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- Lopes, P., et al.
(författare)
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Effects of Cyclosporine and Sirolimus on Insulin-Stimulated Glucose Transport and Glucose Tolerance in a Rat Model
- 2013
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Ingår i: Transplantation Proceedings. - : Elsevier BV. - 0041-1345 .- 1873-2623. ; 45:3, s. 1142-1148
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Tidskriftsartikel (refereegranskat)abstract
- Cyclosporine (CsA) and sirolimus (SRL) have been associated with undesirable side effects, including posttransplantation diabetes and hyperlipidemia, but the molecular mechanisms underlying these effects remain to be elucidated. Animal studies focusing on clinically relevant doses are advised. This study sought to compare the metabolic effects on isolated rat adipocytes treated with either CsA or SRL ex vivo and after long-term in vivo treatment in Wistar rats. We assessed the ex vivo effects of CsA (0.5–30 μmol/L) and SRL (1–250 μmol/L) on insulin-stimulated 14C-glucose uptake in epididymal adipocytes (n = 6–9). In parallel, rats (n = 12) were treated with either vehicle, CsA (5 mg/kg/d) or SRL (1 mg/kg/d) for either 3 or 9 weeks. At the end of the treatment, glucose tolerance test (GTT) and insulin-stimulated 14C-glucose uptake as well as biochemical parameters were analyzed. A significant reduction in the insulin-stimulated glucose uptake over basal was observed among isolated adipocytes, whether exposed ex vivo or in vivo to CsA or SRL treatment. Furthermore, the SRL group showed significantly lighter fat pads and smaller adipocytes at 3 weeks with a smaller gain in body weight throughout the study compared with either the vehicle or CsA cohorts. Glucose intolerance was observed after a GTT, at the end of the treatment with either drug. Additionally, at 9 weeks serum triglycerides were increased by CsA compared with vehicle or SRL treatment. Interestingly, although SRL-treated animals presented higher fed and fasted insulin levels compared with either group, suggesting insulin resistance, the CsA group presented lower fed and fasted insulin values, suggesting a defect in insulin secretion at 9 weeks. These results suggested that either ex vivo treatment of fat cells or in vivo treatment of rats with CsA or SRL impaired insulin-stimulated glucose uptake by adipocytes. Both drugs caused glucose intolerance, which altogether could be responsible for the development of posttransplantation diabetes. The introduction of calcineurin inhibitors, like cyclosporine (CsA), has been important to save lives and improve the safety of organ transplantations. However, the use of these drugs is followed by the emergence of a number of side effects that impact the patient's quality of life. One of the most important is new-onset diabetes mellitus after transplantation (NODAT),1, 2 and 3 which is usually associated with an increased risk of cardiovascular diseases and consequently decreased patient survival.3, 4 and 5 CsA, a peptide of fungal origin, CsA, forms a complex with cyclophilins, which then inhibits calcineurin, preventing the movement of transcription factors into the nucleus, thus blocking interleukin (IL)-2 production and, consequently, proliferation and differentiation of T cells.6 and 7 Studies on purified islets and insulin-producing beta cells have proposed various diabetogenic actions of CsA. Therefore, CsA decreases insulin content of the beta cell, reversibly inhibiting insulin gene transcription and ultimately insulin secretion,8 although the mechanisms that lead to these effects are not well understood.
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| 2. |
- Pereira, Maria J, 1981-, et al.
(författare)
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FKBP5 expression in human adipose tissue increases following dexamethasone exposure and is associated with insulin resistance
- 2014
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Ingår i: Metabolism: Clinical and Experimental. - : Elsevier BV. - 0026-0495 .- 1532-8600. ; 63:9, s. 1198-1208
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Tidskriftsartikel (refereegranskat)abstract
- Objective To study effects of dexamethasone on gene expression in human adipose tissue aiming to identify potential novel mechanisms for glucocorticoid-induced insulin resistance. Materials/methods Subcutaneous and omental adipose tissue, obtained from non-diabetic donors (10 M/15 F; age: 28-60 years; BMI: 20.7-30.6 kg/m2), was incubated with or without dexamethasone (0.003-3 μmol/L) for 24 h. Gene expression was assessed by microarray and real time-PCR and protein expression by immunoblotting. Results FKBP5 (FK506-binding protein 5) and CNR1 (cannabinoid receptor 1) were the most responsive genes to dexamethasone in both subcutaneous and omental adipose tissue (~ 7-fold). Dexamethasone increased FKBP5 gene and protein expression in a dose-dependent manner in both depots. The gene product, FKBP51 protein, was 10-fold higher in the omental than in the subcutaneous depot, whereas the mRNA levels were similar. Higher FKBP5 gene expression in omental adipose tissue was associated with reduced insulin effects on glucose uptake in both depots. Furthermore, FKBP5 gene expression in subcutaneous adipose tissue was positively correlated with serum insulin, HOMA-IR and subcutaneous adipocyte diameter and negatively with plasma HDL-cholesterol. FKBP5 SNPs were found to be associated with type 2 diabetes and diabetes-related phenotypes in large population-based samples. Conclusions Dexamethasone exposure promotes expression of FKBP5 in adipose tissue, a gene that may be implicated in glucocorticoid-induced insulin resistance. © 2014 Elsevier Inc.
