| 11. |
- Planck, Tereza, et al.
(författare)
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COX-2 and SCD, markers of inflammation and adipogenesis, are related to disease activity in Graves' ophthalmopathy
- 2007
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Ingår i: Thyroid. - : Mary Ann Liebert Inc. - 1557-9077 .- 1050-7256. ; 17:6, s. 511-517
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Tidskriftsartikel (refereegranskat)abstract
- Context: Inflammation and adipogenesis are two parallel processes with increased activity in severe Graves' ophthalmopathy. Objective: The aim of this work was to define target genes for therapeutic intervention in adipogenesis and inflammation in Graves' ophthalmopathy. Design: Orbital tissue was obtained from patients with ophthalmopathy in acute or chronic phase undergoing orbital surgery to study gene expression followed by the study of potential intervention mechanisms in preadipocytes. Setting: Clinic of Endocrinology, University Hospital, Malmo, Sweden. Participants: Patients in acute severe or in chronic phase of ophthalmopathy. Interventions: Lateral orbital decompression in acute phase and restorative surgery in chronic phase. In vitro treatment of preadipocytes with rosiglitazone and diclofenac. Main outcome measure: Gene expression in intraorbital tissue or preadipocytes and differentiation of preadipocytes. Results: A marker of adipose tissue, stearoyl-coenzyme A desaturase (SCD), and the proinflammatory gene, cyclooxygenase-2 (COX-2), were overexpressed in patients in active phase compared to the chronic phase of ophthalmopathy. In growth-arrested preadipocytes stimulated with rosiglitazone, COX-2 expression increased temporarily within 1 hour and decreased to undetectable levels after 48 hours. In contrast, SCD and peroxisome proliferator-activated receptor-gamma (PPAR-gamma) expression increased continuously from day 2 to day 7 during adipogenesis. Diclofenac, an inhibitor of cyclooxygenases with antagonistic effects on PPAR-gamma, reduced the number of mature adipocytes by approximately 50%. Conclusion: We conclude that inflammation and adipogenesis decrease with a decrease in activity of ophthalmopathy and that the nonsteroidal antiinflammatory drug diclofenac inhibits adipogenesis. This may represent a putative future treatment of endocrine ophthalmopathy.
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| 12. |
- Planck, Tereza, et al.
(författare)
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Gene Expression in Graves' Ophthalmopathy and Arm Lymphedema: Similarities and Differences.
- 2011
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Ingår i: Thyroid. - : Mary Ann Liebert Inc. - 1557-9077 .- 1050-7256. ; 21, s. 663-674
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Tidskriftsartikel (refereegranskat)abstract
- Background: Graves' ophthalmopathy (GO) and lymphedema share some pathogenetic mechanisms, such as edema, inflammation, and adipogenesis. The aim of this study was to examine similarities and differences between chronic GO and chronic lymphedema. Methods: Intraorbital adipose tissue was collected from patients with active (n = 10) or chronic GO (n = 10) and thyroid-healthy controls (n = 10). Arm subcutaneous adipose tissue was obtained from patients with chronic arm lymphedema (n = 10), where the unaffected arm served as a control. Gene expression was studied using microarray and real-time polymerase chain reaction. Results: The following genes were significantly upregulated (p < 0.05) in lymphedema but not in GO and have functions in wound healing, fibrosis, fat metabolism, inflammation, differentiation, development, adhesion, and the cytoskeleton: ATP-binding cassette, sub-family G (WHITE), member 1 (ABCG1), actin, alpha 2, smooth muscle, aorta (ACTA2), secreted frizzled-related protein 2 (SFRP2), tenascin C (TNC), pentraxin-related gene, rapidly induced by IL-1 beta (PTX3), and carboxypeptidase X (M14 family), member 1 (CPMX1). In chronic GO, but not in lymphedema, adipocyte-related immediate early genes known to be overexpressed in patients with active GO were upregulated but at a lower level than previously shown for the active phase. Genes of the Wnt pathway, such as secreted frizzled-related protein 1, 2, and 3, were up- and downregulated in both chronic GO and lymphedema. Parathyroid hormone-like hormone (PTHLH) was downregulated (p = 0.01) and apolipoprotein L domain containing 1 (APOLD1) was upregulated (p = 0.05) in both active and chronic GO. Conclusions: There are more differences than similarities between chronic ophthalmopathy and chronic lymphedema, but both conditions exhibit less inflammation and adipogenesis compared to the active phases. In lymphedema, fibrosis dominates. PTHLH, which can inhibit adipogenesis, is downregulated both in active and chronic ophthalmopathy, indicating the possibility of an increased risk of adipogenesis.
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| 13. |
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| 14. |
- Saxena, Richa, et al.
