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  • 1. Bao, Cuiping
    et al.
    Yang, Xilin
    Xu, Weili
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Tianjin Med Univ, Dept Epidemiol & Biostat, Sch Publ Hlth, Tianjin, Peoples R China.
    Luo, Hongbin
    Xu, Zhongliang
    Su, Cheng
    Qi, Xiuying
    Diabetes mellitus and incidence and mortality of kidney cancer: A meta-analysis2013In: Journal of diabetes and its complications, ISSN 1056-8727, E-ISSN 1873-460X, Vol. 27, no 4, p. 357-364Article in journal (Refereed)
    Abstract [en]

    Background: Diabetes is associated with increased risk of a spectrum of cancers, but there are few meta-analyses on the association between diabetes and kidney cancer. We performed a meta-analysis of case-control studies and cohort studies to address the incidence and mortality of kidney cancer in diabetes. Methods: Studies were identified by searching PubMed database and manual assessment of the cited references in the retrieved articles. Study-specific relative risks (RRs) and 95% confidence intervals (CIs) were estimated using a random-effect model. Study quality was assessed using the Newcastle-Ottawa scale. Results: A total of 24 studies were included. We found that diabetes was significantly associated with increased risk of kidney cancer (RR=1.40, 95% CI = 1.16 to 1.69), and the results were consistent between case-control and cohort studies. A slightly stronger positive relation was observed in women (RR = 1.47, 95% CI=1.18 to 1.83) than in men (RR=1.28, 95% CI=1.10 to 1.48). Additional analyses indicated that the increased risk of kidney cancer was independent of alcohol consumption, body mass index (BMI)/obesity and smoking. However, there was no association between diabetes and mortality of kidney cancer (RR=1.12, 95% CI=0.99 to 1.20), without heterogeneity (P = 0.419, I-2 = 1.8%). Conclusions: Diabetes mellitus may increase the risk of kidney cancer in both women and men.

  • 2. Barregard, Lars
    et al.
    Haghdoost, Siamak
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Cooke, Marcus S.
    Human and Methodological Sources of Variability in the Measurement of Urinary 8-Oxo-7,8-dihydro-2 '-deoxyguanosine2013In: Antioxidants and Redox Signaling, ISSN 1523-0864, E-ISSN 1557-7716, Vol. 18, no 18, p. 2377-2391Article in journal (Refereed)
    Abstract [en]

    Aims: Urinary 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) is a widely used biomarker of oxidative stress. However, variability between chromatographic and ELISA methods hampers interpretation of data, and this variability may increase should urine composition differ between individuals, leading to assay interference. Furthermore, optimal urine sampling conditions are not well defined. We performed inter-laboratory comparisons of 8-oxodG measurement between mass spectrometric-, electrochemical- and ELISA-based methods, using common within-technique calibrants to analyze 8-oxodG-spiked phosphate-buffered saline and urine samples. We also investigated human subject- and sample collection-related variables, as potential sources of variability. Results: Chromatographic assays showed high agreement across urines from different subjects, whereas ELISAs showed far more inter-laboratory variation and generally overestimated levels, compared to the chromatographic assays. Excretion rates in timed 'spot' samples showed strong correlations with 24 h excretion (the 'gold' standard) of urinary 8-oxodG (r(p) 0.67-0.90), although the associations were weaker for 8-oxodG adjusted for creatinine or specific gravity (SG). The within-individual excretion of 8-oxodG varied only moderately between days (CV 17% for 24 h excretion and 20% for first void, creatinine-corrected samples). Innovation: This is the first comprehensive study of both human and methodological factors influencing 8-oxodG measurement, providing key information for future studies with this important biomarker. Conclusion: ELISA variability is greater than chromatographic assay variability, and cannot determine absolute levels of 8-oxodG. Use of standardized calibrants greatly improves intra-technique agreement and, for the chromatographic assays, importantly allows integration of results for pooled analyses. If 24 h samples are not feasible, creatinine- or SG-adjusted first morning samples are recommended.

