Publications by authors named "Per-Anders Jansson"

57 Publications

Literature review: Evidence-based health outcomes and perceptions of the built environment in pediatric hospital facilities.

J Pediatr Nurs 2021 Apr 16. Epub 2021 Apr 16.

Sahlgrenska University Hospital, Gothia Forum for Clinical Trials, Gothenburg, Sweden; Center for Ethics, Law, and Mental Health (CELAM), Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Problem: The current knowledge of evidence-based design for adults is not always implemented when hospital buildings are designed. Scientific data are sparse on the effects of hospital design in pediatric settings on health outcomes in children, parents, and staff. The objective of this review is to determine the evidence-based impact of the built environment in pediatric hospital facilities on health outcomes in children, parents, and staff.

Eligibility Criteria: A systematic literature review was carried out on the electronic databases Cochrane Library, Embase, Medline and CINAHL from the period of 2008 to 2019. The review considered studies using either quantitative, qualitative, or mixed methodologies.

Sample: Out of 1414 reviewed articles the result is based on eight included articles.

Results: Two of these eight articles included health outcomes. The other six articles presented results on measures of perceptions and/or satisfaction for children, parents or staff with the built environment when transitioning to a new or renovated facility. These were generally higher for the new compared to the old facility.

Conclusions: Given the small number of studies addressing the question posed in this review, no firm conclusions can be drawn.

Implications: The review illustrates the need for more research in the pediatric setting assessing the evidence-based health outcomes of aspects of physical environmental design in pediatric hospitals or units in children, parents and staff.
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http://dx.doi.org/10.1016/j.pedn.2021.04.013DOI Listing
April 2021

Identification of human glucocorticoid response markers using integrated multi-omic analysis from a randomized crossover trial.

Elife 2021 04 6;10. Epub 2021 Apr 6.

Department of Internal Medicine and Clinical Nutrition, Institute of Medicine at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Background: Glucocorticoids are among the most commonly prescribed drugs, but there is no biomarker that can quantify their action. The aim of the study was to identify and validate circulating biomarkers of glucocorticoid action.

Methods: In a randomized, crossover, single-blind, discovery study, 10 subjects with primary adrenal insufficiency (and no other endocrinopathies) were admitted at the in-patient clinic and studied during physiological glucocorticoid exposure and withdrawal. A randomization plan before the first intervention was used. Besides mild physical and/or mental fatigue and salt craving, no serious adverse events were observed. The transcriptome in peripheral blood mononuclear cells and adipose tissue, plasma miRNAomic, and serum metabolomics were compared between the interventions using integrated multi-omic analysis.

Results: We identified a transcriptomic profile derived from two tissues and a multi-omic cluster, both predictive of glucocorticoid exposure. A microRNA (miR-122-5p) that was correlated with genes and metabolites regulated by glucocorticoid exposure was identified (p=0.009) and replicated in independent studies with varying glucocorticoid exposure (0.01 ≤ p≤0.05).

Conclusions: We have generated results that construct the basis for successful discovery of biomarker(s) to measure effects of glucocorticoids, allowing strategies to individualize and optimize glucocorticoid therapy, and shedding light on disease etiology related to unphysiological glucocorticoid exposure, such as in cardiovascular disease and obesity.

Funding: The Swedish Research Council (Grant 2015-02561 and 2019-01112); The Swedish federal government under the LUA/ALF agreement (Grant ALFGBG-719531); The Swedish Endocrinology Association; The Gothenburg Medical Society; Wellcome Trust; The Medical Research Council, UK; The Chief Scientist Office, UK; The Eva Madura's Foundation; The Research Foundation of Copenhagen University Hospital; and The Danish Rheumatism Association.

Clinical Trial Number: NCT02152553.
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http://dx.doi.org/10.7554/eLife.62236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024021PMC
April 2021

Hyperinsulinemia and insulin resistance in the obese may develop as part of a homeostatic response to elevated free fatty acids: A mechanistic case-control and a population-based cohort study.

EBioMedicine 2021 Mar 9;65:103264. Epub 2021 Mar 9.

The Wallenberg Laboratory and Sahlgrenska Center for Cardiovascular and Metabolic Research, Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden. Electronic address:

Background: It is commonly accepted that in obesity free fatty acids (FFA) cause insulin resistance and hyperglycemia, which drives hyperinsulinemia. However, hyperinsulinemia is observed in subjects with normoglycaemia and thus the paradigm above should be reevaluated.

Methods: We describe two studies: MD-Lipolysis, a case control study investigating the mechanisms of obesity-driven insulin resistance by a systemic metabolic analysis, measurements of adipose tissue lipolysis by microdialysis, and adipose tissue genomics; and POEM, a cohort study used for validating differences in circulating metabolites in relation to adiposity and insulin resistance observed in the MD-Lipolysis study.

Findings: In insulin-resistant obese with normal glycaemia from the MD-Lipolysis study, hyperinsulinemia was associated with elevated FFA. Lipolysis, assessed by glycerol release per adipose tissue mass or adipocyte surface, was similar between obese and lean individuals. Adipose tissue from obese subjects showed reduced expression of genes mediating catecholamine-driven lipolysis, lipid storage, and increased expression of genes driving hyperplastic growth. In the POEM study, FFA levels were specifically elevated in obese-overweight subjects with normal fasting glucose and high fasting levels of insulin and C-peptide.

