1. |
- Holst, Birgitte, et al.
(författare)
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G Protein-Coupled Receptor 39 Deficiency Is Associated with Pancreatic Islet Dysfunction
- 2009
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Ingår i: Endocrinology. - : The Endocrine Society. - 0013-7227 .- 1945-7170. ; 150, s. 2577-2585
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Tidskriftsartikel (refereegranskat)abstract
- G protein-coupled receptor (GPR)-39 is a seven-transmembrane receptor expressed mainly in endocrine and metabolic tissues that acts as a Zn++ sensor signaling mainly through the G(q) and G(12/13) pathways. The expression of GPR39 is regulated by hepatocyte nuclear factor (HNF)-1 alpha and HNF-4 alpha, and in the present study, we addressed the importance of GPR39 for glucose homeostasis and pancreatic islets function. The expression and localization of GPR39 were characterized in the endocrine pancreas and pancreatic cell lines. Gpr39(-/-) mice were studied in vivo, especially in respect of glucose tolerance and insulin sensitivity, and in vitro in respect of islet architecture, gene expression, and insulin secretion. Gpr39 was down-regulated on differentiation of the pluripotent pancreatic cell line AR42J cells toward the exocrine phenotype but was along with Pdx-1 strongly up-regulated on differentiation toward the endocrine phenotype. Immunohistochemistry demonstrated that GRP39 is localized selectively in the insulin-storing cells of the pancreatic islets as well as in the duct cells of the exocrine pancreas. Gpr39(-/-) mice displayed normal insulin sensitivity but moderately impaired glucose tolerance both during oral and iv glucose tolerance tests, and Gpr39(-/-) mice had decreased plasma insulin response to oral glucose. Islet architecture was normal in the Gpr39 null mice, but expression of Pdx-1 and Hnf-1 alpha was reduced. Isolated, perifused islets from Gpr39 null mice secreted less insulin in response to glucose stimulation than islets from wild-type littermates. It is concluded that GPR39 is involved in the control of endocrine pancreatic function, and it is suggested that this receptor could be a novel potential target for the treatment of diabetes. (Endocrinology 150: 2577-2585, 2009)
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2. |
- Backe, Marie Balslev, et al.
(författare)
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The Lysine Demethylase KDM5B Regulates Islet Function and Glucose Homeostasis
- 2019
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Ingår i: Journal of Diabetes Research. - : Hindawi Limited. - 2314-6753 .- 2314-6745. ; 2019
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Tidskriftsartikel (refereegranskat)abstract
- Aims: Posttranslational modifications of histones and transcription factors regulate gene expression and are implicated in beta-cell failure and diabetes. We have recently shown that preserving H3K27 and H3K4 methylation using the lysine demethylase inhibitor GSK-J4 reduces cytokine-induced destruction of beta-cells and improves beta-cell function. Here, we investigate the therapeutic potential of GSK-J4 to prevent diabetes development and examine the importance of H3K4 methylation for islet function. Materials and Methods: We used two mouse models of diabetes to investigate the therapeutic potential of GSK-J4. To clarify the importance of H3K4 methylation, we characterized a mouse strain with knockout (KO) of the H3K4 demethylase KDM5B. Results: GSK-J4 administration failed to prevent the development of experimental diabetes induced by multiple low-dose streptozotocin or adoptive transfer of splenocytes from acutely diabetic NOD to NODscid mice. KDM5B-KO mice were growth retarded with altered body composition, had low IGF-1 levels, and exhibited reduced insulin secretion. Interestingly, despite secreting less insulin, KDM5B-KO mice were able to maintain normoglycemia following oral glucose tolerance test, likely via improved insulin sensitivity, as suggested by insulin tolerance testing and phosphorylation of proteins belonging to the insulin signaling pathway. When challenged with high-fat diet, KDM5B-deficient mice displayed similar weight gain and insulin sensitivity as wild-type mice. Conclusion: Our results show a novel role of KDM5B in metabolism, as KDM5B-KO mice display growth retardation and improved insulin sensitivity.
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3. |
- Egerod, Kristoffer L., et al.
(författare)
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beta-Cell Specific Overexpression of GPR39 Protects against Streptozotocin-Induced Hyperglycemia
- 2011
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Ingår i: International Journal of Endocrinology. - : Hindawi Limited. - 1687-8337 .- 1687-8345.