  • 3. Chatterjee, Saion
    et al.
    Peters, Sanne A. E.
    Woodward, Mark
    Mejia Arango, Silvia
    Batty, G. David
    Beckett, Nigel
    Beiser, Alexa
    Borenstein, Amy R.
    Crane, Paul K.
    Haan, Mary
    Hassing, Linda B.
    Hayden, Kathleen M.
    Kiyohara, Yutaka
    Larson, Eric B.
    Li, Chung-Yi
    Ninomiya, Toshiharu
    Ohara, Tomoyuki
    Peters, Ruth
    Russ, Tom C.
    Seshadri, Sudha
    Strand, Bjørn H.
    Walker, Rod
    Xu, Weili
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Tianjin Medical University, China .
    Huxley, Rachel R.
    Type 2 Diabetes as a Risk Factor for Dementia in Women Compared With Men: A Pooled Analysis of 2.3 Million People Comprising More Than 100,000 Cases of Dementia2016In: Diabetes Care, ISSN 0149-5992, E-ISSN 1935-5548, Vol. 39, no 2, p. 300-307Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE Type 2 diabetes confers a greater excess risk of cardiovascular disease in women than in men. Diabetes is also a risk factor for dementia, but whether the association is similar in women and men remains unknown. We performed a metaanalysis of unpublished data to estimate the sex-specific relationship between women and men with diabetes with incident dementia. RESEARCH DESIGN AND METHODS A systematic search identified studies published prior to November 2014 that had reported on the prospective association between diabetes and dementia. Study authors contributed unpublished sex-specific relative risks (RRs) and 95% CIs on the association between diabetes and all dementia and its subtypes. Sex-specific RRs and the women-to-men ratio of RRs (RRRs) were pooled using random-effects meta-analyses. RESULTS Study-level data from 14 studies, 2,310,330 individuals, and 102,174 dementia case patients were included. In multiple-adjusted analyses, diabetes was associated with a 60% increased risk of any dementia in both sexes (women: pooled RR 1.62 [95% CI 1.45-1.80]; men: pooled RR 1.58 [95% CI 1.38-1.81]). The diabetes-associated RRs for vascular dementia were 2.34 (95% CI 1.86-2.94) in women and 1.73 (95% CI 1.61-1.85) in men, and for nonvascular dementia, the RRs were 1.53 (95% CI 1.35-1.73) in women and 1.49 (95% CI 1.31-1.69) in men. Overall, women with diabetes had a 19% greater risk for the development of vascular dementia than men (multiple-adjusted RRR 1.19 [95% CI 1.08-1.30]; P < 0.001). CONCLUSIONS Individuals with type 2 diabetes are at similar to 60% greater risk for the development of dementia compared with those without diabetes. For vascular dementia, but not for nonvascular dementia, the additional risk is greater in women.

