| 1. |
- 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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| 4. |
- Ahmed, Fozia, et al.
(författare)
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Role of Estrogen and Its Receptors in Adipose Tissue Glucose Metabolism in Pre- and Postmenopausal Women
- 2022
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : Endocrine Society. - 0021-972X .- 1945-7197. ; 107:5, s. E1879-E1889
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Tidskriftsartikel (refereegranskat)abstract
- Context: Reduced estrogen levels in postmenopausal women predispose them to metabolic side effects, including insulin resistance and type 2 diabetes; however, the cellular mechanisms are not well understood.Objective: This work aimed to study the expression of estrogen receptors in adipose tissue from pre- and postmenopausal women and the effects of estradiol (E2) on glucose uptake of adipocytes.Methods: Subcutaneous (SAT) and visceral adipose tissue (VAT) obtained from pre- and postmenopausal women (19-51 and 46-75 years old, respectively) were used to measure gene expression of ESR1 and ESR2. SAT tissue was incubated with E2, and glucose uptake and estrogen receptor levels were measured. Polymorphisms in ESR1 and ESR2 were addressed in public databases to identify single nucleotide polymorphisms associated with metabolic traits.Results: ESR2 expression was lower in pre- vs postmenopausal women, corresponding to lower ESR1:ESR2 gene expression ratio in postmenopausal women. In premenopausal women, the expression of ESR1 was higher in VAT than in SAT. In both pre- and postmenopausal women, ESR2 expression was lower in VAT than in SAT. In late, but not pre- or early postmenopausal women, E2 reduced glucose uptake and GLUT4 protein and increased expression of ESR2. ESR1 polymorphisms were associated with weight, body fat distribution, and total cholesterol, and ESR2 polymorphisms were associated with total cholesterol and triglyceride levels and with body fat percentage.Conclusion: E2 inhibits glucose utilization in human adipocytes in late postmenopausal women. Changes in glucose utilization over time since menopause may be explained by a lower ESR1:ESR2 ratio. This can have clinical implications on the timing of estrogen treatment in postmenopausal women.
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| 5. |
- Boersma, Greta J., et al.
(författare)
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Altered Glucose Uptake in Muscle, Visceral Adipose Tissue, and Brain Predict Whole-Body Insulin Resistance and may Contribute to the Development of Type 2 Diabetes: A Combined PET/MR Study
- 2018
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Ingår i: Hormone and Metabolic Research. - : Georg Thieme Verlag KG. - 0018-5043 .- 1439-4286. ; 50:8
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Tidskriftsartikel (refereegranskat)abstract
- We assessed glucose uptake in different tissues in type 2 diabetes (T2D), prediabetes, and control subjects to elucidate its impact in the development of whole-body insulin resistance and T2D. Thirteen T2D, 12 prediabetes, and 10 control subjects, matched for age and BMI, underwent OGTT and abdominal subcutaneous adipose tissue (SAT) biopsies. Integrated whole-body 18F-FDG PET and MRI were performed during a hyperinsulinemic euglycemic clamp to asses glucose uptake rate (MRglu) in several tissues. MRglu in skeletal muscle, SAT, visceral adipose tissue (VAT), and liver was significantly reduced in T2D subjects and correlated positively with M-values (r = 0.884, r = 0.574, r = 0.707 and r = 0.403, respectively). Brain MRglu was significantly higher in T2D and prediabetes subjects and had a significant inverse correlation with M-values (r = -0.616). Myocardial MRglu did not differ between groups and did not correlate with the M-values. A multivariate model including skeletal muscle, brain and VAT MRglu best predicted the M-values (adjusted r2 = 0.85). In addition, SAT MRglu correlated with SAT glucose uptake ex vivo (r = 0.491). In different stages of the development of T2D, glucose uptake during hyperinsulinemia is elevated in the brain in parallel with an impairment in peripheral organs. Impaired glucose uptake in skeletal muscle and VAT together with elevated glucose uptake in brain were independently associated with whole-body insulin resistance, and these tissue-specific alterations may contribute to T2D development.
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| 8. |
- Ferreira, Vitor, et al.
