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| 2. |
- Brokken, Leon, et al.
(författare)
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Non-linear association between androgen receptor CAG and GGN repeat lengths and reproductive parameters in fertile European and Inuit men.
- 2013
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Ingår i: Molecular and Cellular Endocrinology. - : Elsevier BV. - 1872-8057 .- 0303-7207. ; 370:1-2, s. 163-171
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Tidskriftsartikel (refereegranskat)abstract
- Recently the dogma that there is an inverse linear association between androgen receptor (AR) CAG and GGN polymorphisms and receptor activity has been challenged. We analysed the pattern of association between 21 male reproductive phenotypes and AR CAG/GGN repeat lengths in 557 proven-fertile men. A linear association was only found between sperm DNA fragmentation index (DFI) and CAG length, and between inhibin B and GGN length. Men with longer CAG then the reference (22-24), had higher oestradiol levels, whereas men with shorter CAG stretches had a higher DFI and a higher proportion of Fas-positive germ cells. Subjects with either short or long CAG had increased seminal levels of prostate-specific antigen and neutral α-glucosidase activity. Compared to men with the median GGN length of 23, those with shorter GGN repeats had higher levels of inhibin B, higher proportions of normal and progressive sperm, and a higher fraction of Fas-positive sperm, while men with longer GGN had higher oestradiol levels. These data indicate that at least for some markers of male reproductive function the association with CAG or GGN repeat length is curvilinear.
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| 3. |
- Groop, Leif, et al.
(författare)
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Genetics of diabetes - Are we missing the genes or the disease?
- 2013
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Ingår i: Molecular and Cellular Endocrinology. - : Elsevier BV. - 1872-8057 .- 0303-7207.
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Tidskriftsartikel (refereegranskat)abstract
- Diabetes is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. The chronic hyperglycemia of diabetes is associated with long-term damage, dysfunction, and failure of different organs, especially the eyes, kidneys, nerves, heart, and blood vessels. Several pathogenic processes are involved in the development of diabetes. These range from autoimmune destruction of the beta-cells of the pancreas with consequent insulin deficiency to abnormalities that result in resistance to insulin action (American Diabetes Association, 2011). The vast majority of cases of diabetes fall into two broad categories. In type 1 diabetes (T1D), the cause is an absolute deficiency of insulin secretion, whereas in type 2 diabetes (T2D), the cause is a combination of resistance to insulin action and an inadequate compensatory insulin secretory response. However, the subdivision into two main categories represents a simplification of the real situation, and research during the recent years has shown that the disease is much more heterogeneous than a simple subdivision into two major subtypes assumes. Worldwide prevalence figures estimate that there are 280 million diabetic patients in 2011 and more than 500 million in 2030 (http://www.diabetesatlas.org/). In Europe, about 6-8% of the population suffer from diabetes, of them about 90% has T2D and 10% T1D, thereby making T2D to the fastest increasing disease in Europe and worldwide. This epidemic has been ascribed to a collision between the genes and the environment. While our knowledge about the genes is clearly better for T1D than for T2D given the strong contribution of variation in the HLA region to the risk of T1D, the opposite is the case for T2D, where our knowledge about the environmental triggers (obesity, lack of exercise) is much better than the understanding of the underlying genetic causes. This lack of knowledge about the underlying genetic causes of diabetes is often referred to as missing heritability (Manolio et al., 2009) which exceeds 80% for T2D but less than 25% for T1D. In the following review, we will discuss potential sources of this missing heritability which also includes the possibility that our definition of diabetes and its subgroups is imprecise and thereby making the identification of genetic causes difficult.
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| 4. |
- Ingeson-Carlsson, Camilla, et al.
(författare)
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Switching from MAPK-dependent to MAPK-independent repression of the sodium-iodide symporter in 2D and 3D cultured normal thyroid cells.