Interpretation: In obese subjects with normal glycaemia elevated circulating levels of FFA at fasting are the major metabolic derangement candidate driving fasting hyperinsulinemia. Elevated FFA in obese with normal glycaemia were better explained by increased fat mass rather than by adipose tissue insulin resistance. These results support the idea that hyperinsulinemia and insulin resistance may develop as part of a homeostatic adaptive response to increased adiposity and FFA.

Funding: Swedish-Research-Council (2016-02660); Diabetesfonden (DIA2017-250; DIA2018-384; DIA2020-564); Novo-Nordisk-Foundation (NNF17OC0027458; NNF19OC0057174); Cancerfonden (CAN2017/472; 200840PjF); Swedish-ALF-agreement (2018-74560).
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http://dx.doi.org/10.1016/j.ebiom.2021.103264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7992078PMC
March 2021

Longitudinal plasma protein profiling of newly diagnosed type 2 diabetes.

EBioMedicine 2021 Jan 3;63:103147. Epub 2020 Dec 3.

Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden; Department of Clinical Physiology, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden.

Background: Comprehensive proteomics profiling may offer new insights into the dysregulated metabolic milieu of type 2 diabetes, and in the future, serve as a useful tool for personalized medicine. This calls for a better understanding of circulating protein patterns at the early stage of type 2 diabetes as well as the dynamics of protein patterns during changes in metabolic status.

Methods: To elucidate the systemic alterations in early-stage diabetes and to investigate the effects on the proteome during metabolic improvement, we measured 974 circulating proteins in 52 newly diagnosed, treatment-naïve type 2 diabetes subjects at baseline and after 1 and 3 months of guideline-based diabetes treatment, while comparing their protein profiles to that of 94 subjects without diabetes.

Findings: Early stage type 2 diabetes was associated with distinct protein patterns, reflecting key metabolic syndrome features including insulin resistance, adiposity, hyperglycemia and liver steatosis. The protein profiles at baseline were attenuated during guideline-based diabetes treatment and several plasma proteins associated with metformin medication independently of metabolic variables, such as circulating EPCAM.

Interpretation: The results advance our knowledge about the biochemical manifestations of type 2 diabetes and suggest that comprehensive protein profiling may serve as a useful tool for metabolic phenotyping and for elucidating the biological effects of diabetes treatments.

Funding: This work was supported by the Swedish Heart and Lung Foundation, the Swedish Research Council, the Erling Persson Foundation, the Knut and Alice Wallenberg Foundation, and the Swedish state under the agreement between the Swedish government and the county councils (ALF-agreement).
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http://dx.doi.org/10.1016/j.ebiom.2020.103147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718461PMC
January 2021

Report from an effort to prevent type 2 diabetes development in primary care.

Prim Care Diabetes 2021 Apr 6;15(2):240-244. Epub 2020 Sep 6.

Department of Public Health and Community Medicine/Primary Health Care, The Sahlgrenska Academy at the University of Gothenburg, Sweden. Electronic address:

Background: In a clinical trial 2009-2012, individuals with prediabetes were randomised to a lifestyle intervention (LI) focused on physical activity or care as usual (CAU), with the aim of reducing development of type 2 diabetes (T2DM). At study termination after three years, there was a significantly less of an increase in insulin resistance in LI compared with the CAU group. The aim of this extended follow-up was to investigate whether positive results concerning metabolic variables remained five years after study termination.

Method: All participants from the original study were contacted for a new follow-up with an oral glucose tolerance test, anthropometric measurements, blood pressure and blood samples. Questionnaires about lifestyle were completed.

Results: A total of 69 of the original 123 participants were examined, and personal data for another five participants were collected from the medical charts (n = 74). The LI group showed a decrease in diastolic blood pressure (-4 mmHg, CI 95% 0.8-6.8, p = 0.014) and body weight (-3 kg, CI 95% 1.2-4.9, p = 0.002) since base-line. Weight loss in the LI group was significantly greater compared with weight loss in the CAU group (-3 kg, CI 0.1-5.9, p = 0.044). Insulin resistance markers and incident T2DM were similar among the groups.

Conclusion: Although without modifying the incidence of diabetes or the level of insulin resistance, a physical activity intervention may be used to induce sustainable weight change in subjects with prediabetes at the primary care level.
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http://dx.doi.org/10.1016/j.pcd.2020.08.019DOI Listing
April 2021

Integration of molecular profiles in a longitudinal wellness profiling cohort.

Nat Commun 2020 09 8;11(1):4487. Epub 2020 Sep 8.

Science for Life Laboratory, Department of Protein Science, KTH Royal Institute of Technology, Stockholm, Sweden.

An important aspect of precision medicine is to probe the stability in molecular profiles among healthy individuals over time. Here, we sample a longitudinal wellness cohort with 100 healthy individuals and analyze blood molecular profiles including proteomics, transcriptomics, lipidomics, metabolomics, autoantibodies and immune cell profiling, complemented with gut microbiota composition and routine clinical chemistry. Overall, our results show high variation between individuals across different molecular readouts, while the intra-individual baseline variation is low. The analyses show that each individual has a unique and stable plasma protein profile throughout the study period and that many individuals also show distinct profiles with regards to the other omics datasets, with strong underlying connections between the blood proteome and the clinical chemistry parameters. In conclusion, the results support an individual-based definition of health and show that comprehensive omics profiling in a longitudinal manner is a path forward for precision medicine.
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http://dx.doi.org/10.1038/s41467-020-18148-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479148PMC
September 2020

Galectin-1 is inversely associated with type 2 diabetes independently of obesity - A SCAPIS pilot study.

