| 1. |
- Eriksson, Jan W., et al.
(författare)
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Effects of dapagliflozin and n-3 carboxylic acids on non-alcoholic fatty liver disease in people with type 2 diabetes: a double-blind randomised placebo-controlled study
- 2018
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 61:9, s. 1923-1934
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis The EFFECT-II study aimed to investigate the effects of dapagliflozin and omega-3 (n-3) carboxylic acids (OM-3CA). individually or combined, on liver fat content in individuals with type 2 diabetes and non-alcoholic fatty liver disease (NAFLD). Methods This randomised placebo-controlled double-blind parallel-group study was performed at five clinical research centres at university hospitals in Sweden. 84 participants with type 2 diabetes and NAFLD were randomly assigned 1:1:1:1 to four treatments by a centralised randomisation system, and all participants as well as investigators and staff involved in the study conduct and analyses were blinded to treatments. Each group received oral doses of one of the following: 10 mg dapagliflozin (n = 21). 4 g OM3-CA (n = 20), a combination of both (n = 22) or placebo (n = 21). The primary endpoint was liver fat content assessed by MRI (proton density fat fraction [PDFF]) and, in addition, total liver volume and markers of glucose and lipid metabolism as well as of hepatocyte injury and oxidative stress were assessed at baseline and after 12 weeks of treatment (completion of the trial). Results Participants had a mean age of 65.5 years (SD 5.9), BMI 31.2 kg/m(2) (3.5) and liver PDFF 18% (9.3). All active treatments significantly reduced liver PDFF from baseline, relative changes: OM-3CA, -15%; dapagliflozin, -13%; OM-3CA + dapagliflozin, -21%. Only the combination treatment reduced liver PDFF (p = 0.046) and total liver fat volume (relative change, -24%,p = 0.037) in comparison with placebo. There was an interaction between the PNPLA31148M polymorphism and change in liver PDFF in the active treatment groups (p = 0.03). Dapagliflozin monotherapy, but not the combination with OM-3CA, reduced the levels of hepatocyte injury biomarkers, including alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transfcrase (gamma-GT), cytokeratin (CK) 18-M30 and CK 18-M65 and plasma fibroblast growth factor 21 (FGF21). Changes in gamma-GT correlated with changes in liver PDFF (rho = 0.53, p = 0.02). Dapagliflozin alone and in combination with OM-3CA improved glucose control and reduced body weight and abdominal fat volumes. Fatty acid oxidative stress biomarkers were not affected by treatments. There were no new or unexpected adverse events compared with previous studies with these treatments. Conclusions/interpretation Combined treatment with dapagliflozin and OM-3CA significantly reduced liver fat content. Dapagliflozin monotherapy reduced all measured hepatocyte injury biomarkers and FGF21, suggesting a disease-modifying effect in NAFLD.
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| 2. |
- Fryk, Emanuel, et al.
(författare)
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Microdialysis and proteomics of subcutaneous interstitial fluid reveals increased galectin-1 in type 2 diabetes patients
- 2016
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Ingår i: Metabolism-Clinical and Experimental. - : Elsevier BV. - 0026-0495 .- 1532-8600. ; 65:7, s. 998-1006
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Tidskriftsartikel (refereegranskat)abstract
- Objective. To identify a potential therapeutic target for type 2 diabetes by comparing the subcutaneous interstitial fluid from type 2 diabetes patients and healthy men. Methods. Proteomics was performed on the interstitial fluid of subcutaneous adipose tissue obtained by microdialysis from 7 type 2 diabetes patients and 8 healthy participants. 851 proteins were detected, of which 36 (including galectin-1) showed significantly altered expression in type 2 diabetes. We also measured galectin-1 expression in: (1) adipocytes isolated from adipose tissue biopsies from these participants; (2) subcutaneous adipose tissue of 24 obese participants before, during and after 16 weeks on a very low calorie diet (VLCD); and (3) adipocytes isolated from 6 healthy young participants after 4 weeks on a diet and lifestyle intervention to promote weight gain. We also determined the effect of galectin-1 on glucose uptake in human adipose tissue. Results. Galectin-1 protein levels were elevated in subcutaneous dialysates from type 2 diabetes compared with healthy controls (p < 0.05). In agreement, galectin-1 mRNA expression was increased in adipocytes from the type 2 diabetes patients (p < 0.05). Furthermore, galectin-1 mRNA expression was decreased in adipose tissue after VLCD (p < 0.05) and increased by overfeeding (p < 0.05). Co-incubation of isolated human adipocytes with galectin-1 reduced glucose uptake (p < 0.05) but this was independent of the insulin signal. Conclusion. Proteomics of the interstitial fluid in subcutaneous adipose tissue in vivo identified a novel adipokine, galectin-1, with a potential role in the pathophysiology of type 2 diabetes. (C) 2016 Elsevier Inc. All rights reserved.
