranular hydrostatic pressure.
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| 15. |
- Borssen, A. D., et al.
(author)
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Histological improvement of liver fibrosis in well-treated patients with autoimmune hepatitis A cohort study
- 2017
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In: Medicine (United States). - : Ovid Technologies (Wolters Kluwer Health). - 0025-7974. ; 96:34
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Journal article (peer-reviewed)abstract
- Autoimmune hepatitis (AIH) is a chronic autoimmune liver disease that if left untreated may lead to the development of cirrhosis. Previous studies on AIH patients have suggested that fibrosis and even cirrhosis can be reversed by medical treatment. The aim of this study was to evaluate the efficacy of medical treatment for protection of developing fibrosis and cirrhosis. A total of 258 liver biopsies from 101 patients (72 women, 29 men) were analyzed by a single pathologist and classified according to the Ishak grading (inflammation) and staging (fibrosis) system. Liver histology was stratified according to the temporal changes of fibrosis stage (increased, decreased, or stable), and groups were compared. Complete or partial response to medical treatment was 94.9%. Reduction of fibrosis stage from the first to the last biopsy was seen in 63 patients (62.4%). We found an association between a reduction in the fibrosis stage and continuous glucocorticoid medication, as well as lowered scores of inflammation at last biopsy. Twenty-one patients had cirrhosis (Ishak stage 6) at least in one of the previous biopsies, but only 5 patients at the last biopsy. Histological improvement is common in AIH patients that respond to medical treatment, and a reduction or stabilization of fibrosis stage occurs in about 2/3 of such patients.
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| 31. |
- Haythorne, E., et al.
(author)
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Diabetes causes marked inhibition of mitochondrial metabolism in pancreatic beta-cells
- 2019
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10
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Journal article (peer-reviewed)abstract
- Diabetes is a global health problem caused primarily by the inability of pancreatic beta-cells to secrete adequate levels of insulin. The molecular mechanisms underlying the progressive failure of beta-cells to respond to glucose in type-2 diabetes remain unresolved. Using a combination of transcriptomics and proteomics, we find significant dysregulation of major metabolic pathways in islets of diabetic beta V59M mice, a non-obese, eulipidaemic diabetes model. Multiple genes/proteins involved in glycolysis/gluconeogenesis are upregulated, whereas those involved in oxidative phosphorylation are downregulated. In isolated islets, glucose-induced increases in NADH and ATP are impaired and both oxidative and glycolytic glucose metabolism are reduced. INS-1 beta-cells cultured chronically at high glucose show similar changes in protein expression and reduced glucose-stimulated oxygen consumption: targeted metabolomics reveals impaired metabolism. These data indicate hyperglycaemia induces metabolic changes in beta-cells that markedly reduce mitochondrial metabolism and ATP synthesis. We propose this underlies the progressive failure of beta-cells in diabetes.
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| 32. |
- Hedin, Charlotte Rose Hawkey, et al.
(author)
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Effects of Tumor Necrosis Factor Antagonists in Patients With Primary Sclerosing Cholangitis
- 2020
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In: Clinical Gastroenterology and Hepatology. - : Elsevier BV. - 1542-3565 .- 1542-7714. ; 18:10, s. 2-2304
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Journal article (peer-reviewed)abstract
- Background & Aims: Few patients with primary sclerosing cholangitis (PSC) and inflammatory bowel diseases (IBDs) are exposed to tumor necrosis factor (TNF) antagonists because of the often mild symptoms of IBD. We assessed the effects of anti-TNF agents on liver function in patients with PSC and IBD, and their efficacy in treatment of IBD. Methods: We performed a retrospective analysis of 141 patients with PSC and IBD receiving treatment with anti-TNF agents (infliximab or adalimumab) at 20 sites (mostly tertiary-care centers) in Europe and North America. We collected data on the serum level of alkaline phosphatase (ALP). IBD response was defined as either endoscopic response or, if no endoscopic data were available, clinical response, as determined by the treating clinician or measurements of fecal calprotectin. Remission was defined more stringently as endoscopic mucosal healing. We used linear regression analysis to identify factors associated significantly with level of ALP during anti-TNF therapy. Results: Anti-TNF treatment produced a response of IBD in 48% of patients and remission of IBD in 23%. There was no difference in PSC symptom frequency before or after drug exposure. The most common reasons for anti-TNF discontinuation were primary nonresponse of IBD (17%) and side effects (18%). At 3 months, infliximab-treated patients had a median reduction in serum level of ALP of 4% (interquartile range, reduction of 25% to increase of 19%) compared with a median 15% reduction in ALP in adalimumab-treated patients (interquartile range, reduction of 29% to reduction of 4%; P =.035). Factors associated with lower ALP were normal ALP at baseline (P <.01), treatment with adalimumab (P =.090), and treatment in Europe (P =.083). Conclusions: In a retrospective analysis of 141 patients with PSC and IBD, anti-TNF agents were moderately effective and were not associated with exacerbation of PSC symptoms or specific side effects. Prospective studies are needed to investigate the association between use of adalimumab and reduced serum levels of ALP further.