Metabol Open 2019 Dec 5;4:100017. Epub 2019 Sep 5.

Department of Molecular and Clinical Medicine, Wallenberg Laboratory, Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg and the Sahlgrenska University Hospital, Gothenburg, Sweden.

Objectives: Galectin-1 is a recently discovered adipokine that increases with obesity and increased energy intake in adipose tissue. Our aim was to assess whether serum galectin-1 is associated with type 2 diabetes (T2D) and other parameters of the metabolic syndrome independently of body mass index (BMI) in a cohort from the general population.

Methods: In this cross-sectional population-based cohort study from the western part of Sweden, we investigated associations between serum galectin-1, clinical characteristics and inflammatory markers in 989 women and men aged 50-65 years [part of the Swedish CArdioPulmonary bioImage Study (SCAPIS) pilot cohort].

Results: We showed in linear models that serum galectin-1 was independently and: (1) inversely associated with T2D (p < 0.05) and glucose (p < 0.05); and (2) positively associated with age (p < 0.01), sex (p < 0.01), BMI (p < 0.01), insulin (p < 0.01) and C-reactive protein (p < 0.01). Furthermore, galectin-1 demonstrated univariate correlations with triglycerides (r = 0.20, p < 0.01), homeostasis model assessment for insulin resistance (r = 0.24, p < 0.01), tumor necrosis factor-α (r = 0.24, p < 0.01), interleukin-6 (IL-6; r = 0.20, p < 0.01) and HbA1c (r = 0.14, p < 0.01).

Conclusion: In a cross-sectional study of a middle-aged population, we showed that serum galectin-1 is: (1) inversely associated with T2D independently of BMI; and (2) independently associated with other markers of the metabolic syndrome These results warrant prospective and functional studies on the role of galectin-1 in T2D.
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http://dx.doi.org/10.1016/j.metop.2019.100017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7424824PMC
December 2019

Wide QRS-T angles are associated with markers of increased inflammatory activity independently of hypertension and diabetes.

Ann Noninvasive Electrocardiol 2020 11 8;25(6):e12781. Epub 2020 Jul 8.

Region Västra Götaland, Department of Clinical Chemistry, Sahlgrenska University Hospital, Gothenburg, Sweden.

Background: Wide QRS-T angles and inflammatory activity are markers of future cardiovascular events including sudden cardiac death (SCD). The association between wide QRS-T angles and inflammatory activation is however not fully understood.

Methods: 1,094 study participants of both sexes, 50-64 years old, were included from a randomly selected population-based cohort as a part of the Swedish CArdioPulmonary bioImage Study (SCAPIS) pilot study. Serum samples were analyzed for markers of inflammation, cardiac wall stress/injury, and the metabolic syndrome. Wide QRS-T angles were defined using Frank vectorcardiography. Variables were analyzed through unsupervised principal component analysis (PCA) as well as Orthogonal Projections to Latent Structures (OPLS) modeling. In addition, a subset of study participants was analyzed in a post hoc matched group design.

Results: Wide QRS-T angles correlated positively with markers of inflammation, cardiac wall stress/injury, the metabolic syndrome, and male sex in both PCA and OPLS models. In the matched post hoc analysis, participants with wide QRS-T angles had significantly higher counts of white blood cells (WBC) and neutrophils in comparison with matched controls. WBC as well as the number of neutrophils, monocytes, basophils, eosinophils and levels of C-reactive protein, IL-1, IL-4, IL-6, TNF-α, and NT-pro-BNP were also significantly higher in comparison with healthy controls.

Conclusions: Markers of inflammatory activation and cardiac injury/wall stress were significantly higher in the presence of wide QRS-T angles. These results corroborate an association between abnormal electrophysiological function and inflammatory activation and may have implications for the prediction of SCD.
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http://dx.doi.org/10.1111/anec.12781DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7679831PMC
November 2020

Increased weight loading reduces body weight and body fat in obese subjects - A proof of concept randomized clinical trial.

EClinicalMedicine 2020 May 30;22:100338. Epub 2020 Apr 30.

Department of Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.

Background: Recently we provided evidence for a leptin-independent homeostatic regulation, , of body weight in rodents. The aim of the present translational proof of concept study was to test the gravitostat hypothesis in humans.

Methods: We conducted a randomized controlled single center trial (ClinicalTrial.gov number, NCT03672903), to evaluate the efficacy of artificially increased weight loading on body weight in subjects with mild obesity (BMI 30-35 kg/m). Subjects were either treated with a heavy (=high load; 11% of body weight) or light (=low load; 1% of body weight) weight vest for eight hours per day for three weeks. The primary outcome was change in body weight. Secondary outcomes included change in body fat mass and fat-free mass as measured using bioelectrical impedance analysis.

Findings: In total 72 participants underwent randomization and 69 (36 high load and 33 low load) completed the study for the primary outcome. High load treatment resulted in a more pronounced relative body weight loss compared to low load treatment (mean difference -1.37%, 95% confidence interval (CI), -1.96 to -0.79;  = 1.5 × 10). High load treatment reduced fat mass (-4.04%, 95% CI, -6,53 to -1.55;  = 1.9 × 10) but not fat free mass (0.43%, 95% CI, -1.47 to 2.34;  = 0.65) compared to low load treatment.

Interpretation: Increased weight loading reduces body weight and fat mass in obese subjects in a similar way as previously shown in obese rodents. These findings demonstrate that there is weight loading dependent homeostatic regulation of body weight, the gravitostat, also in humans.