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Tidskriftsartikel (refereegranskat)abstract
- Mice deficient in the zinc-sensor GPR39, which has been demonstrated to protect cells against endoplasmatic stress and cell death in vitro, display moderate glucose intolerance and impaired glucose-induced insulin secretion. Here, we use the Tet-On system under the control of the proinsulin promoter to selectively overexpress GPR39 in the beta cells in a double transgenic mouse strain and challenge them with multiple low doses of streptozotocin, which in the wild-type littermates leads to a gradual increase in nonfasting glucose levels and glucose intolerance observed during both food intake and OGTT. Although the overexpression of the constitutively active GPR39 receptor in animals not treated with streptozotocin appeared by itself to impair the glucose tolerance slightly and to decrease the beta-cell mass, it nevertheless totally protected against the gradual hyperglycemia in the steptozotocin-treated animals. It is concluded that GPR39 functions in a beta-cell protective manner and it is suggested that it is involved in some of the beneficial, beta-cell protective effects observed for Zn(++) and that GPR39 may be a target for antidiabetic drug intervention.
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4. |
- Graae, Anne-Sofie, et al.
(författare)
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ADAMTS9 Regulates Skeletal Muscle Insulin Sensitivity Through Extracellular Matrix Alterations
- 2019
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 68:3, s. 502-514
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Tidskriftsartikel (refereegranskat)abstract
- The ADAMTS9 rs4607103 C allele is one of the few gene variants proposed to increase the risk of type 2 diabetes through an impairment of insulin sensitivity. We show that the variant is associated with increased expression of the secreted ADAMTS9 and decreased insulin sensitivity and signaling in human skeletal muscle. In line with this, mice lacking Adamts9 selectively in skeletal muscle have improved insulin sensitivity. The molecular link between ADAMTS9 and insulin signaling was characterized further in a model where ADAMTS9 was overexpressed in skeletal muscle. This selective over expression resulted in decreased insulin signaling presumably mediated through alterations of the integrin 131 signaling pathway and disruption of the intracellular cytoskeletal organization. Furthermore, this led to impaired mitochondria! function in mouse muscle-an observation found to be of translational character because humans carrying the ADAMTS9 risk allele have decreased expression of mitochondrial markers. Finally, we found that the link between ADAMTS9 overexpression and impaired insulin signaling could be due to accumulation of harmful lipid intermediates. Our findings contribute to the understanding of the molecular mechanisms underlying insulin resistance and type 2 diabetes and point to inhibition of ADAMTS9 as a potential novel mode of treating insulin resistance.
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5. |
- Holst, Anders G., et al.
(författare)
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Inhibition of the KCa2 potassium channel in atrial fibrillation: a randomized phase 2 trial
- 2023
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Ingår i: Nature Medicine. - 1078-8956 .- 1546-170X.
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Tidskriftsartikel (refereegranskat)abstract
- Existing antiarrhythmic drugs to treat atrial fibrillation (AF) have incomplete efficacy, contraindications and adverse effects, including proarrhythmia. AP30663, an inhibitor of the KCa2 channel, has demonstrated AF efficacy in animals; however, its efficacy in humans with AF is unknown. Here we conducted a phase 2 trial in which patients with a current episode of AF lasting for 7 days or less were randomized to receive an intravenous infusion of 3 or 5 mg kg−1 AP30663 or placebo. The trial was prematurely discontinued because of slow enrollment during the coronavirus disease 2019 pandemic. The primary endpoint of the trial was cardioversion from AF to sinus rhythm within 90 min from the start of the infusion, analyzed with Bayesian statistics. Among 59 patients randomized and included in the efficacy analyses, the primary endpoint occurred in 42% (5 of 12), 55% (12 of 22) and 0% (0 of 25) of patients treated with 3 mg kg−1 AP30663, 5 mg kg−1 AP30663 or placebo, respectively. Both doses demonstrated more than 99.9% probability of superiority over placebo, surpassing the prespecified 95% threshold. The mean time to cardioversion, a secondary endpoint, was 47 (s.d. = 23) and 41 (s.d. = 24) minutes for 3 mg kg−1 and 5 mg kg−1 AP30663, respectively. AP30663 caused a transient increase in the QTcF interval, with a maximum mean effect of 37.7 ms for the 5 mg kg−1 dose. For both dose groups, no ventricular arrhythmias occurred and adverse event rates were comparable to the placebo group. AP30663 demonstrated AF cardioversion efficacy in patients with recent-onset AF episodes. KCa2 channel inhibition may be an attractive mechanism for rhythm control of AF that should be studied further in randomized trials. ClinicalTrials.gov registration: NCT04571385 .