- 2013
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Ingår i: Molecular and cellular endocrinology. - : Elsevier BV. - 1872-8057 .- 0303-7207. ; 381:1-2, s. 241-54
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Tidskriftsartikel (refereegranskat)abstract
- Loss of sodium-iodide symporter (NIS) expression in thyroid tumour cells primarily caused by constitutive MAPK pathway activation is often refractory to small molecule MAPK inhibitors. Suggested mechanisms are rebound MAPK signalling and activation of alternative signalling pathways. Here we provide evidence that failure to recover down-regulated NIS by MEK inhibition is not specific to tumour cells. NIS mRNA levels remained repressed in TSH-stimulated primary thyroid cells co-treated with epidermal growth factor (EGF) and pan-MEK inhibitor U0126 in the presence of 5% fetal bovine serum or, independently of serum, in 3D cultured thyroid follicles. This led to inhibited iodide transport and iodination. In contrast, U0126 restituted thyroglobulin synthesis in EGF-treated follicular cells. Serum potentiated TSH-stimulated NIS expression in 2D culture. U0126 blocked down-regulation of NIS only in serum-starved cells with a diminished TSH response. Together, this suggests that morphogenetic signals modify the expression of NIS and recovery response to MEK inhibition.
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| 6. |
- Meidute, Sandra, et al.
(författare)
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GPR40 protein levels are crucial to the regulation of stimulated hormone secretion in pancreatic islets. Lessons from spontaneous obesity-prone and non-obese type 2 diabetes in rats.
- 2013
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Ingår i: Molecular and Cellular Endocrinology. - : Elsevier BV. - 1872-8057 .- 0303-7207. ; 381:1-2, s. 150-159
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Tidskriftsartikel (refereegranskat)abstract
- The role of islet GPR40 protein in the pathogenesis of diabetes is unclear. We explored the influence of GPR40 protein levels on hormone secretion in islets from two rat models of spontaneous type 2 diabetes displaying either hyperlipidaemia or hyperglycaemia. GPR40 expression was analysed by confocal microscopy, Western blot and qPCR in islets from preobese Zucker (fa/fa) rats, diabetic Goto-Kakizaki (GK) rats, and controls. Confocal microscopy of control islets showed expression of GPR40 protein in insulin, glucagon and somatostatin cells. GPR40 expression was strongly increased in islets of hyperlipidaemic fa/fa rats and coincided with a concentration-related increase in palmitate-induced release of insulin and glucagon and its inhibition of somatostatin release. Conversely, hyperglycaemic GK islets displayed an extremely faint expression of GPR40 as did high-glucose-cultured control islets. This was reflected in abolished palmitate-induced hormone response in GK islets and high-glucose-cultured control islets. The palmitate antagonist rosiglitazone promoted reappearance of GPR40 in high-glucose-cultured islets and served as partial agonist in glucose-stimulated insulin release. GPR40 protein is abundantly expressed in pancreatic islets and modulates stimulated hormone secretion. Mild hyperlipidaemia in obesity-prone diabetes creates increased GPR40 expression and increased risk for an exaggerated palmitate-induced insulin response and lipotoxicity, a metabolic situation suitable for GPR40 antagonist treatment. Chronic hyperglycaemia creates abrogated GPR40 expression and downregulated insulin release, a metabolic situation suitable for GPR40 agonist treatment to avoid glucotoxicity. GPR40 protein is interactively modulated by both free fatty acids and glucose and is a promising target for pharmacotherapy in different variants of type 2 diabetes.
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| 7. |
- Nerstedt, Annika, 1960, et al.