Funding: Funded by Jane and Dan Olsson (JADO) Foundation, the Torsten Söderberg Foundation, The Knut and Alice Wallenberg's Foundation and the Novo Nordisk Foundation.
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http://dx.doi.org/10.1016/j.eclinm.2020.100338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7264953PMC
May 2020

Effects of free omega-3 carboxylic acids and fenofibrate on liver fat content in patients with hypertriglyceridemia and non-alcoholic fatty liver disease: A double-blind, randomized, placebo-controlled study.

J Clin Lipidol 2018 Nov - Dec;12(6):1390-1403.e4. Epub 2018 Aug 10.

Department of Medical Sciences, Uppsala University, Uppsala, Sweden.

Background: Treatment with omega-3 fatty acids and fenofibrates reduces serum triglyceride levels, but few studies have compared the effect of these agents on liver fat.

Objective: The aim of the EFFECT I trial (NCT02354976) was to determine the effects of free omega-3 carboxylic acids (OM-3CA) and fenofibrate on liver fat in overweight or obese individuals with non-alcoholic fatty liver disease and hypertriglyceridemia.

Methods: Seventy-eight patients were randomized to receive oral doses of 4 g OM-3CA (n = 25), 200 mg fenofibrate (n = 27), or placebo (n = 26) for 12 weeks in a double-blind, parallel-group study. Liver proton density fat fraction (PDFF) and volume, pancreas volume, and adipose tissue volumes were assessed by magnetic resonance imaging.

Results: Changes in liver PDFF at 12 weeks were not significantly different across treatment groups (relative changes from baseline: placebo, +4%; OM-3CA, -2%; and fenofibrate, +17%). The common PNPLA3 genetic polymorphism (I148M) did not significantly influence the effects of OM-3CA or fenofibrate on liver PDFF. Fenofibrate treatment significantly increased liver and pancreas volumes vs placebo treatment, and the changes in liver and pancreas volumes were positively correlated (rho 0.45, P = .02). Total liver fat volume increased significantly in patients using fenofibrate vs OM-3CA (+23% vs -3%, P = .04). Compared with OM-3CA, fenofibrate increased total liver fat and liver volume. Serum triglycerides decreased with OM-3CA (-26%, P = .02) and fenofibrate (-38%, P < .001) vs placebo. In contrast to OM-3CA, fenofibrate reduced plasma docosahexaenoic acid levels and increased plasma acetylcarnitine and butyrylcarnitine levels, estimated delta-9 desaturase activity and the concentration of urine F2-isoprostanes.

Conclusions: OM-3CA and fenofibrate reduced serum triglycerides but did not reduce liver fat. Fenofibrate increased total liver volume and total liver fat volume vs OM-3CA, indicating a complex effect of fenofibrate on human hepatic lipid metabolism.
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http://dx.doi.org/10.1016/j.jacl.2018.08.003DOI Listing
October 2019

Plasma metabolomic patterns in patients with exhaustion disorder.

Stress 2019 01 7;22(1):17-26. Epub 2018 Aug 7.

b The Institute of Stress Medicine , Gothenburg , Sweden Region Västra Götaland.

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. Lay summary Exhaustion disorder (ED) patients suffer from stress-related symptoms including a reduced energy level. This study investigates the body's metabolism in patients with ED, both fasting and after a meal. New potential markers that may help future investigations on ED were identified.
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http://dx.doi.org/10.1080/10253890.2018.1494150DOI Listing
January 2019

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.

Diabetologia 2018 09 3;61(9):1923-1934. Epub 2018 Jul 3.

AstraZeneca Gothenburg, Gothenburg, Sweden.

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 OM-3CA (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 (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 PNPLA3 I148M 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, γ-glutamyl transferase (γ-GT), cytokeratin (CK) 18-M30 and CK 18-M65 and plasma fibroblast growth factor 21 (FGF21). Changes in γ-GT correlated with changes in liver PDFF (ρ = 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.

Trial Registration: ClinicalTrials.gov NCT02279407 FUNDING: The study was funded by AstraZeneca.
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http://dx.doi.org/10.1007/s00125-018-4675-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6096619PMC
September 2018

Metabolic effects of Lactobacillus reuteri DSM 17938 in people with type 2 diabetes: A randomized controlled trial.

Diabetes Obes Metab 2017 04 7;19(4):579-589. Epub 2017 Feb 7.

Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.

Aims: To investigate the metabolic effects of 12-week oral supplementation with Lactobacillus reuteri DSM 17938 in patients with type 2 diabetes on insulin therapy.

Materials And Methods: In a double-blind trial, we randomized 46 people with type 2 diabetes to placebo or a low (10  CFU/d) or high dose (10  CFU/d) of L. reuteri DSM 17938 for 12 weeks. The primary endpoint was the effect of supplementation on glycated haemoglobin (HbA1c). Secondary endpoints were insulin sensitivity (assessed by glucose clamp), liver fat content, body composition, body fat distribution, faecal microbiota composition and serum bile acids.

Results: Supplementation with L. reuteri DSM 17938 for 12 weeks did not affect HbA1c, liver steatosis, adiposity or microbiota composition. Participants who received the highest dose of L. reuteri exhibited increases in insulin sensitivity index (ISI) and serum levels of the secondary bile acid deoxycholic acid (DCA) compared with baseline, but these differences were not significant in the between-group analyses. Post hoc analysis showed that participants who responded with increased ISI after L. reuteri supplementation had higher microbial diversity at baseline, and increased serum levels of DCA after supplementation. In addition, increases in DCA levels correlated with improvement in insulin sensitivity in the probiotic recipients.