  • 4. Cheung, L.
    et al.
    Gertow, J.
    Werngren, O.
    Folkersen, L.
    Petrovic, Natasa
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Nedergaard, Jan
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Franco-Cereceda, A.
    Eriksson, P.
    Fisher, R. M.
    Human mediastinal adipose tissue displays certain characteristics of brown fat2013In: Nutrition & Diabetes, ISSN 2044-4052, E-ISSN 2044-4052, Vol. 3, no UNSP e66Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The amount of intra-thoracic fat, of which mediastinal adipose tissue comprises the major depot, is related to various cardiometabolic risk factors. Autopsy and imaging studies indicate that the mediastinal depot in adult humans could contain brown adipose tissue (BAT). To gain a better understanding of this intra-thoracic fat depot, we examined possible BAT characteristics of human mediastinal in comparison with subcutaneous adipose tissue. MATERIALS AND METHODS: Adipose tissue biopsies from thoracic subcutaneous and mediastinal depots were obtained during open-heart surgery from 33 subjects (26 male, 63.7 +/- 13.8 years, body mass index 29.3 +/- 5.1 kg m(-2)). Microarray analysis was performed on 10 patients and genes of interest confirmed by quantitative PCR (qPCR) in samples from another group of 23 patients. Adipocyte size was determined and uncoupling protein 1 (UCP1) protein expression investigated with immunohistochemistry. RESULTS: The microarray data showed that a number of BAT-specific genes had significantly higher expression in the mediastinal depot than in the subcutaneous depot. Higher expression of UCP1 (24-fold, P < 0.001) and PPARGC1A (1.7-fold, P = 0.0047), and lower expression of SHOX2 (0.12-fold, P < 0.001) and HOXC8 (0.14-fold, P < 0.001) in the mediastinal depot was confirmed by qPCR. Gene set enrichment analysis identified two gene sets related to mitochondria, which were significantly more highly expressed in the mediastinal than in the subcutaneous depot (P < 0.01). No significant changes in UCP1 gene expression were observed in the subcutaneous or mediastinal depots following lowering of body temperature during surgery. UCP1 messenger RNA levels in the mediastinal depot were lower than those in murine BAT and white adipose tissue. In some mediastinal adipose tissue biopsies, a small number of multilocular adipocytes that stained positively for UCP1 were observed. Adipocytes were significantly smaller in the mediastinal than the subcutaneous depot (cross-sectional area 2400 +/- 810 versus 3260 +/- 980 mu m(2), P < 0.001). CONCLUSIONS: Human mediastinal adipose tissue displays some characteristics of BAT when compared with the subcutaneous depot at microscopic and molecular levels.

  • 5. Dixen, Karen
    et al.
    Basse, Astrid L.
    Murholm, Maria
    Isidor, Marie S.
    Hansen, Lillian H. L.
    Petersen, M. Christine H.
    Madsen, Lise
    Petrovic, Natasa
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Nedergaard, Jan
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Quistorff, Bjorn
    Hansen, Jacob B.
    ERR gamma Enhances UCP1 Expression and Fatty Acid Oxidation in Brown Adipocytes2013In: Obesity, ISSN 1930-7381, E-ISSN 1930-739X, Vol. 21, no 3, p. 516-524Article in journal (Refereed)
    Abstract [en]

    Objective: Estrogen-related receptors (ERRs) are important regulators of energy metabolism. Here we investigated the hypothesis that ERR gamma impacts on differentiation and function of brown adipocytes. Design and Methods: We characterize the expression of ERR gamma in adipose tissues and cell models and investigate the effects of modulating ERR? activity on UCP1 gene expression and metabolic features of brown and white adipocytes. Results: ERR gamma was preferentially expressed in brown compared to white fat depots, and ERR gamma was induced during cold-induced browning of subcutaneous white adipose tissue and brown adipogenesis. Overexpression of ERR gamma positively regulated uncoupling protein 1 (UCP1) expression levels during brown adipogenesis. This ERR gamma-induced augmentation of UCP1 expression was independent of the presence of peroxisome proliferator-activated receptor coactivator-1 (PGC-1 alpha) but was associated with increased rates of fatty acid oxidation in adrenergically stimulated cells. ERR? did not influence mitochondrial biogenesis, and its reduced expression in white adipocytes could not explain their low expression level of UCP1. Conclusions: Through its augmenting effect on expression of UCP1, ERR gamma may physiologically be involved in increasing the potential for energy expenditure in brown adipocytes, a function that is becoming of therapeutic interest.

  • 6. Dludla, Phiwayinkosi V.
    et al.
    Nkambule, Bongani B.
    Tiano, Luca
    Louw, Johan
    Jastroch, Martin
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Helmholtz-Zentrum München, German Research Center for Environmental Health (GmbH), Germany; German Center for Diabetes Research (DZD), Germany.
    Mazibuko-Mbeje, Sithandiwe E.
    Uncoupling proteins as a therapeutic target to protect the diabetic heart2018In: Pharmacological Research, ISSN 1043-6618, E-ISSN 1096-1186, Vol. 137, p. 11-24Article, review/survey (Refereed)
    Abstract [en]