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| 37. |
- Henriksson, Ida, 1980-, et al.
(author)
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Clinical outcomes and sick leave in relation to UDCA treatment in Swedish patients with primary biliary cholangitis
- 2023
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In: Scandinavian Journal of Gastroenterology. - : Informa UK Limited. - 0036-5521 .- 1502-7708. ; 58:1, s. 70-75
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Journal article (peer-reviewed)abstract
- Objectives Primary biliary cholangitis (PBC) is an autoimmune liver disease that may progress into liver cirrhosis. Ursodeoxycholic acid (UDCA) is known to prevent or delay the disease progression, but little is known about work incapacity in PBC patients. We aimed to compare clinical outcomes (transplantation-free survival; cirrhosis development) and sick leave in patients with PBC with and without UDCA therapy. Methods The medical records of 526 patients with PBC diagnosed from 2004 to 2016 were reviewed retrospectively. Sick leave data retrieved from the Swedish Social Insurance Agency were analysed for a sub-cohort of patients and matched controls. Cox regression was used for analysis of clinical outcomes. Logistic and conditional logistic regressions were used for sick leave analysis. Results A total of 10.6% of patients died and 3.4% received liver transplantation over a median follow-up time of 5.7 years. UDCA-untreated patients (HR 3.62 (95%CI 2.02-6.49)) and UDCA non-responders (HR 3.78 (95% CI 1.87-7.66)) had higher mortality or transplantation rates than UDCA responders. Patients with PBC had higher odds of sick leave (OR 2.50; 95% CI 1.69-3.70) than matched controls. Untreated patients were more likely to be on sick leave (OR 3.22; 95% CI 1.12-9.25) two years after diagnosis than UDCA responders. Conclusion Both untreated patients and UDCA non-responders had lower liver transplantation-free survival rates than UDCA responders. Patients with PBC were more likely to be on sick leave compared to matched controls from the general population.
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| 44. |
- Jeans, Alexander F., et al.
(author)
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A dominant mutation in Snap25 causes impaired vesicle trafficking, sensorimotor gating, and ataxia in the blind-drunk mouse
- 2007
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In: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 104:7, s. 2431-2436
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Journal article (peer-reviewed)abstract
- The neuronal soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex is essential for synaptic vesicle exocytosis, but its study has been limited by the neonatal lethality of murine SNARE knockouts. Here, we describe a viable mouse line carrying a mutation in the b-isoform of neuronal SNARE synaptosomal-associated protein of 25 kDa (SNAP-25) The causative I67T missense mutation results in increased binding affinities within the SNARE complex, impaired exocytotic vesicle recycling and granule exocytosis in pancreatic beta-cells, and a reduction in the amplitude of evoked cortical excitatory postsynaptic potentials. The mice also display ataxia and impaired sensorimotor gating, a phenotype which has been associated with psychiatric disorders in humans. These studies therefore provide insights into the role of the SNARE complex in both diabetes and psychiatric disease.
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| 45. |
- Karwen, T., et al.
