| 1. |
- Curman, Philip, et al.
(författare)
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Increased risk of depression and anxiety in individuals with Darier disease
- 2024
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Ingår i: British Journal of Dermatology. - : Wiley-Blackwell Publishing Inc.. - 0007-0963 .- 1365-2133.
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Tidskriftsartikel (refereegranskat)abstract
- Patients with Darier disease have an increased risk of depression and anxiety, which agrees with patterns of increased prescription of antidepressants and anxiolytics in people with the disease.
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| 2. |
- Martin, Cederlöf, 1980-, et al.
(författare)
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Individuals with Darier disease have an increased risk of suicide and self-injurious behaviours
- 2024
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Ingår i: British Journal of Dermatology. - : Wiley-Blackwell Publishing Inc.. - 0007-0963 .- 1365-2133. ; 190:2, s. 284-285
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Tidskriftsartikel (refereegranskat)abstract
- In a large population-based registry study of 935 patients in Sweden with Darier disease, we show that patients with the disease display significantly increased risks of suicide and self-injurious behaviours.
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| 3. |
- Zhong, Lei, et al.
(författare)
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The Histone Deacetylase Sirt6 Regulates Glucose Homeostasis via Hif1 alpha
- 2010
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Ingår i: Cell. - : Elsevier BV. - 0092-8674 .- 1097-4172. ; 140:2, s. 280-293
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Tidskriftsartikel (refereegranskat)abstract
- SIRT6 is a member of a highly conserved family of NAD(+)-dependent deacetylases with various roles in metabolism, stress resistance, and life span. SIRT6-deficient mice develop normally but succumb to a lethal hypoglycemia early in life; however, the mechanism underlying this hypoglycemia remained unclear. Here, we demonstrate that SIRT6 functions as a histone H3K9 deacetylase to control the expression of multiple glycolytic genes. Specifically, SIRT6 appears to function as a corepressor of the transcription factor Hif1 alpha, a critical regulator of nutrient stress responses. Consistent with this notion, SIRT6-deficient cells exhibit increased Hif1 alpha activity and show increased glucose uptake with upregulation of glycolysis and diminished mitochondrial respiration. Our studies uncover a role for the chromatin factor SIRT6 as a master regulator of glucose homeostasis and may provide the basis for novel therapeutic approaches against metabolic diseases, such as diabetes and obesity.
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| 4. |
- Curman, Philip, et al.
(författare)
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Hailey-Hailey Disease is Associated with Diabetes : A Population-based Cohort Study, Clinical Cohort Study, and Pedigree Analysis
- 2023
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Ingår i: Acta Dermato-Venereologica. - : Medical Journals Sweden. - 0001-5555 .- 1651-2057. ; 103
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Tidskriftsartikel (refereegranskat)abstract
- Hailey-Hailey disease is a rare hereditary skin disease caused by mutations in the ATP2C1 gene encoding the secretory pathway Ca2+/Mn2+-ATPase 1 (SPCA1) protein. Extracutaneous manifestations of Hailey-Hailey disease are plausible but still largely unknown. The aim of this study was to explore the association between Hailey-Hailey disease and diabetes. A population-based cohort study of 347 individuals with Hailey-Hailey disease was performed to assess the risks of type 1 diabetes and type 2 diabetes, using Swedish nationwide registries. Pedigrees from 2 Swedish families with Hailey-Hailey disease were also investigated: 1 with concurrent type 1 diabetes and HLA-DQ3, the other with type 2 diabetes. Lastly, a clinical cohort with 23 individuals with Hailey-Hailey disease and matched healthy controls was evaluated regarding diabetes. In the register data males with Hailey-Hailey disease had a 70% elevated risk of type 2 diabetes, whereas no excess risk among women could be confirmed. In both pedigrees an unusually high inheritance for diabetes was observed. In the clinical cohort, individuals with Hailey-Hailey disease displayed a metabolic phenotype indicative of type 2 diabetes. Hailey-Hailey disease seems to act as a synergistic risk factor for diabetes. This study indicates, for the first time, an association between Hailey-Hailey disease and diabetes and represents human evidence that SPCA1 and the Golgi apparatus may be implicated in diabetes pathophysiology.
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| 5. |
- Robson-Doucette, Christine A., et al.