Conclusions: Intake of L. reuteri DSM 17938 for 12 weeks did not affect HbA1c in people with type 2 diabetes on insulin therapy; however, L. reuteri improved insulin sensitivity in a subset of participants and we propose that high diversity of the gut microbiota at baseline may be important.
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http://dx.doi.org/10.1111/dom.12861DOI Listing
April 2017

A lifestyle intervention in primary care prevents deterioration of insulin resistance in patients with impaired glucose tolerance: A randomised controlled trial.

Scand J Public Health 2016 Nov 22;44(7):718-725. Epub 2016 Aug 22.

1 Department of Public Health and Community Medicine/Primary Health Care, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Aims: 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.

Methods: 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.

Results: 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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http://dx.doi.org/10.1177/1403494816663539DOI Listing
November 2016

A Genome-Wide mQTL Analysis in Human Adipose Tissue Identifies Genetic Variants Associated with DNA Methylation, Gene Expression and Metabolic Traits.

PLoS One 2016 20;11(6):e0157776. Epub 2016 Jun 20.

Department of Clinical Sciences, Epigenetics and Diabetes, Lund University Diabetes Centre, Clinical Research Centre, Malmö, Sweden.

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, high-density 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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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0157776PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4913906PMC
July 2017

Microdialysis and proteomics of subcutaneous interstitial fluid reveals increased galectin-1 in type 2 diabetes patients.

Metabolism 2016 07 13;65(7):998-1006. Epub 2016 Apr 13.

Department of Molecular and Clinical Medicine, Wallenberg Laboratory, Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. Electronic address:

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 16weeks on a very low calorie diet (VLCD); and (3) adipocytes isolated from 6 healthy young participants after 4weeks 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.
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http://dx.doi.org/10.1016/j.metabol.2016.04.003DOI Listing
July 2016

DNA methylation of loci within ABCG1 and PHOSPHO1 in blood DNA is associated with future type 2 diabetes risk.

Epigenetics 2016 07 5;11(7):482-8. Epub 2016 May 5.

a Epigenetics and Diabetes Unit, Department of Clinical Sciences, Lund University Diabetes Center , Malmö , Sweden.

Identification of subjects with a high risk of developing type 2 diabetes (T2D) is fundamental for prevention of the disease. Consequently, it is essential to search for new biomarkers that can improve the prediction of T2D. The aim of this study was to examine whether 5 DNA methylation loci in blood DNA (ABCG1, PHOSPHO1, SOCS3, SREBF1, and TXNIP), recently reported to be associated with T2D, might predict future T2D in subjects from the Botnia prospective study. We also tested if these CpG sites exhibit altered DNA methylation in human pancreatic islets, liver, adipose tissue, and skeletal muscle from diabetic vs. non-diabetic subjects. DNA methylation at the ABCG1 locus cg06500161 in blood DNA was associated with an increased risk for future T2D (OR = 1.09, 95% CI = 1.02-1.16, P-value = 0.007, Q-value = 0.018), while DNA methylation at the PHOSPHO1 locus cg02650017 in blood DNA was associated with a decreased risk for future T2D (OR = 0.85, 95% CI = 0.75-0.95, P-value = 0.006, Q-value = 0.018) after adjustment for age, gender, fasting glucose, and family relation. Furthermore, the level of DNA methylation at the ABCG1 locus cg06500161 in blood DNA correlated positively with BMI, HbA1c, fasting insulin, and triglyceride levels, and was increased in adipose tissue and blood from the diabetic twin among monozygotic twin pairs discordant for T2D. DNA methylation at the PHOSPHO1 locus cg02650017 in blood correlated positively with HDL levels, and was decreased in skeletal muscle from diabetic vs. non-diabetic monozygotic twins. DNA methylation of cg18181703 (SOCS3), cg11024682 (SREBF1), and cg19693031 (TXNIP) was not associated with future T2D risk in subjects from the Botnia prospective study.
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http://dx.doi.org/10.1080/15592294.2016.1178418DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4939923PMC
July 2016

Endothelin-1 as a predictor of impaired glucose tolerance and type 2 diabetes--A longitudinal study in the Vara-Skövde Cohort.

Diabetes Res Clin Pract 2016 Mar 2;113:33-7. Epub 2016 Feb 2.

The Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. Electronic address:

We addressed whether endothelin-1, a marker of endothelial dysfunction, predicts impaired glucose tolerance (IGT) and type 2 diabetes mellitus (T2DM) in a population study in south-western Sweden. Follow-up after 9.7 years showed an association between circulating endothelin-1 levels at baseline and development of IGT/T2DM in women but not in men.
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http://dx.doi.org/10.1016/j.diabres.2016.01.027DOI Listing
March 2016

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.

J Phys Act Health 2016 06 21;13(6):625-31. Epub 2015 Dec 21.

Dept of Primary Health Care, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.

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 (Δ0.6 mg/L, P = .004). However, this difference could not be found in men with IGT reporting more intense physical activity (Δ0.01 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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http://dx.doi.org/10.1123/jpah.2015-0168DOI Listing
June 2016

Circulating concentrations of endothelin-1 predict coronary heart disease in women but not in men: a longitudinal observational study in the Vara-Skövde Cohort.

BMC Cardiovasc Disord 2015 Nov 14;15:146. Epub 2015 Nov 14.