(author)
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Platelet-derived lipids promote insulin secretion of pancreatic beta cells
- 2023
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In: Embo Molecular Medicine. - 1757-4676. ; 15:9
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Journal article (peer-reviewed)abstract
- Hyperreactive platelets are commonly observed in diabetic patients indicating a potential link between glucose homeostasis and platelet reactivity. This raises the possibility that platelets may play a role in the regulation of metabolism. Pancreatic beta cells are the central regulators of systemic glucose homeostasis. Here, we show that factor(s) derived from beta cells stimulate platelet activity and platelets selectively localize to the vascular endothelium of pancreatic islets. Both depletion of platelets and ablation of major platelet adhesion or activation pathways consistently resulted in impaired glucose tolerance and decreased circulating insulin levels. Furthermore, we found platelet-derived lipid classes to promote insulin secretion and identified 20-Hydroxyeicosatetraenoic acid (20-HETE) as the main factor promoting beta cells function. Finally, we demonstrate that the levels of platelet-derived 20-HETE decline with age and that this parallels with reduced impact of platelets on beta cell function. Our findings identify an unexpected function of platelets in the regulation of insulin secretion and glucose metabolism, which promotes metabolic fitness in young individuals.
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| 46. |
- Kim, Angela, et al.
(author)
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Arginine-vasopressin mediates counter-regulatory glucagon release and is diminished in type 1 diabetes.
- 2021
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In: eLife. - 2050-084X. ; 10
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Journal article (peer-reviewed)abstract
- Insulin-induced hypoglycemia is a major treatment barrier in type-1 diabetes (T1D). Accordingly, it is important that we understand the mechanisms regulating the circulating levels of glucagon. Varying glucose over the range of concentrations that occur physiologically between the fed and fuel-deprived states (8 to 4 mM) has no significant effect on glucagon secretion in the perfused mouse pancreas or in isolated mouse islets (in vitro), and yet associates with dramatic increases in plasma glucagon. The identity of the systemic factor(s) that elevates circulating glucagon remains unknown. Here, we show that arginine-vasopressin (AVP), secreted from the posterior pituitary, stimulates glucagon secretion. Alpha-cells express high levels of the vasopressin 1b receptor (V1bR) gene (Avpr1b). Activation of AVP neurons in vivo increased circulating copeptin (the C-terminal segment of the AVP precursor peptide) and increased blood glucose; effects blocked by pharmacological antagonism of either the glucagon receptor or V1bR. AVP also mediates the stimulatory effects of hypoglycemia produced by exogenous insulin and 2-deoxy-D-glucose on glucagon secretion. We show that the A1/C1 neurons of the medulla oblongata drive AVP neuron activation in response to insulin-induced hypoglycemia. AVP injection increased cytoplasmic Ca2+ in alpha-cells (implanted into the anterior chamber of the eye) and glucagon release. Hypoglycemia also increases circulating levels of AVP/copeptin in humans and this hormone stimulates glucagon secretion from human islets. In patients with T1D, hypoglycemia failed to increase both copeptin and glucagon. These findings suggest that AVP is a physiological systemic regulator of glucagon secretion and that this mechanism becomes impaired in T1D.
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| 47. |
- Knudsen, J. G., et al.
(author)
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Dysregulation of Glucagon Secretion by Hyperglycemia-Induced Sodium-Dependent Reduction of ATP Production
- 2019
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In: Cell Metabolism. - : Elsevier BV. - 1550-4131. ; 29:2
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Journal article (peer-reviewed)abstract
- Diabetes is a bihormonal disorder resulting from combined insulin and glucagon secretion defects. Mice lacking fumarase (Fh1) in their beta cells (Fh1 beta KO mice) develop progressive hyperglycemia and dysregulated glucagon secretion similar to that seen in diabetic patients (too much at high glucose and too little at low glucose). The glucagon secretion defects are corrected by low concentrations of tolbutamide and prevented by the sodium-glucose transport (SGLT) inhibitor phlorizin. These data link hyperglycemia, intracellular Na+ accumulation, and acidification to impaired mitochondrial metabolism, reduced ATP production, and dysregulated glucagon secretion. Protein succination, reflecting reduced activity of fumarase, is observed in alpha cells from hyperglycemic Fh1 beta KO and beta-V59M gain-of-function K-ATP channel mice, diabetic Goto-Kakizaki rats, and patients with type 2 diabetes. Succination is also observed in renal tubular cells and cardiomyocytes from hyperglycemic Fh1 beta KO mice, suggesting that the model can be extended to other SGLT-expressing cells and may explain part of the spectrum of diabetic complications.
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| 48. |
- Lampinen, M., et al.