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| 3. |
- Sjögren, Lovisa, et al.
(författare)
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Postprandial effects of the phosphodiesterase-5 inhibitor tadalafil in people with well-controlled Type 2 diabetes mellitus: a randomized controlled trial.
- 2016
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Ingår i: Diabetic medicine : a journal of the British Diabetic Association. - : Wiley. - 1464-5491. ; 33:9, s. 1299-1301
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Tidskriftsartikel (refereegranskat)abstract
- Type 2 diabetes mellitus is a serious global health problem that is hard to treat in the long term, prompting great efforts to find new drug targets. Little attention has been paid, however, to the metabolic significance of the microcirculation in insulin-sensitive tissues, despite the fact that microvascular insulin resistance and endothelial dysfunction are closely associated and have been shown to precede Type 2 diabetes [1]. Endothelial nitric oxide plays a major role in mediating the beneficial effects of insulin on capillary recruitment and muscle glucose uptake [2] and in suppression of inflammatory pathways, including those activated by a high-fat diet [3]. This article is protected by copyright. All rights reserved.
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| 4. |
- Volkov, Petr, et al.
(författare)
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A Genome-Wide mQTL Analysis in Human Adipose Tissue Identifies Genetic Variants Associated with DNA Methylation, Gene Expression and Metabolic Traits
- 2016
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 11:6
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Tidskriftsartikel (refereegranskat)abstract
- Little is known about the extent to which interactions between genetics and epigenetics may affect the risk of complex metabolic diseases and/or their intermediary phenotypes. We performed a genome-wide DNA methylation quantitative trait locus (mQTL) analysis in human adipose tissue of 119 men, where 592,794 single nucleotide polymorphisms (SNPs) were related to DNA methylation of 477,891 CpG sites, covering 99% of RefSeq genes. SNPs in significant mQTLs were further related to gene expression in adipose tissue and obesity related traits. We found 101,911 SNP-CpG pairs (mQTLs) in cis and 5,342 SNP-CpG pairs in trans showing significant associations between genotype and DNA methylation in adipose tissue after correction for multiple testing, where cis is defined as distance less than 500 kb between a SNP and CpG site. These mQTLs include reported obesity, lipid and type 2 diabetes loci, e.g. ADCY3/POMC, APOA5, CETP, FADS2, GCKR, SORT1 and LEPR. Significant mQTLs were overrepresented in intergenic regions meanwhile underrepresented in promoter regions and CpG islands. We further identified 635 SNPs in significant cis-mQTLs associated with expression of 86 genes in adipose tissue including CHRNA5, G6PC2, GPX7, RPL27A, THNSL2 and ZFP57. SNPs in significant mQTLs were also associated with body mass index (BMI), lipid traits and glucose and insulin levels in our study cohort and public available consortia data. Importantly, the Causal Inference Test (CIT) demonstrates how genetic variants mediate their effects on metabolic traits (e.g. BMI, cholesterol, highdensity lipoprotein (HDL), hemoglobin A1c (HbA1c) and homeostatic model assessment of insulin resistance (HOMA-IR)) via altered DNA methylation in human adipose tissue. This study identifies genome-wide interactions between genetic and epigenetic variation in both cis and trans positions influencing gene expression in adipose tissue and in vivo (dys) metabolic traits associated with the development of obesity and diabetes.
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| 5. |
- Daka, Bledar, 1976, et al.