(författare)
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Modulation of hypothalamic AMPK phosphorylation by olanzapine controls energy balance and body weight
- 2022
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Ingår i: Metabolism. - : Elsevier. - 0026-0495 .- 1532-8600. ; 137
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Tidskriftsartikel (refereegranskat)abstract
- Background: Second-generation antipsychotics (SGAs) are a mainstay therapy for schizophrenia. SGA-treated patients present higher risk for weight gain, dyslipidemia and hyperglycemia. Herein, we evaluated the effects of olanzapine (OLA), widely prescribed SGA, in mice focusing on changes in body weight and energy balance. We further explored OLA effects in protein tyrosine phosphatase-1B deficient (PTP1B-KO) mice, a preclinical model of leptin hypersensitivity protected against obesity. Methods: Wild-type (WT) and PTP1B-KO mice were fed an OLA-supplemented diet (5 mg/kg/day, 7 months) or treated with OLA via intraperitoneal (i.p.) injection or by oral gavage (10 mg/kg/day, 8 weeks). Readouts of the crosstalk between hypothalamus and brown or subcutaneous white adipose tissue (BAT and iWAT, respectively) were assessed. The effects of intrahypothalamic administration of OLA with adenoviruses expressing constitutive active AMPK alpha 1 in mice were also analyzed. Results: Both WT and PTP1B-KO mice receiving OLA-supplemented diet presented hyperphagia, but weight gain was enhanced only in WT mice. Unexpectedly, all mice receiving OLA via i.p. lost weight without changes in food intake, but with increased energy expenditure (EE). In these mice, reduced hypothalamic AMPK phosphorylation concurred with elevations in UCP-1 and temperature in BAT. These effects were also found by intrahypothalamic OLA injection and were abolished by constitutive activation of AMPK in the hypothalamus. Additionally, OLA i. p. treatment was associated with enhanced Tyrosine Hydroxylase (TH)-positive innervation and less sympathetic neuron-associated macrophages in iWAT. Both central and i.p. OLA injections increased UCP-1 and TH in iWAT, an effect also prevented by hypothalamic AMPK activation. By contrast, in mice fed an OLA-supplemented diet, BAT thermogenesis was only enhanced in those lacking PTP1B. Our results shed light for the first time that a threshold of OLA levels reaching the hypothalamus is required to activate the hypothalamus BAT/iWAT axis and, therefore, avoid weight gain. Conclusion: Our results have unraveled an unexpected metabolic rewiring controlled by hypothalamic AMPK that avoids weight gain in male mice treated i.p. with OLA by activating BAT thermogenesis and iWAT browning and a potential benefit of PTP1B inhibition against OLA-induced weight gain upon oral treatment.
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| 10. |
- Katsogiannos, Petros, et al.
(författare)
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Early Changes in Adipose Tissue Morphology, Gene Expression, and Metabolism After RYGB in Patients With Obesity and T2D
- 2019
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 104:7, s. 2601-2613
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Tidskriftsartikel (refereegranskat)abstract
- Context: Roux-en-Y gastric bypass (RYGB) surgery effectively prevents or treats type 2 diabetes (T2D). Adipose tissue (AT) mechanisms may be of importance.Objective: To assess the relationship between early changes in whole-body and AT metabolism in surgically treated patients with T2D.Design and Setting: A randomized single-center study.Patients: Nineteen patients with T2D with body mass index 30 to 45 kg/m(2).Interventions: Thirteen patients were assessed at baseline and 4 and 24 weeks after RYGB (preceded by a 4-week low-calorie diet) and compared with 6 control patients continuing standard medical treatment: oral glucose tolerance test, subcutaneous AT biopsies for gene expression, adipocyte size, glucose uptake, lipolysis, and insulin action.Results: At 4 and 24 weeks post-RYGB, all patients but one had stopped diabetes medication. Fasting glucose, HbA(1c), and insulin levels decreased and the Matsuda index increased compared with baseline (P < 0.01 for all), indicating improved whole-body insulin sensitivity. Mean adipocyte size significantly reduced, more at 4 than at 24 weeks; at 4 weeks, glucose uptake per adipocyte was lowered, and isoproterenol-stimulated lipolysis tended to increase, whereas the fold insulin effects on glucose uptake and lipolysis were unchanged. Expression of genes involved in fatty acid oxidation, CPT1b and adiponectin, was increased at 4 weeks, whereas leptin and E2F1 (involved in cell proliferation) were reduced (P < 0.05 for all).Conclusion: Glycemic control and in vivo insulin sensitivity improved 4 weeks after RYGB, but adipocyte insulin sensitivity did not change despite a marked reduction in adipocyte size. Thus, mechanisms for a rapid improvement of T2D after RYGB may occur mainly in other tissues than adipose.
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