(author)
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Eosinophil granulocytes are activated during the remission phase of ulcerative colitis
- 2005
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In: Gut. ; 54:12, s. 1714-20
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Journal article (peer-reviewed)abstract
- AIM: The aim of this study was to establish a method of investigating intestinal eosinophil and neutrophil granulocytes by flow cytometry, and to compare the distribution and activity of these cells in different stages of ulcerative colitis (UC). METHODS: Biopsy samples were taken from six locations of the entire colon and from the terminal ileum in 10 patients with active total UC, 10 patients with inactive total UC, eight patients with active distal UC, and 11 control subjects. Cell suspensions from biopsies and from peripheral blood were incubated with fluorophore conjugated monoclonal antibodies. The use of scatter plot-gating and specific antibodies was established in a flow cytometry assay. RESULTS: Eosinophils were more numerous and more active in patients with active UC than in controls. Interestingly, during inactive UC, the number of activated eosinophils was even larger. Eosinophil activity was high in the rectum of patients with distal colitis but was also slightly elevated in the proximal colon. Neutrophils were increased in number and activity during active but not inactive UC. In patients with distal colitis, activated neutrophils were only found in the sigmoid colon and rectum. CONCLUSION: With this method, we confirm that neutrophils participate in the inflammatory process during active UC, and that they express a resting phenotype during remission. The finding of activated eosinophils in inflamed intestine strengthens the view of these cells as proinflammatory and tissue damaging. Nevertheless, our new finding of high eosinophil activation during inactive UC suggests that eosinophils play a role in repair of injured epithelium.
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| 49. |
- Montagnese, Sara, et al.
(author)
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A pilot study of golexanolone, a new GABA-A receptor-modulating steroid antagonist, in patients with covert hepatic encephalopathy
- 2021
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In: Journal of Hepatology. - : Elsevier. - 0168-8278 .- 1600-0641. ; 75:1, s. 98-107
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Journal article (peer-reviewed)abstract
- Background & Aims: Golexanolone is a novel small molecule GABA-A receptor-modulating steroid antagonist under development for the treatment of cognitive and vigilance disorders caused by allosteric over-activation of GABA-A receptors by neurosteroids. It restored spatial learning and motor coordination in animal models of hepatic encephalopathy (HE) and mitigated the effects of intravenous allopregnanolone in healthy adults in a dose-dependent fashion. Herein, we report data on the safety, pharmacokinetics (PK) and efficacy of golexanolone in adult patients with cirrhosis.Methods: Following single/multiple ascending dose studies, adults with Child-Pugh A/B cirrhosis and abnormal continuous reaction time (CRT) on screening were randomized to 3 weeks’ dosing with golexanolone (10, 40 or 80 mg BID) or placebo. CRT, psychometric hepatic encephalopathy score (PHES), animal naming test (ANT), Epworth sleepiness scale (ESS) and electroencephalogram (mean dominant frequency [MDF]; delta+theta/alpha+beta ratio [DT/AB]) were obtained at baseline, 10, and 21 days.Results: Golexanolone exhibited satisfactory safety and PK. Baseline characteristics were similar between the 12 and 33 patients randomized to placebo or golexanolone, respectively. By prespecified analyses, golexanolone was associated with directionally favourable changes vs. placebo in ESS (p = 0.047), MDF (p = 0.142) and DT/AB (p = 0.021). All patients also showed directionally favourable changes in CRT, PHES and ANT, but with no statistical difference between golexanolone and placebo. Post hoc analyses taking into account the variability and improvement in CRT, PHES and ANT observed between screening and baseline suggested an efficacy signal by cognitive measures as well.Conclusion: Golexanolone was well tolerated and associated with improvement in cognitive performance. These results implicate GABA-A receptor-modulating neurosteroids in the pathogenesis of HE and support the therapeutic potential of golexanolone.Lay summary: Many patients with cirrhosis experience subtle but disabling cognitive problems, including sleepiness and poor attention span, that impair their ability to be gainfully employed or carry out activities of daily living. This pilot study tested the hypothesis that these problems with cognition, for which there is no approved treatment, might be improved by an experimental drug, golexanolone, designed to normalize the function of receptors which inhibit brain function. The results of this study suggest that golexanolone is well tolerated and may improve cognition, as reflected by measures of sleepiness, attention span and brain wave activity, paving the way for future larger studies of this promising experimental drug.Clinical trial registration number: EudraCT 2016-003651-30.
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