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6. |
- Kristinsson, Hjalti
(författare)
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Effects of Free Fatty Acids on Insulin and Glucagon Secretion : – with special emphasis on the role of Free fatty acid receptor 1
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Prevalence of type 2 diabetes mellitus (T2DM) is still rising and even so in the juvenile population. Obesity is highly associated with increased risk for developing T2DM. The development has been related to elevated fasting concentrations of the pancreatic islet hormones insulin and glucagon as well as to an increase in plasma lipids that occurs during obesity. Specifically, research has indicated that chronic exposure to high levels of saturated free fatty acids cause dysfunction in islet alpha- and beta-cells. Fatty acids can affect islet cells by various mechanisms one of which is the G-protein coupled receptor FFAR1/GPR40. The role of the receptor in the effects of fatty acids on pancreatic islet-cell function is not clear. The aim of this thesis was to clarify the role of FFAR1 in how fatty acids, and more specifically the long-chain saturated fatty acid palmitate, affect insulin and glucagon secretion.In children and adolescents with obesity elevated fasting levels of insulin and glucagon were positively correlated with lipid parameters. Specifically, plasma triglycerides and free fatty acids were positively correlated with insulin and glucagon at fasting as well as with visceral adipose tissue volume. Elevated glucagon levels at fasting were associated with worsening of glucose tolerance in the same population. In in vitro studies of isolated human islets palmitate stimulated basal insulin and glucagon secretion as well as mitochondrial respiration at fasting glucose levels. The effect was mediated by FFAR1 and fatty acid beta-oxidation. At higher glucose concentrations the receptor was involved in the potentiation of insulin secretion from isolated human islets and insulin-secreting MIN6 cells. Furthermore, we found that the effects of palmitate on hormone secretion were associated with enhanced mitochondrial respiration mediated by FFAR1 Gαq signaling and PKC activity as well as increased intracellular metabolism induced by the fatty acid. When islets were exposed to palmitate for long time periods and in the presence of FFAR1 antagonist, normalized insulin and glucagon secretion during culture and insulin response to glucose after culture were observed. In MIN6 cells chronic palmitate treatment increased mitochondrial uncoupling irrespective of FFAR1 involvement. However, FFAR1 antagonism during palmitate exposure resulted in elevated respiration and reduced apoptosis.In conclusion, children and adolescents with obesity have elevated fasting concentrations of insulin and glucagon that correlate with free fatty acids and fatty acid sources. High glucagon levels are linked to worsening of glucose tolerance in these subjects. In vitro the combination or synergy of FFAR1 activation and intracellular metabolism caused by palmitate is decisive for both the short-term enhancement effects and the negative chronic effects on insulin and glucagon secretion.
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7. |
- Krog-Mikkelsen, Inger, et al.