(författare)
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Circulating concentrations of endothelin-1 predict coronary heart disease in women but not in men: A longitudinal observational study in the Vara-Skövde Cohort
- 2015
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Ingår i: BMC Cardiovascular Disorders. - : Springer Science and Business Media LLC. - 1471-2261. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- © 2015 Daka et al.Background: The vasoconstricting peptide endothelin-1 has been proposed to be a marker of cardiovascular disease. Our aim was to investigate whether circulating endothelin-1 levels predict coronary heart disease (CHD) in Sweden. Methods: In 2002-2005, 2816 adult participants (30-74 years) were randomly selected from two municipalities in south-western Sweden. Cardiovascular risk factors and endothelin-1 levels were assessed at baseline, and incident CHD was followed-up in all participants through 2011. After exclusion of 50 participants due to known CHD at baseline and 21 participants because of unsuccessful analysis of endothelin-1, 2745 participants were included in the study. In total, 72 CHD events (52 in men and 20 in women) were registered during the follow-up time. Results: We showed that baseline circulating endothelin-1 levels were higher in women with incident CHD than in women without CHD (3.2 pg/ml, SE: 0.36 vs 2.4 pg/ml, SE: 0.03, p = 0.003) whereas this difference was not observed in men (2.3 pg/ml, SE: 0.16 vs 2.3 pg/ml, SE: 0.04, p = 0.828). An age-adjusted Cox proportional regression analysis showed an enhanced risk of CHD with increasing baseline endothelin-1 levels in women (hazard ratio (HR) = 1.51, 95 % CI = 1.1-2.1, p = 0.015) but not in men (HR = 0.98, 95 % CI = 0.8-1.2, p = 0.854). Furthermore, the predictive value of endothelin-1 for incident CHD in women was still significant after adjustments for age, HOMA-IR, apolipoprotein (apo)B/apoA1 and smoking (HR = 1.53, CI = 1.1-1.2, p = 0.024). Conclusion: Circulating endothelin-1 levels may predict CHD in women.
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| 6. |
- Daka, Bledar, 1976, et al.
(författare)
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Low concentrations of serum testosterone predict acute myocardial infarction in men with type 2 diabetes mellitus
- 2015
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Ingår i: Bmc Endocrine Disorders. - : Springer Science and Business Media LLC. - 1472-6823. ; 15
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Tidskriftsartikel (refereegranskat)abstract
- Background: The aim of the present study was to investigate the associations between endogenous testosterone concentrations and the incidence of acute myocardial infarction (AMI) in men and women with and without type 2 diabetes. Methods: The study comprised 1109 subjects >= 40 years of age (mean age 62 +/- 12 years) participating in a baseline survey in Sweden in 1993-94. Information about smoking habits and physical activity was obtained using validated questionnaires. Serum concentrations of testosterone and sex hormone-binding globulin (SHBG) were obtained using radioimmunoassay. Diagnosis of type 2 diabetes was based on WHO's 1985 criteria. Individual patient information on incident AMI was ascertained by record linkage with national inpatient and mortality registers from baseline through 2011. Results: The prevalence of type 2 diabetes at baseline was 10.0 % in men and 7.5 % in women. During a mean follow-up of 14.1 years (+/- 5.3), there were 74 events of AMI in men and 58 in women. In age-adjusted Cox models, a significant inverse association between concentrations of testosterone and AMI-morbidity was found in men with type 2 diabetes (HR = 0.86 CI (0.75-0.98)). In a final model also including waist-to-hip ratio, systolic blood pressure, total cholesterol and active smoking, the association still remained statistically significant (HR = 0.754 CI (0.61-0.92)). Conclusion: Low concentrations of testosterone predicted AMI in men with type 2 diabetes independent of other risk factors. Trials with testosterone investigating the effect regarding cardiovascular outcome are still lacking. Future trials in this field should take into account a modification effect of diabetes.
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| 8. |
- Hadrévi, Jenny, 1977-, et al.
(författare)
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Plasma metabolomic patterns in patients with exhaustion disorder
- 2019
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Ingår i: Stress. - : Taylor & Francis. - 1025-3890 .- 1607-8888. ; 22:1, s. 17-26
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Tidskriftsartikel (refereegranskat)abstract
- Exhaustion disorder (ED) is a stress-related disorder that often implies a great burden on the individual patient as well as on society. Previous studies have shown that ED is associated with metabolic deviations, such as lowered fasting glucose. Several mechanisms have been discussed as a plausible explanation of the lack of energy described by these patients. Metabolic processes and reduced ability to mobilize energy have been suggested as important factors. This study investigated metabolomics in 20 patients diagnosed with ED and compared them with 21 healthy controls. Plasma metabolic profiles were examined in both fasting and nonfasting (postprandial) conditions. Blood plasma samples were analyzed for metabolite content using gas chromatography mass spectrometry. A total of 62 different metabolites were simultaneously detected in each of the samples. Multivariate models indicated systematic differences between patients with ED and healthy controls in both their fasting and nonfasting plasma metabolite levels. Lysine and octadecenoic acid were more abundant and glutamine, glycine, serine and gluconic acid were less abundant in the patients across both conditions. In the present study, we comprehensively and simultaneously screen for changes in a large number of metabolites. Our results show a difference in systemic metabolites between patients with exhaustion disorder and healthy controls both in the fasting and in the postprandial states. Here, we present new potential biomarkers mirroring exhaustion disorder metabolism.