(författare)
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beta-Cell Uncoupling Protein 2 Regulates Reactive Oxygen Species Production, Which Influences Both Insulin and Glucagon Secretion
- 2011
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 60:11, s. 2710-2719
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE-The role of uncoupling protein 2 (UCP2) in pancreatic beta-cells is highly debated, partly because of the broad tissue distribution of UCP2 and thus limitations of whole-body UCP2 knockout mouse models. To investigate the function of UCP2 in the beta-cell, beta-cell-specific UCP2 knockout mice (UCP2BKO) were generated and characterized. RESEARCH DESIGN AND METHODS-UCP2BKO mice were generated by crossing loxUCP2 mice with mice expressing rat insulin promoter-driven Cre recombinase. Several in vitro and in vivo parameters were measured, including respiration rate, mitochondrial membrane potential, islet ATP content, reactive oxygen species (ROS) levels, glucose-stimulated insulin secretion (GSIS), glucagon secretion, glucose and insulin tolerance, and plasma hormone levels. RESULTS-UCP2BKO beta-cells displayed mildly increased glucose-induced mitochondrial membrane hyperpolarization but unchanged rates of uncoupled respiration and islet ATP content. UCP2BKO islets had elevated intracellular ROS levels that associated with enhanced GSIS. Surprisingly, UCP2BKO mice were glucose-intolerant, showing greater alpha-cell area, higher islet glucagon content, and aberrant ROS-dependent glucagon secretion under high glucose conditions. CONCLUSIONS-Using a novel beta-cell-specific UCP2K0 mouse model, we have shed light on UCP2 function in primary beta-cells. UCP2 does not behave as a classical metabolic uncoupler in the beta-cell, but has a more prominent role in the regulation of intracellular ROS levels that contribute to GSIS amplification. In addition, beta-cell UCP2 contributes to the regulation of intraislet ROS signals that mediate changes in alpha-cell morphology and glucagon secretion. Diabetes 60:2710-2719, 2011
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| 6. |
- Sandqvist, Anna, et al.
(författare)
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Plasma l-arginine levels distinguish pulmonary arterial hypertension from left ventricular systolic dysfunction
- 2018
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Ingår i: Heart and Vessels. - : Springer. - 0910-8327 .- 1615-2573. ; 33:3, s. 255-263
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Tidskriftsartikel (refereegranskat)abstract
- Pulmonary arterial hypertension (PAH) is a life-threatening condition, characterized by an imbalance of vasoactive substances and remodeling of pulmonary vasculature. Nitric oxide, formed from l-arginine, is essential for homeostasis and smooth muscle cell relaxation in PAH. Our aim was to compare plasma concentrations of l-arginine, asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA) in PAH compared to left ventricular systolic dysfunction (LVSD) and healthy subjects. This was an observational, multicenter study comparing 21 patients with PAH to 14 patients with LVSD and 27 healthy subjects. Physical examinations were obtained and blood samples were collected. Plasma levels of ADMA, SDMA, l-arginine, l-ornithine, and l-citrulline were analyzed using liquid chromatography–tandem mass spectrometry (LC–MS/MS). Plasma levels of ADMA and SDMA were higher, whereas l-arginine and l-arginine/ADMA ratio were lower in PAH patients compared to healthy subjects (p < 0.001). Patients with PAH also had lower levels of l-arginine than patients with LVSD (p < 0.05). l-Arginine correlated to 6 min walking distance (6MWD) (r s = 0.58, p = 0.006) and l-arginine/ADMA correlated to WHO functional class (r s = −0.46, p = 0.043) in PAH. In conclusion, l-arginine levels were significantly lower in treatment naïve PAH patients compared to patients with LVSD. Furthermore, l-arginine correlated with 6MWD in PAH. l-arginine may provide useful information in differentiating PAH from LVSD.
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| 7. |
- Wikström, Jakob D., et al.