(författare)
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A Low Glycemic Index Diet Does Not Affect Postprandial Energy Metabolism but Decreases Postprandial Insulinemia and Increases Fullness Ratings in Healthy Women
- 2011
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Ingår i: Journal of Nutrition. - : Elsevier BV. - 1541-6100 .- 0022-3166. ; 141:9, s. 1679-1684
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Tidskriftsartikel (refereegranskat)abstract
- At present, it is difficult to determine whether glycemic index (GI) is an important tool in the prevention of lifestyle diseases, and long-term studies investigating GI with diets matched in macronutrient composition, fiber content, energy content, and energy density are still scarce. We investigated the effects of 2 high-carbohydrate (55%) diets with low GI (LGI; 79) or high GI (HGI; 103) on postprandial blood profile, subjective appetite sensations, energy expenditure (EE), substrate oxidation rates, and ad libitum energy intake (El) from a corresponding test meal (LGI or HGI) after consuming the diets ad libitum for 10 wk. Two groups of a total of 29 healthy, overweight women (age: 30.5 +/- 6.6 y; BMI: 27.6 +/- 1.5 kg/m(2)) participated in the 10-wk intervention and a subsequent 4-h meal test. The breakfast test meals differed in GI but were equal in total energy, macronutrient composition, fiber content, and energy density. The LGI meal resulted in lower plasma glucose, serum insulin, and plasma glucagon-like peptide (GLP)-1 and higher plasma glucose-dependent insulinotropic polypeptide concentrations than the HGI meal (P <= 0.05). Ratings of fullness were slightly higher and the desire to eat something fatty was lower after the test meal in the LGI group (P < 0.05). Postprandial plasma GLP-2, plasma glucagon, serum leptin, plasma ghrelin, EE, substrate oxidation rates, and ad libitum El at lunch did not differ between groups. In conclusion, postprandial glycemia, insulinemia, and subjective appetite ratings after a test meal were better after 10-wk ad libitum intake of a LGI compared to a HGI diet. EE and substrate oxidation rates were, however, not affected. These findings give some support to recommendations to consume a LGI diet. J. Nutr. 141: 1679-1684, 2011.
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8. |
- Seidel, Maria, et al.
(författare)
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A Systematic Review and Meta-Analysis Finds Increased Blood Levels of All Forms of Ghrelin in Both Restricting and Binge-Eating/Purging Subtypes of Anorexia Nervosa
- 2021
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Ingår i: Nutrients. - : MDPI. - 2072-6643. ; 13:2
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Tidskriftsartikel (refereegranskat)abstract
- Anorexia nervosa (AN) is a severe psychiatric condition associated with high mortality and chronicity. The hunt for state, trait, subtyping, and prognostic biomarkers is ongoing and the orexigenic hormone ghrelin and its different forms, acyl ghrelin and desacyl ghrelin, have been proposed to be increased in AN, especially in the restrictive subtype. A systematic literature search was performed using established databases up to 30 November 2020. Forty-nine studies met inclusion criteria for cross-sectional and longitudinal meta-analyses on total ghrelin, acyl ghrelin, and desacyl ghrelin. All forms of ghrelin were increased in the acute stage of anorexia nervosa during fasting compared to healthy controls. Previous notions on differences in ghrelin levels between AN subtypes were not supported by current data. In addition, a significant decrease in total ghrelin was observed pre-treatment to follow-up. However, total ghrelin levels at follow-up were still marginally elevated compared to healthy controls, whereas for acyl ghrelin, no overall effect of treatment was observed. Due to heterogeneity in follow-up designs and only few data on long-term recovered patients, longitudinal results should be interpreted with caution. While the first steps towards a biomarker in acute AN have been completed, the value of ghrelin as a potential indicator of treatment success or recovery status or its use in subtype differentiation are yet to be established.
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10. |
- Yfanti, Christina, et al.
(författare)
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A phase 1 trial of AP30663, a KCa2 channel inhibitor in development for conversion of atrial fibrillation
- 2024
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Ingår i: BRITISH JOURNAL OF CLINICAL PHARMACOLOGY. - 0306-5251 .- 1365-2125.
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Tidskriftsartikel (refereegranskat)abstract
- Aims: AP30663 is a novel compound under development for pharmacological conversion of atrial fibrillation by targeting the small conductance Ca2+ activated K+ (K(Ca)2) channel. The aim of this extension phase 1 study was to test AP30663 at higher single doses compared to the first-in-human trial.Methods: Sixteen healthy male volunteers were randomized into 2 cohorts: 6- and 8-mg/kg intravenous single-dose administration of AP30663 vs. placebo. Safety, pharmacokinetic and pharmacodynamic data were collected.Results: AP30663 was associated with mild and transient infusion site reactions with no clustering of other adverse events but with an estimated maximum mean QTcF interval prolongation of 45.2 ms (95% confidence interval 31.5-58.9) in the 6 mg/kg dose level and 50.4 ms (95% confidence interval 36.7-64.0) with 8 mg/kg. Pharmacokinetics was dose proportional with terminal half-life of around 3 h.Conclusion: AP30663 in doses up to 8 mg/kg was associated with mild and transient infusion site reactions and an increase of the QTcF interval. Supporting Information support that the QTc effect may be explained by an off-target inhibition of the I-Kr channel.
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