Department of Public Health and Community Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Box 454, S-405 30, Gothenburg, Sweden.

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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http://dx.doi.org/10.1186/s12872-015-0141-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4647275PMC
November 2015

Low concentrations of serum testosterone predict acute myocardial infarction in men with type 2 diabetes mellitus.

BMC Endocr Disord 2015 Jul 25;15:35. Epub 2015 Jul 25.

Department of Public Health and Community Medicine/Primary Health Care, University of Gothenburg, Gothenburg, Sweden.

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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http://dx.doi.org/10.1186/s12902-015-0034-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4514972PMC
July 2015

Impact of age, BMI and HbA1c levels on the genome-wide DNA methylation and mRNA expression patterns in human adipose tissue and identification of epigenetic biomarkers in blood.

Hum Mol Genet 2015 Jul 10;24(13):3792-813. Epub 2015 Apr 10.

Department of Clinical Sciences, Epigenetics and Diabetes and

Increased age, BMI and HbA1c levels are risk factors for several non-communicable diseases. However, the impact of these factors on the genome-wide DNA methylation pattern in human adipose tissue remains unknown. We analyzed the DNA methylation of ∼480 000 sites in human adipose tissue from 96 males and 94 females and related methylation to age, BMI and HbA1c. We also compared epigenetic signatures in adipose tissue and blood. Age was significantly associated with both altered DNA methylation and expression of 1050 genes (e.g. FHL2, NOX4 and PLG). Interestingly, many reported epigenetic biomarkers of aging in blood, including ELOVL2, FHL2, KLF14 and GLRA1, also showed significant correlations between adipose tissue DNA methylation and age in our study. The most significant association between age and adipose tissue DNA methylation was found upstream of ELOVL2. We identified 2825 genes (e.g. FTO, ITIH5, CCL18, MTCH2, IRS1 and SPP1) where both DNA methylation and expression correlated with BMI. Methylation at previously reported HIF3A sites correlated significantly with BMI in females only. HbA1c (range 28-46 mmol/mol) correlated significantly with the methylation of 711 sites, annotated to, for example, RAB37, TICAM1 and HLA-DPB1. Pathway analyses demonstrated that methylation levels associated with age and BMI are overrepresented among genes involved in cancer, type 2 diabetes and cardiovascular disease. Our results highlight the impact of age, BMI and HbA1c on epigenetic variation of candidate genes for obesity, type 2 diabetes and cancer in human adipose tissue. Importantly, we demonstrate that epigenetic biomarkers in blood can mirror age-related epigenetic signatures in target tissues for metabolic diseases such as adipose tissue.
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http://dx.doi.org/10.1093/hmg/ddv124DOI Listing
July 2015

Primary care screening for individuals with impaired glucose metabolism with focus on impaired glucose tolerance.

Prim Care Diabetes 2015 Aug 24;9(4):261-6. Epub 2014 Nov 24.

Department of Public Health and Community Medicine/Primary Health Care, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Aim: To evaluate the utility of three short questions (the Skövde Form) combined with a random plasma glucose, and HbA1c as alternative tools for detection of individuals with impaired glucose metabolism (IGM), and particularly impaired glucose tolerance (IGT).

Methods: Three questions concerning BMI ≥ 25 kg/m(2), heredity for type 2 diabetes, and known hypertension were asked in a random population of 573 individuals. All with two positive answers or one positive answer and a random plasma glucose > 7.2 mmol/l were invited for an oral glucose tolerance test and an HbA1c examination. FINDRISC was completed for comparison.

Results: The positive predictive value (PPV) for IGM, using the Skövde Form, was 31% while sensitivity and specificity were 59% and 73%, respectively. Corresponding values for IGT were 11%, 50% and 69%. Using HbA1c ≥ 42 mmol/mol, the PPV for IGM was 64% while sensitivity and specificity were 28% and 97%, respectively. The corresponding values for IGT were 15%, 16% and 94%.

Conclusion: The Skövde Form combined with a random plasma glucose may be used as an alternative tool for detection of individuals with IGM and IGT in particular. HbA1c may be used to identify individuals with type 2 diabetes but fails to detect most individuals with prediabetes.
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http://dx.doi.org/10.1016/j.pcd.2014.10.009DOI Listing
August 2015

Insulin resistance predicts early cardiovascular morbidity in men without diabetes mellitus, with effect modification by physical activity.

Eur J Prev Cardiol 2015 Jul 30;22(7):940-9. Epub 2014 May 30.

Department of Public Health and Community Medicine/Primary Health Care, the Sahlgrenska Academy at the University of Gothenburg, Sweden Social Medicine and Global Health, Department of Clinical Science, Malmö, Lund University, Sweden.

Aim: to assess how well insulin resistance predicts cardiovascular disease (CVD) in non-diabetic men and women and to explore the influence of physical activity.

Methods: in this prospective study 2563 men and women without diabetes were examined with an oral glucose tolerance test, anthropometric measurements and blood pressure assessment. Questionnaires about lifestyle and physical activity were completed. Insulin resistance was estimated by fasting concentrations of plasma insulin and by HOMA index for insulin resistance. Participants were followed up for cardiovascular morbidity and mortality during an 8-year period, using information from the National Swedish Inpatient and Mortality registers.