(författare)
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Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels
- 2007
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 1095-9203 .- 0036-8075. ; 316:5829, s. 1331-1336
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Tidskriftsartikel (refereegranskat)abstract
- New strategies for prevention and treatment of type 2 diabetes (T2D) require improved insight into disease etiology. We analyzed 386,731 common single-nucleotide polymorphisms (SNPs) in 1464 patients with T2D and 1467 matched controls, each characterized for measures of glucose metabolism, lipids, obesity, and blood pressure. With collaborators (FUSION and WTCCC/UKT2D), we identified and confirmed three loci associated with T2D - in a noncoding region near CDKN2A and CDKN2B, in an intron of IGF2BP2, and an intron of CDKAL1 - and replicated associations near HHEX and in SLC30A8 found by a recent whole-genome association study. We identified and confirmed association of a SNP in an intron of glucokinase regulatory protein (GCKR) with serum triglycerides. The discovery of associated variants in unsuspected genes and outside coding regions illustrates the ability of genome-wide association studies to provide potentially important clues to the pathogenesis of common diseases.
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| 15. |
- Shaat, Nael, et al.
(författare)
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A variant in the transcription factor 7-like 2 (TCF7L2) gene is associated with an increased risk of gestational diabetes mellitus.
- 2007
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 50:5, s. 972-979
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis Genetic and epidemiological studies suggest an association between gestational diabetes mellitus and type 2 diabetes. Both are polygenic multifactorial disorders characterised by beta cell dysfunction and insulin resistance. Our aim was to investigate whether common genetic variants that have previously been associated with type 2 diabetes or related phenotypes would also confer risk for gestational diabetes mellitus. Materials and methods In 1,881 unrelated pregnant Scandinavian women (649 women with gestational diabetes mellitus, 1,232 non-diabetic control subjects) we genotyped the transcription factor 7-like 2 (TCF7L2 rs7903146), adiponectin (ADIPOQ +276G>T), peroxisome-proliferator activated receptor, gamma 2 (PPARG Pro12Ala), PPARGcoactivator, 1 alpha (PPARGC1A Gly482Ser), forkhead box C2 (FOXC2 −512C>T) and β3-adrenergic receptor (ADRB3 Trp64Arg) polymorphisms using TaqMan allelic discrimination assay or RFLP. Results The CC, CT and TT genotype frequencies of the TCF7L2 rs7903146 variant differed significantly between women with gestational diabetes mellitus and control women (46.3, 43.6 and 10.1% vs 58.5, 35.3 and 6.2%, p=3.7×10−6, corrected p value [Pc] for multiple testing Pc=2.2×10−5). The T-allele was associated with an increased risk of gestational diabetes mellitus (odds ratio 1.49 [95% CI 1.28–1.75], p=4.9×10−7 [Pc=2.8×10−6]). Compared with wild-type CC-genotype carriers, heterozygous (CT-genotype) and homozygous (TT-genotype) carriers had a 1.6-fold (95% CI 1.26–1.93, p=3.7×10−5 [Pc=0.0002]) and a 2.1-fold (95% CI 1.41–2.99, p=0.0001 [Pc=0.0008]) increased risk of gestational diabetes mellitus, respectively. The other polymorphisms studied were not significantly associated with gestational diabetes mellitus (ADIPOQ +276G>T: 1.17 [1.01–1.36], p=0.039 [Pc=0.23]; PPARG Pro12Ala: 1.06 [0.87–1.29], p=0.53; PPARGC1A Gly482Ser: 0.96 [0.83–1.10], p=0.54; FOXC2 −512C>T: 1.01 [0.87–1.16], p=0.94; and ADRB3 Trp64Arg: 1.22 [0.95–1.56], p=0.12). Conclusions/interpretation The TCF7L2 rs7903146 variant is associated with an increased risk of gestational diabetes mellitus in Scandinavian women.
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| 16. |
- Shaat, Nael, et al.
(författare)
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Common variants in MODY genes increase the risk of gestational diabetes mellitus.
- 2006
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 49:7, s. 1545-1551
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis Impaired beta cell function is the hallmark of gestational diabetes mellitus (GDM) and MODY. In addition, women with MODY gene mutations often present with GDM, but it is not known whether common variants in MODY genes contribute to GDM. Subjects and methods We genotyped five common variants in the glucokinase (GCK, commonly known as MODY2), hepatocyte nuclear factor 1-α (HNF1A, commonly known as MODY3) and 4-α (HNF4A commonly known as MODY1) genes in 1,880 Scandinavian women (648 women with GDM and 1,232 pregnant non-diabetic control women). Results The A allele of the GCK −30G→A polymorphism was more common in GDM women than in control subjects (odds ratio [OR] 1.28 [95% CI 1.06−1.53], p=0.008, corrected p value, p=0.035). Under a recessive model [AA vs GA+GG], the OR increased further to 2.12 (95% CI 1.21−3.72, p=0.009). The frequency of the L allele of the HNF1A I27L polymorphism was slightly higher in GDM than in controls (1.16 [95% CI 1.001−1.34], p=0.048, corrected p value, p=0.17). However, the OR increased under a dominant model (LL+IL vs II; 1.31 [95% CI 1.08−1.60], p=0.007). The rs2144908, rs2425637 and rs1885088 variants, which are located downstream of the primary beta cell promoter (P2) of HNF4A, were not associated with GDM. Conclusions/interpretation The −30G→A polymorphism of the beta-cell-specific promoter of GCK and the I27L polymorphism of HNF1A seem to increase the risk of GDM in Scandinavian women.
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