    Myocardial remodeling and dysfunction caused by accelerated oxidative damage is a widely reported phenomenon within a diabetic state. Altered myocardial substrate preference appears to be the major cause of enhanced oxidative stress-mediated cell injury within a diabetic heart. During this process, exacerbated free fatty acid flux causes an abnormal increase in mitochondrial membrane potential leading to the overproduction of free radical species and subsequent cell damage. Uncoupling proteins (UCPs) are expressed within the myocardium and can protect against free radical damage by modulating mitochondrial respiration, leading to reduced production of reactive oxygen species. Moreover, transgenic animals lacking UCPs have been shown to be more susceptible to oxidative damage and display reduced cardiac function when compared to wild type animals. This suggests that tight regulation of UCPs is necessary for normal cardiac function and in the prevention of diabetes-induced oxidative damage. This review aims to enhance our understanding of the pathophysiological mechanisms relating to the role of UCPs in a diabetic heart, and further discuss known pharmacological compounds and hormones that can protect a diabetic heart through the modulation of UCPs.

  • 7.
    Eriksson, Birgitta S.
    Stockholm University, Faculty of Social Sciences.
    Ett år med diabetes: beskrivning av ett förlopp samt analys av faktorer som stött eller hindrat ett framgångsrikt behandlingsresultat1994Doctoral thesis, monograph (Other academic)
  • 8.
    Fischer, Alexander W.
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. University Medical Center Hamburg-Eppendorf, Germany.
    Cannon, Barbara
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Nedergaard, Jan
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Optimal housing temperatures for mice to mimic the thermal environment of humans: An experimental study2018In: Molecular metabolism, ISSN 2212-8778, Vol. 7, p. 161-170Article in journal (Refereed)
    Abstract [en]

    Objectives: The laboratory mouse is presently the most common model for examining mechanisms of human physiology and disease. Housing temperatures can have a large impact on the outcome of such experiments and on their translatability to the human situation. Humans usually create for themselves a thermoneutral environment without cold stress, while laboratory mice under standard conditions (approximate to 20 degrees C) are under constant cold stress. In a well-cited, theoretical paper by Speakman and Keijer in Molecular Metabolism, it was argued that housing mice under close to standard conditions is the optimal way of modeling the human metabolic situation. This tenet was mainly based on the observation that humans usually display average metabolic rates of about 1.6 times basal metabolic rate. The extra heat thereby produced would also be expected to lead to a shift in the 'lower critical temperature' towards lower temperatures.

    Methods: To examine these tenets experimentally, we performed high time-resolution indirect calorimetry at different environmental temperatures on mice acclimated to different housing temperatures.

    Results: Based on the high time-resolution calorimetry analysis, we found that mice already under thermoneutral conditions display mean diurnal energy expenditure rates 1.8 times higher than basal metabolism, remarkably closely resembling the human situation. At any temperature below thermoneutrality, mice metabolism therefore exceeds the human equivalent: Mice under standard conditions display energy expenditure 3.1 times basal metabolism. The discrepancy to previous conclusions is probably attributable to earlier limitations in establishing true mouse basal metabolic rate, due to low time resolution. We also found that the fact that mean energy expenditure exceeds resting metabolic rate does not move the apparent thermoneutral zone (the lower critical temperature) downwards.

    Conclusions: We show that housing mice at thermoneutrality is an advantageous step towards aligning mouse energy metabolism to human energy metabolism.

  • 9.
    Fischer, Alexander W.
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. University Medical Center Hamburg-Eppendorf, Germany.
    Schlein, Christian
    Cannon, Barbara
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Heeren, Joerg
    Nedergaard, Jan
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Intact innervation is essential for diet-induced recruitment of brown adipose tissue2019In: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 316, no 3, p. E487-E503Article in journal (Refereed)
    Abstract [en]