Results: at follow-up, HOMAir predicted CVD morbidity in males (50 events) and females (28 events) combined (HRage/sex-adj 1.4, 95% CI 1.1-1.7); however, when stratified by gender HOMAir was predictive solely in men (HRage-adj 1.8, 95% CI 1.3-2.4), whereas no association was found in women (HRage-adj 1.1, 95% CI 0.8-1.5). When stratifying the data for high and low physical activity, the predictive value of insulin resistance became stronger in sedentary men (HRage-adj 2.3, 95% CI 1.5-3.4) but was abolished in men performing moderate to vigorous physical activity (HRage-adj 1.0, 95% CI 0.6-1.6). The results remained when step-wise adjusted also for BMI, ApoB/ApoA1 and hypertension, as well as for smoking, alcohol consumption and education. Outcome for fasting plasma insulin was similar to HOMAir.

Conclusions: insulin resistance predicts CVD in the general population; however, men may be more vulnerable to increased insulin resistance than women, and physically inactive men seem to be at high risk.
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http://dx.doi.org/10.1177/2047487314537917DOI Listing
July 2015

Feasibility of a randomized controlled intervention with physical activity in participants with impaired glucose tolerance recruited by FINDRISC: A pilot study.

Scand J Public Health 2014 Jul 27;42(5):463-70. Epub 2014 May 27.

Department of Public Health and Community Medicine/Primary Health Care, Sahlgrenska Academy at the University of Gothenburg, Sweden.

Background: This study aimed to explore the feasibility and effect of an intervention in clinical practice with isolated physical activity in individuals with IGT, recruited by the FINDRISC questionnaire.

Methods: The questionnaire was sent to a population of 9734 individuals, 35-75 years old, in Sweden. Those with a risk score ≥15 were encouraged to perform an oral glucose tolerance test. Individuals with IGT were invited to participate in a randomized controlled trial with a focus on physical activity. The participants were allocated to one of three arms; basic intervention, intensive intervention or to care as usual. A total of 52 individuals were carefully examined and questionnaires about diet and lifestyle were completed at baseline and after one year. All analyses were adjusted for differences in age and sex, and calorie intake when relevant.

Results: The prevalence of chronic diseases in the study population was high, creating considerable difficulties in conducting a standardized test for fitness. Waist circumference (p=0.020), sagittal diameter (p=0.035), body weight (p=0.038) and BMI (p=0.043) decreased significantly more in the intensive care group than in care as usual and the basic care group. However, the significance was abolished when differences in energy intake were accounted for.

Conclusions: In an intention to treat, prospective lifestyle interventions with physical activity are feasible, but a high prevalence of comorbidities needs to be considered. Also, an intervention focused on isolated physical activity inevitably led to changes in diet with weight loss and significant improvement of essential risk factors in spite of the participants' burden of chronic diseases.
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http://dx.doi.org/10.1177/1403494814528290DOI Listing
July 2014

Altered DNA methylation and differential expression of genes influencing metabolism and inflammation in adipose tissue from subjects with type 2 diabetes.

Diabetes 2014 Sep 8;63(9):2962-76. Epub 2014 May 8.

Epigenetics and Diabetes, Department of Clinical Sciences, Lund University Diabetes Centre, Lund University, Clinical Research Centre, Malmö, Sweden

Genetics, epigenetics, and environment may together affect the susceptibility for type 2 diabetes (T2D). Our aim was to dissect molecular mechanisms underlying T2D using genome-wide expression and DNA methylation data in adipose tissue from monozygotic twin pairs discordant for T2D and independent case-control cohorts. In adipose tissue from diabetic twins, we found decreased expression of genes involved in oxidative phosphorylation; carbohydrate, amino acid, and lipid metabolism; and increased expression of genes involved in inflammation and glycan degradation. The most differentially expressed genes included ELOVL6, GYS2, FADS1, SPP1 (OPN), CCL18, and IL1RN. We replicated these results in adipose tissue from an independent case-control cohort. Several candidate genes for obesity and T2D (e.g., IRS1 and VEGFA) were differentially expressed in discordant twins. We found a heritable contribution to the genome-wide DNA methylation variability in twins. Differences in methylation between monozygotic twin pairs discordant for T2D were subsequently modest. However, 15,627 sites, representing 7,046 genes including PPARG, KCNQ1, TCF7L2, and IRS1, showed differential DNA methylation in adipose tissue from unrelated subjects with T2D compared with control subjects. A total of 1,410 of these sites also showed differential DNA methylation in the twins discordant for T2D. For the differentially methylated sites, the heritability estimate was 0.28. We also identified copy number variants (CNVs) in monozygotic twin pairs discordant for T2D. Taken together, subjects with T2D exhibit multiple transcriptional and epigenetic changes in adipose tissue relevant to the development of the disease.
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http://dx.doi.org/10.2337/db13-1459DOI Listing
September 2014

Inverse association between serum insulin and sex hormone-binding globulin in a population survey in Sweden.

Endocr Connect 2013 Mar 19;2(1):18-22. Epub 2012 Nov 19.

Institute of Medicine University of Gothenburg PO Box 454SE-405 30, Gothenburg Sweden ; Department of Primary Health Care University of Gothenburg PO Box 454SE-405 30, Gothenburg Sweden.

Objectives: Obesity is associated with low levels of sex hormone-binding globulin (SHBG). While the reason is not fully understood, we aimed to study the association between serum insulin and levels of SHBG in a random population.

Design And Methods: Between 2001 and 2005, a random sample of 2816 participants aged 30-74 years were enrolled in a cross-sectional survey in the South-west of Sweden. Fasting blood samples were collected and an oral glucose tolerance test (OGTT) was conducted in all subjects without known diabetes. Diabetes mellitus was defined according to criteria from WHO, and clinical characteristics were used to discriminate between type 1 (T1D) and type 2 diabetes (T2D). Analyses of SHBG were successful in 2782 participants (98%), who thus constituted the current study population.