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| 9. |
- Hellgren, Margareta, 1955, et al.
(författare)
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A lifestyle intervention in primary care prevents deterioration of insulin resistance in patients with impaired glucose tolerance: A randomised controlled trial.
- 2016
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Ingår i: Scandinavian journal of public health. - : SAGE Publications. - 1651-1905 .- 1403-4948. ; 44:7, s. 718-725
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Tidskriftsartikel (refereegranskat)abstract
- We hypothesised that the expected increase in insulin resistance over three years' time in individuals with impaired glucose tolerance (IGT) and/or impaired fasting glucose could be attenuated by an intervention with focus on physical activity in ordinary primary care.We conducted a randomised controlled trial with 96 participants over three years. Examination of the participants included anthropometric measures, blood pressure, body weight and height, blood samples, an oral glucose tolerance test, and questionnaires about diet and lifestyle. The study subjects were randomised to either an intense intervention with information, group sessions, referral to physical activity and a step-counter (n = 31), a less intense intervention without the group sessions (n = 35), or care as usual group (CAUG) (n = 30). Differences between the groups were analysed with general linear models adjusted for age, gender, baseline values and time in the intervention.Individual insulin resistance increased in the CAUG. Due to having a similar effect, we combined the two intervention groups into a combined intervention group (CIG; n = 66) in the analyses. In individuals with IGT, the increase in the homeostatic model assessment-insulin resistance differed significantly between those in the CAUG and the CIG (Δ = 0.8; CI: 0.1-1.6; p = 0.034). Likewise, diastolic blood pressure decreased more in the CIG than in the CAUG (Δ = 5.1; CI: 0.1-10.0; p = 0.047). A total of 17 individuals developed Type 2 diabetes, 23% were in the CIG and 33% in the CAUG; so there was a 32% reduced risk in the intervention group. CONCLUSIONS A LIFESTYLE INTERVENTION FOCUSED ON PHYSICAL ACTIVITY IS FEASIBLE IN ORDINARY PRIMARY CARE AND PREVENTS DETERIORATION IN INSULIN SENSITIVITY IN INDIVIDUALS WITH IGT OVER A THREE-YEAR PERIOD.
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| 10. |
- Hellgren, Margareta, 1955, et al.
(författare)
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C-Reactive Protein Concentrations and Level of Physical Activity in Men and Women With Normal and Impaired Glucose Tolerance: A Cross-Sectional Population-Based Study in Sweden
- 2016
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Ingår i: Journal of Physical Activity & Health. - : Human Kinetics. - 1543-3080 .- 1543-5474. ; 13:6, s. 625-631
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Tidskriftsartikel (refereegranskat)abstract
- Background: We aimed to explore the association between self-reported leisure time physical activity (LTPA) and C-reactive protein (CRP) concentrations in men and women with and without impaired glucose tolerance (IGT). Methods: In a cross-sectional study, a random sample (n = 2,816) was examined with an oral glucose tolerance test, CRP and information about LTPA. Those with IGT or normal glucose tolerance (NGT) and CRP value <= 10 mg/L were selected (n = 2,367) for the study. Results: An inverse association between LTPA and CRP concentrations was observed in the population (P < .001), though, only in men with IGT (P = .023) and in women with NGT. Men with IGT, reporting slight physical activity up to 4 hours a week presented significantly higher CRP concentrations than normoglycemic men (Delta 0.6 mg/L, P = .004). However, this difference could not be found in men with IGT reporting more intense physical activity (Delta 0.01 mg/L, P = .944). Conclusions: Physical inactivity seems to have greater inflammatory consequences for men (vs. women) with IGT. More importantly, although 4 hours of physical activity per week is more than the usual minimum recommendation, an even greater intensity of LTPA appears to be required to limit subclinical inflammation in men with IGT.
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