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| 3. |
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| 4. |
- 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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| 5. |
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| 6. |
- Pereira, Maria J, 1981
(författare)
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Effects of immunosuppressive drugs on human adipose tissue metabolism
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The immunosuppressive agents (IAs) rapamycin, cyclosporin A and tacrolimus, as well as glucocorticoids are used to prevent rejection of transplanted organs and to treat autoimmune disorders. Despite their desired action on the immune system, these agents have serious long-term metabolic side-effects, including dyslipidemia and new onset diabetes mellitus after transplantation. The overall aim is to study the effects of IAs on human adipose tissue glucose and lipid metabolism, and to increase our understanding of the molecular mechanisms underlying the development of insulin resistance during immunosuppressive therapy. In Paper I and II, it was shown that rapamycin and the calcineurin inhibitors, cyclosporin A and tacrolimus, at therapeutic concentrations, had a concentration-dependent inhibitory effect on basal and insulin-stimulated glucose uptake in human subcutaneous and omental adipocytes. Rapamycin inhibited mammalian target of rapamycin complex (mTORC) 1 and 2 assembly and phosphorylation of protein kinase B (PKB) at Ser473 and of the PKB substrate AS160, and this leads to impaired insulin signalling (Paper I). On the other hand, cyclosporin A and tacrolimus had no effects on expression or phosphorylation of insulin signalling proteins (insulin receptor substrate 1 and 2, PKB, AS160), as well as the glucose transport proteins, GLUT4 and GLUT1 (Paper II). Instead, removal of GLUT4 from the cell surface was observed, probably mediated through increased endocytosis, as shown in L6 muscle-derived cells. These studies suggest a different mechanism for cyclosporin A and tacrolimus, in comparison to rapamycin, with respect to impairment of glucose uptake in adipocytes. In Paper III, all three IAs increased isoproterenol-stimulated lipolysis and enhanced phosphorylation of one of the main lipases involved in lipolysis, hormone-sensitive lipase. The agents also inhibited lipid storage, and tacrolimus and rapamycin down-regulated gene expression of lipogenic genes in adipose tissue. All three IAs increased interleukin-6 (IL-6), but not tumor necrosis factor α (TNF-alpha) or adiponectin, gene expression and secretion. In Paper IV, we proposed that FKBP5 is a novel gene regulated by dexamethasone, a synthetic glucocorticoid, in both subcutaneous and omental adipose tissue. FKBP5 expression in subcutaneous adipose tissue is correlated with clinical and biochemical markers of insulin resistance and adiposity. In addition, the FKBP5 gene product was more abundant in omental than in subcutaneous adipose tissue. In conclusion, adverse effects of immunosuppressive drugs on human adipose tissue glucose and lipid metabolism can contribute to the development of insulin resistance, type 2 diabetes and dyslipidemia in patients on immunosuppressive therapy. The cellular mechanisms that are described in this thesis should be further explored in order to mitigate the metabolic perturbations caused by current immunosuppressive therapies. The findings in this thesis could potentially also provide novel pharmacological mechanisms for type 2 diabetes as well as other forms of diabetes.
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| 7. |
- Svensson, Per-Arne, 1969, et al.
(författare)
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The TGR5 gene is expressed in human subcutaneous adipose tissue and is associated with obesity,Weight loss and resting metabolic rate
- 2013
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Ingår i: Biochemical and Biophysical Research Communications - BBRC. - : Elsevier BV. - 0006-291X .- 1090-2104. ; 433:4, s. 563-566
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Tidskriftsartikel (refereegranskat)abstract
- Bile acids have emerged as a new class of signaling molecules that play a role in metabolism. Studies in mice have shown that the bile acid receptor TGR5 mediates several of these effects but the metabolic function of TGR5 in humans is less well established. Here we show that human adipose tissue TGR5 expression is positively correlated to obesity and reduced during diet-induced weight loss. Adipose tissue TGR5 expression was also positively correlated to resting metabolic rate. Our study indicates that human adipose tissue contributes to the TGR5 mediated metabolic effects of bile acids and plays a role in energy expenditure. (C) 2013 Elsevier Inc. All rights reserved.
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