    The possibility that recruitment and activation of brown adipose tissue (BAT) thermogenesis could be beneficial for curtailing obesity development in humans prompts a need for a better understanding of the control of these processes [that are often referred to collectively as diet-induced thermogenesis (DIT)]. Dietary conditions are associated with large changes in blood-borne factors that could be responsible for BAT recruitment, but BAT is also innervated by the sympathetic nervous system. To examine the significance of the innervation for DIT recruitment, we surgically denervated the largest BAT depot, i.e., the interscapular BAT depot in mice and exposed the mice at thermoneutrality to a high-fat diet versus a chow diet. Denervation led to an alteration in feeding pattern but did not lead to enhanced obesity, but obesity was achieved with a lower food intake, as denervation increased metabolic efficiency. Conclusively. denervation totally abolished the diet-induced increase in total UCP1 protein levels observed in the intact mice, whereas basal UCP1 expression was not dependent on innervation. The denervation of interscapular BAT did not discernably hyper-recruit other BAT depots, and no UCP1 protein could be detected in the principally browning-competent inguinal white adipose tissue depot under any of the examined conditions. We conclude that intact innervation is essential for diet-induced thermogenesis and that circulating factors cannot by themselves initiate recruitment of brown adipose tissue under obesogenic conditions. Therefore, the processes that link food intake and energy storage to activation of the nervous system are those of significance for the further understanding of diet-induced thermogenesis.

  • 10.
    Gustafsson, Helena
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Söderdahl, Therése
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Jönsson, Gunn
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Bratteng, Jan-Ove
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Forsby, Anna
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Insulin-like growth factor type 1 prevents hyperglycemia-induced uncoupling protein 3 down-regulation and oxidative stress2004In: Journal of Neuroscience Research, ISSN 0360-4012, E-ISSN 1097-4547, Vol. 77, no 2, p. 285-291Article in journal (Refereed)
    Abstract [en]

    Uncoupling proteins (UCPs) have been reported to decrease the mitochondrial production of reactive oxygen species (ROS) by lowering the mitochondrial inner membrane potential (MMP). We have previously shown that UCP3 expression is positively regulated by insulin-like growth factor-1 (IGF-1). The aim of this study was to investigate the role of UCPs in IGF-1-mediated protection from hyperglycemia-induced oxidative stress and neurodegeneration. Human neuroblastoma SH-SY5Y cells were differentiated with retinoic acid for 6 days, after which exposure to 8, 30, or 60 mM glucose with or without 10 nM IGF-1 was started. After 48-72 hr, the number of neurites per cell, UCP3 protein expression, MMP, and intracellular levels of ROS and total glutathione were examined. These studies showed that glucose concentration-dependently reduced the number of neurites per cell, with a 50% reduction at 60 mM. In parallel, the UCP3 protein expression was down-regulated, and the MMP was raised 3.5-fold, compared with those in cells incubated with 8 mM glucose. Also, the ROS levels were increased, showing a twofold maximum at 60 mM glucose. This was accompanied by a twofold elevation of total glutathione levels, confirming an altered cellular redox state. IGF-1 treatment prevented the glucose-induced neurite degeneration and UCP3 down-regulation. Furthermore, the MMP and the intracellular levels of ROS and glutathione were normalized to those of control cells. These data indicate that IGF-1 may protect from hyperglycemia-induced oxidative stress and neuronal injuries by regulating MMP, possibly by the involvement of UCP3.

  • 11. Gyberg, Viveca
    et al.
    Hasson, Dan
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Tuomilehto, Jaakko
    Rydén, Lars
    Measuring risk online-Feasibility of using FINDRISC in an online workplace survey2012In: Primary Care Diabetes, ISSN 1751-9918, E-ISSN 1878-0210, Vol. 6, no 2, p. 103-107Article in journal (Refereed)
    Abstract [en]

    AIMS: With the globally increasing prevalence of diabetes and the knowledge on how to prevent the disease there is a high demand for an effective way of identifying people at risk. The hypothesis behind this investigation was that incorporation of the FINnish Diabetes Risk SCore (FINDRISC) questionnaire in a regular workplace survey would be a feasible way to identify individuals and groups at risk for diabetes that could benefit from preventive interventions.

    METHOD: The eight FINDRISC questions were slightly modified and incorporated to Webb-QPS, an online work place survey, and distributed by e-mail to 5166 employees at Karolinska University Hospital (KUH).