(författare)
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Pharmacological activation of AMPK suppresses inflammatory response evoked by IL-6 signalling in mouse liver and in human hepatocytes
- 2013
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Ingår i: Molecular and Cellular Endocrinology. - : Elsevier BV. - 0303-7207. ; 375:1-2, s. 68-78
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Tidskriftsartikel (refereegranskat)abstract
- Interleukin-6 (IL-6) induces inflammatory signalling in liver, leading to impaired insulin action in hepatocytes. In this study, we demonstrate that pharmacological activation of AMP-activated protein kinase (AMPK) represses IL-6-stimulated expression of proinflammatory markers serum amyloid A (Saa) as well as suppressor of cytokine signalling 3 (Socs3) in mouse liver. Further studies using the human hepatocellular carcinoma cell line HepG2 suggest that AMPK inhibits IL-6 signalling by repressing IL-6-stimulated phosphorylation of several downstream components of the pathway such as Janus kinase 1 (JAK1), SH2-domain containing protein tyrosine phosphatase 2 (SHP2) and signal transducer and activator of transcription 3 (STAT3). In summary, inhibition of IL-6 signalling cascade in liver by the metabolic master switch of the body, AMPK, supports the role of this kinase as a crucial point of convergence of metabolic and inflammatory pathways in hepatocytes.
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| 8. |
- Pereira, Maria J, 1981, et al.
(författare)
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The immunosuppressive agents rapamycin, cyclosporin A and tacrolimus increase lipolysis, inhibit lipid storage and alter expression of genes involved in lipid metabolism in human adipose tissue.
- 2013
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Ingår i: Molecular and cellular endocrinology. - : Elsevier BV. - 1872-8057 .- 0303-7207. ; 365:2, s. 260-9
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Tidskriftsartikel (refereegranskat)abstract
- Cyclosporin A (CsA), tacrolimus and rapamycin are immunosuppressive agents (IAs) associated with insulin resistance and dyslipidemia, although their molecular effects on lipid metabolism in adipose tissue are unknown. We explored IAs effects on lipolysis, lipid storage and expression of genes involved on lipid metabolism in isolated human adipocytes and/or adipose tissue obtained via subcutaneous and omental fat biopsies. CsA, tacrolimus and rapamycin increased isoproterenol-stimulated lipolysis and inhibited lipid storage by 20-35% and enhanced isoproterenol-stimulated hormone-sensitive lipase Ser552 phosphorylation. Rapamycin also increased basal lipolysis (∼20%) and impaired insulin's antilipolytic effect. Rapamycin, down-regulated the gene expression of perilipin, sterol regulatory element-binding protein 1 (SREBP1) and lipin 1, while tacrolimus down-regulated CD36 and aP2 gene expression. All three IAs increased IL-6 gene expression and secretion, but not expression and secretion of TNF-α or adiponectin. These findings suggest that CsA, tacrolimus and rapamycin enhance lipolysis, inhibit lipid storage and expression of lipogenic genes in adipose tissue, which may contribute to the development of dyslipidemia and insulin resistance associated with immunosuppressive therapy.
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| 9. |
- Stener-Victorin, Elisabet, 1964
(författare)
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Hypothetical physiological and molecular basis for the effect of acupuncture in the treatment of polycystic ovary syndrome
- 2013
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Ingår i: Molecular and Cellular Endocrinology. - : Elsevier BV. - 0303-7207. ; 373:1-2, s. 83-90
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Tidskriftsartikel (refereegranskat)abstract
- Clinical and experimental evidence indicates that acupuncture may be a safe alternative or complement in the treatment of endocrine and reproductive function in women with polycystic ovary syndrome (PCOS). This review describes potential etiological factors of PCOS with the aim to support potential mechanism of action of acupuncture to relieve PCOS related symptoms. The theory that increased sympathetic activity contributes to the development and maintenance of PCOS is presented, and that the effects of acupuncture are, at least in part, mediated by modulation of sympathetic outflow. While there are no relevant randomized controlled studies on the use of acupuncture to treat metabolic abnormalities in women with PCOS, a number of experimental studies indicate that acupuncture may improve metabolic dysfunction. For each aspect of PCOS, it is important to pursue new treatment strategies that have fewer negative side effects than drug treatments, as women with PCOS often require prolonged treatment. (C) 2013 Elsevier Ireland Ltd. All rights reserved.
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