(författare)
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A novel high throughput assay for islet respiration reveals uncoupling of rodent and human islets
- 2012
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 7:5, s. e33023-
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Tidskriftsartikel (refereegranskat)abstract
- Background: The pancreatic beta cell is unique in its response to nutrient by increased fuel oxidation. Recent studies have demonstrated that oxygen consumption rate (OCR) may be a valuable predictor of islet quality and long term nutrient responsiveness. To date, high-throughput and user-friendly assays for islet respiration are lacking. The aim of this study was to develop such an assay and to examine bioenergetic efficiency of rodent and human islets. Methodology/Principal Findings: The XF24 respirometer platform was adapted to islets by the development of a 24-well plate specifically designed to confine islets. The islet plate generated data with low inter-well variability and enabled stable measurement of oxygen consumption for hours. The F1F0 ATP synthase blocker oligomycin was used to assess uncoupling while rotenone together with myxothiazol/antimycin was used to measure the level of non-mitochondrial respiration. The use of oligomycin in islets was validated by reversing its effect in the presence of the uncoupler FCCP. Respiratory leak averaged to 59% and 49% of basal OCR in islets from C57Bl6/J and FVB/N mice, respectively. In comparison, respiratory leak of INS-1 cells and C2C12 myotubes was measured to 38% and 23% respectively. Islets from a cohort of human donors showed a respiratory leak of 38%, significantly lower than mouse islets. Conclusions/Significance: The assay for islet respiration presented here provides a novel tool that can be used to study islet mitochondrial function in a relatively high-throughput manner. The data obtained in this study shows that rodent islets are less bioenergetically efficient than human islets as well as INS1 cells.
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| 8. |
- Wikström, Jakob D., et al.
(författare)
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Hormone-induced mitochondrial fission is utilized by brown adipocytes as an amplification pathway for energy expenditure
- 2014
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Ingår i: EMBO Journal. - : Wiley. - 0261-4189 .- 1460-2075. ; 33:5, s. 418-436
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Tidskriftsartikel (refereegranskat)abstract
- Adrenergic stimulation of brown adipocytes (BA) induces mitochondrial uncoupling, thereby increasing energy expenditure by shifting nutrient oxidation towards thermogenesis. Here we describe that mitochondrial dynamics is a physiological regulator of adrenergically-induced changes in energy expenditure. The sympathetic neurotransmitter Norepinephrine (NE) induced complete and rapid mitochondrial fragmentation in BA, characterized by Drp1 phosphorylation and Opa1 cleavage. Mechanistically, NE-mediated Drp1 phosphorylation was dependent on Protein Kinase-A (PKA) activity, whereas Opa1 cleavage required mitochondrial depolarization mediated by FFAs released as a result of lipolysis. This change in mitochondrial architecture was observed both in primary cultures and brown adipose tissue from cold-exposed mice. Mitochondrial uncoupling induced by NE in brown adipocytes was reduced by inhibition of mitochondrial fission through transient Drp1 DN overexpression. Furthermore, forced mitochondrial fragmentation in BA through Mfn2 knock down increased the capacity of exogenous FFAs to increase energy expenditure. These results suggest that, in addition to its ability to stimulate lipolysis, NE induces energy expenditure in BA by promoting mitochondrial fragmentation. Together these data reveal that adrenergically-induced changes to mitochondrial dynamics are required for BA thermogenic activation and for the control of energy expenditure.
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| 9. |
- Wikström, Jakob D, 1978-
(författare)
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Mitochondrial form and function in pancreatic β-cells and brown adipocytes
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis is focused on the role of mitochondria in pancreatic β-cells and brown adipose tissue (BAT). Two main aspects of mitochondria were explored; mitochondrial functional efficiency and the interrelationship between mitochondrial shape and function. Mitochondria in β-cells were found to exhibit heterogeneity in mitochondrial membrane potential. This functional diversity decreased when cells were challenged with glucose stimuli, suggesting that at higher fuel levels low-activity mitochondria are recruited into a pool of high-activity mitochondria. Glucolipotoxic conditions increased the functional diversity suggesting that this may be of importance for diabetes pathophysiology. To examine mitochondrial efficiency in intact islets a high throughput islet respirometry method was developed. Due to increased uncoupling, islets from a diabetic animal model exhibit lower respiratory efficiency. Glucose, free fatty acids and amino acids all decreased respiratory efficiency. A large portion of the respiratory efficiency was mediated by reactive oxygen species and the adenine nucleotide translocase. In β-cells mitochondria were found to undergo cycles of fusion and fission. During glucolipotoxicity mitochondria fragmented and lost their fusion ability. Knock down of the fission protein Fis1 rescued the β-cells from glucolipotoxic induced cell death. BAT mitochondria also showed fusion and fission. The mitochondrial dynamics proteins Mfn2 and Drp1 were shown to strongly affect BAT mitochondrial morphology. In response to a combination of adrenergic and free fatty acid stimuli mitochondria drastically changed from long filamentous structures to fragmented spheres. Inhibiting fission by the negative form of Drp1 decreased BAT response to adrenergic stimuli by half. In conclusion, mitochondrial efficiency may be of importance for normal as well as compromised β-cell and islet function. Mitochondrial morphology appears critical for mitochondrial function in β-cells and BAT.
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