    RESULTS: The total number of responders to Webb-QPS was 3581 (69%). Of those responding 3029 (84%) replied to the FINDRISC section which comprises 59% of the original population. A group of 1082 high risk individuals could be considered for intervention whereof 298 (9.8%) are expected to develop diabetes the upcoming 10 years if left without intervention.

    CONCLUSION: It is feasible to incorporate a diabetes risk score such as the FINDRISC in a workplace survey. A group that could be subject to preventive intervention programs was identified.

  • 12. Hedström, Anna Karin
    et al.
    Katsoulis, Michail
    Hössjer, Ola
    Stockholm University, Faculty of Science, Department of Mathematics.
    Bomfim, Izaura L.
    Oturai, Annette
    Bach Sondergaard, Helle
    Sellebjerg, Finn
    Ullum, Henrik
    Wegner Thørner, Lise
    Wendel Gustavsen, Marte
    Harbo, Hanne F.
    Obradovic, Dragana
    Gianfrancesco, Milena A.
    Barcellos, Lisa F.
    Schaefer, Catherine A.
    Hillert, Jan
    Kockum, Ingrid
    Olsson, Tomas
    Alfredsson, Lars
    The interaction between smoking and HLA genes in multiple sclerosis: replication and refinement2017In: European Journal of Epidemiology, ISSN 0393-2990, E-ISSN 1573-7284, Vol. 32, no 10, p. 909-919Article in journal (Refereed)
    Abstract [en]

    Interactions between environment and genetics may contribute to multiple sclerosis (MS) development. We investigated whether the previously observed interaction between smoking and HLA genotype in the Swedish population could be replicated, refined and extended to include other populations. We used six independent case-control studies from five different countries (Sweden, Denmark, Norway, Serbia, United States). A pooled analysis was performed for replication of previous observations (7190 cases, 8876 controls). Refined detailed analyses were carried out by combining the genetically similar populations from the Nordic studies (6265 cases, 8401 controls). In both the pooled analyses and in the combined Nordic material, interactions were observed between HLA-DRB*15 and absence of HLA-A*02 and between smoking and each of the genetic risk factors. Two way interactions were observed between each combination of the three variables, invariant over categories of the third. Further, there was also a three way interaction between the risk factors. The difference in MS risk between the extremes was considerable; smokers carrying HLA-DRB1*15 and lacking HLA-A*02 had a 13-fold increased risk compared with never smokers without these genetic risk factors (OR 12.7, 95% CI 10.8-14.9). The risk of MS associated with HLA genotypes is strongly influenced by smoking status and vice versa. Since the function of HLA molecules is to present peptide antigens to T cells, the demonstrated interactions strongly suggest that smoking alters MS risk through actions on adaptive immunity.

  • 13.
    Hooshmand, Babak
    et al.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Ulm University Hospital, Germany.
    Rusanen, Minna
    Ngandu, Tiia
    Leiviskä, Jaana
    Sindi, Shireen
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    von Arnim, Christine A. F.
    Falkai, Peter
    Soininen, Hilkka
    Tuomilehto, Jaakko
    Kivipelto, Miia
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). University of Eastern Finland, Finland; Karolinska Institute, Sweden.
    Serum Insulin and Cognitive Performance in Older Adults: A Longitudinal Study2019In: American Journal of Medicine, ISSN 0002-9343, E-ISSN 1555-7162, Vol. 132, no 3, p. 367-373Article in journal (Refereed)
    Abstract [en]

    Purpose

    The aim of this study was to examine the association of serum glucose, insulin, and insulin resistance with cognitive functioning 7 years later in a longitudinal population-based study of Finnish older adults.

    Methods

    Serum glucose and insulin were measured at baseline in 269 dementia-free individuals aged 65-79 years, from the Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) study. Insulin resistance was estimated with the homeostasis model assessment (HOMA-IR). Participants were reexamined 7 years later, and global cognition, episodic memory, executive functioning, verbal expression, and psychomotor speed were assessed, both at baseline and at follow-up. Multiple linear regression was used to investigate the associations with cognitive performance at follow-up, after adjusting for several potential confounders, including common vascular risk factors.