Results: WE FOUND SIGNIFICANT INVERSE ASSOCIATION BETWEEN LEVELS OF SHBG AND FASTING SERUM INSULIN IN BOTH GENDERS (MEN: β=-0.090, P=0.001; women: β=-0.197, P<0.001), which was independent of differences in age and BMI. The associations remained when also differences in fasting plasma glucose were accounted for (men: β=-0.062, P=0.022; women: β=-0.176, P≤0.001). Subjects with T1D exhibited higher levels of SHBG than both T2D (men: δ=15.9 nmol/l, P<0.001; women: δ=71.1 nmol/l, P<0.001) and non-diabetic subjects (men: δ=15.1 nmol/l, P<0.001; women: δ=72.9 nmol/l, P<0.001) independent of age, BMI and fasting glucose levels.

Conclusion: These findings are consistent with high levels of SHBG in T1D, and correspondingly low levels in T2D subjects, suggesting an inhibitory effect of insulin on the SHBG production in the liver.
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http://dx.doi.org/10.1530/EC-12-0057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3680959PMC
March 2013

Low sex hormone-binding globulin is associated with hypertension: a cross-sectional study in a Swedish population.

BMC Cardiovasc Disord 2013 Apr 18;13:30. Epub 2013 Apr 18.

Department of Primary Health Care, Institute of Medicine, Gothenburg, Sweden.

Background: The aim of this study was to investigate the association of sex hormone-binding globulin (SHBG) and hypertension in a Swedish population.

Methods: The study is based on a random sample of a Swedish population of men and women aged 30-74 years (n=2,816). Total testosterone, oestradiol and SHBG were measured in 2,782 participants. Free androgen index was then calculated according to the formula FAI=100 × (Total testosterone)/SHBG. Hypertension was diagnosed according to JNC7.

Results: In men, but not in women, significant association between SHBG and both diastolic (diastolic blood pressure: β=-0.143 p<0.001) and systolic blood pressure (systolic blood pressure β=-0.114 p<0.001) was found. The association was still significant after adjusting for age, body mass index (BMI), homeostatic model assessment insulin resistance (HOMA-IR), triglycerides, high density lipoproteins (HDL) and C-reactive protein (CRP) (diastolic blood pressure: β=-0.113 p<0.001; systolic blood pressure β=-0.093 p=0.001). An inverse association was observed between SHBG and hypertension in both men (B=-0.024 p<0.001) and women (B=-0.022 p<0.001). The association was still significant in women older than 50 years after adjustments for age, BMI, physical activity, CRP and alcohol consumption (B=-0.014, p=0.008).

Conclusion: In conclusion, these results show a strong association between SHBG and blood pressure independent of major determinants of high blood pressure. This association might be addressed to direct effects of SHBG in endothelial cells through the receptor for SHBG. If this is confirmed by other observational and experimental studies, it might become a new field for the development of therapies for lowering blood pressure.
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http://dx.doi.org/10.1186/1471-2261-13-30DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3663757PMC
April 2013

The selective phosphodiesterase-5 inhibitor tadalafil induces microvascular and metabolic effects in type 2 diabetic postmenopausal females.

J Clin Endocrinol Metab 2013 Jan 1;98(1):245-54. Epub 2012 Nov 1.

Department of Internal Medicine, Diabetes, Endocrinology, and Obesity, Assisi Hospital, V. Muller 1, I-06081 Assisi (Perugia), Italy.

Objective: The objective of the study was to explore the acute in vivo effects of the selective phosphodiesterase-5 inhibitor tadalafil on local microcirculation and regional metabolism in skeletal muscle and adipose tissue (AT).

Design, Setting, And Participants: We studied eight postmenopausal female patients with type 2 diabetes (T2D) and eight nondiabetic controls (Ctrl) in the postabsorptive state and 180 min after the administration of tadalafil 10 mg. Intramuscular and sc microdialysis were combined with measurements of forearm (FBF) and AT blood flow as well as with arterial and deep venous blood sampling. Muscle capillary recruitment, as ascertained by the permeability surface area product for glucose (PS(glu)), forearm glucose uptake (FGU), interstitial lactate, and glycerol concentrations, was measured.

Results: When compared with Ctrl, T2D patients exhibited lower (P = 0.01) PS(glu) but similar FGU and FBF. After tadalafil, PS(glu) (P = 0.01) and muscle interstitial-arterial (I-A) lactate concentration gradient (P < 0.01) increased significantly in both groups, whereas FBF, FGU, and I-A glycerol remained unchanged. In AT, tadalafil did not significantly affect local blood flow, whereas the sc interstitial (I) lactate and I-A lactate concentrations increased (P < 0.01), and the I-A glycerol decreased in both groups. Finally, in multivariate analysis the PS(glu) was a strong and independent predictor of muscle glucose disposal (β: 0.737 and 0.963, P < 0.05, in Ctrl and T2D, respectively).

Conclusions: Tadalafil emerges as an acutely acting modulator of microvascular recruitment and glucose metabolism in skeletal muscle and adipose tissue. We suggest that selective phosphodiesterase-5 blockade may provide a path forward to new therapeutics in the setting of insulin resistance.
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http://dx.doi.org/10.1210/jc.2012-1830DOI Listing
January 2013