    Results

    In the multivariable-adjusted linear regression models, no associations of insulin resistance with cognitive functioning were observed. After excluding 19 incident dementia cases, higher baseline HOMA-IR values were related to worse performance in global cognition (beta [standard error (SE)] -.050 [0.02]; P =.043) and psychomotor speed (beta [SE] -.064 [. 03]; P = [.043]) 7 years later. Raised serum insulin levels were associated with lower scores on global cognition (b [SE] -.054 [.03]; P =.045) and tended to relate to poorer performance in psychomotor speed (beta [SE] -.061 [.03]; P =.070).

    Conclusions

    Serum insulin and insulin resistance may be independent predictors of cognitive performance 7 years later in elderly individuals without dementia. Randomized controlled trials are needed to determine this issue.

  • 14. Idrees, M.
    et al.
    Sohail, Ayesha
    Javed, Sana
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab). Comsats University Islamabad, Pakistan.
    Forecasting the critical role of intermittent therapies for the control of bone resorption2019In: Clinical Biomechanics, ISSN 0268-0033, E-ISSN 1879-1271, Vol. 68, p. 128-136Article in journal (Refereed)
    Abstract [en]

    Background: Osteoporosis is a chronic metabolic disease characterized by an imbalance of bone resorption and formation, leading to bone fragility and increased susceptibility to fracture. Parathyroid hormone is approved therapy for the treatment of osteoporosis.

    Methods: The intermittent therapy of parathyroid hormone requires accurate administration. Meta-analysis is conducted to draw a clear picture of the impact of intermittent therapy and dose rates relative to time, on the osteoporotic patients. A novel mathematical model is presented in this article synchronised with the parametric values, depicted from meta-analysis.

    Findings: Results obtained from the mathematical model are in close agreement with the results obtained from the clinical trials. The model can be used to forecast the drug potency and dosage rates, to control the vicious cycle of osteoporosis.

    Interpretations: The intermittent administration of parathyroid hormone, rather than the continuous administration, is more effective, furthermore it is also concluded that a mathematical model, linked with the extensive literature of clinical trials, using meta-analysis can help in drug administration and future clinical studies of drug development.

  • 15. Jespersen, Naja Z.
    et al.
    Feizi, Amir
    Andersen, Eline S.
    Heywood, Sarah
    Hattel, Helle B.
    Daugaard, Søren
    Peijs, Lone
    Bagi, Per
    Feldt-Rasmussen, Bo
    Schultz, Heidi S.
    Hansen, Ninna S.
    Krogh-Madsen, Rikke
    Pedersen, Bente K.
    Petrovic, Natasa
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Nielsen, Søren
    Scheele, Camilla
    Heterogeneity in the perirenal region of humans suggests presence of dormant brown adipose tissue that contains brown fat precursor cells2019In: Molecular Metabolism, ISSN 2212-8778, Vol. 24, p. 30-43Article in journal (Refereed)
    Abstract [en]

    Objective:

    Increasing the amounts of functionally competent brown adipose tissue (BAT) in adult humans has the potential to restore dysfunctional metabolism and counteract obesity. In this study, we aimed to characterize the human perirenal fat depot, and we hypothesized that there would be regional, within-depot differences in the adipose signature depending on local sympathetic activity.

    Methods:

    We characterized fat specimens from four different perirenal regions of adult kidney donors, through a combination of qPCR mapping, immunohistochemical staining, RNA-sequencing, and pre-adipocyte isolation. Candidate gene signatures, separated by adipocyte morphology, were recapitulated in a murine model of unilocular brown fat induced by thermoneutrality and high fat diet.

    Results:

    We identified widespread amounts of dormant brown adipose tissue throughout the perirenal depot, which was contrasted by multilocular BAT, primarily found near the adrenal gland. Dormant BAT was characterized by a unilocular morphology and a distinct gene expression profile, which partly overlapped with that of subcutaneous white adipose tissue (WAT). Brown fat precursor cells, which differentiated into functional brown adipocytes were present in the entire perirenal fat depot, regardless of state. We identified SPARC as a candidate adipokine contributing to a dormant BAT state, and CLSTN3 as a novel marker for multilocular BAT.

    Conclusions:

    We propose that perirenal adipose tissue in adult humans consists mainly of dormant BAT and provide a data set for future research on factors which can reactivate dormant BAT into active BAT, a potential strategy for combatting obesity and metabolic disease.

  • 16.
    Kalinovich, Anastasia V.
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Lomonosov Moscow State University, Russian Federation.
    Mattsson, C. L.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Youssef, M. R.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Petrovic, Natasa
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Ost, M.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Skulachev, V. P.
    Shabalina, Irina G.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Lomonosov Moscow State University, Russian Federation.
    Mitochondria-targeted dodecyltriphenylphosphonium (C12TPP) combats high-fat-diet-induced obesity in mice2016In: International Journal of Obesity, ISSN 0307-0565, E-ISSN 1476-5497, Vol. 40, no 12, p. 1864-1874Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: A membrane-penetrating cation, dodecyltriphenylphosphonium (C12TPP), facilitates the recycling of fatty acids in the artificial lipid membrane and mitochondria. C12TPP can dissipate mitochondrial membrane potential and may affect total energy expenditure and body weight in animals and humans. METHODS: We investigated the metabolic effects of C12TPP in isolated brown-fat mitochondria, brown adipocyte cultures and mice in vivo. Experimental approaches included the measurement of oxygen consumption, carbon dioxide production, western blotting, magnetic resonance imaging and bomb calorimetry. RESULTS: In mice, C12TPP (50 mu mol per (day.kg body weight)) in the drinking water significantly reduced body weight (12%, P<0.001) and body fat mass (24%, P<0.001) during the first 7 days of treatment. C12TPP did not affect water palatability and intake or the energy and lipid content in feces. The addition of C12TPP to isolated brown-fat mitochondria resulted in increased oxygen consumption. Three hours of pretreatment with C12TPP also increased oligomycin-insensitive oxygen consumption in brown adipocyte cultures (P<0.01). The effects of C12TPP on mitochondria, cells and mice were independent of uncoupling protein 1 (UCP1). However, C12TPP treatment increased the mitochondrial protein levels in the brown adipose tissue of both wild-type and UCP1-knockout mice. Pair-feeding revealed that one-third of the body weight loss in C12TPP-treated mice was due to reduced food intake. C12TPP treatment elevated the resting metabolic rate (RMR) by up to 18% (P<0.05) compared with pair-fed animals. C12TPP reduced the respiratory exchange ratio, indicating enhanced fatty acid oxidation in mice. CONCLUSIONS: C12TPP combats diet-induced obesity by reducing food intake, increasing the RMR and enhancing fatty acid oxidation.

  • 17. Kärvestedt, Lars
    et al.
    Mårtensson, Eva
    Grill, Valdemar
    Elofsson, Stig
    Stockholm University, Faculty of Social Sciences, Department of Social Work.
    von Wendt, Gunvor
    Hamsten, Anders
    Brismar, Kerstin
    The prevalence of peripheral neuropathy in a population-based study of patients with type 2 diabetes in Sweden2011In: Journal of diabetes and its complications, ISSN 1056-8727, E-ISSN 1873-460X, Vol. 25, no 2, p. 97-106Article in journal (Refereed)
    Abstract [en]

    Aims

    To assess peripheral neuropathy following a standardized foot examination protocol in a representative population-based cohort of subjects with type 2 diabetes.

    Methods

    In a geographically defined population, aged 40–70 years with diabetes prevalence of 3.5% according to medical records, we investigated 156 type 2 diabetic subjects, 95% Caucasian, mean age 61.7±7.2 years, duration of diabetes 7.0±5.7 years, and HbA1c 7.3±2.4% (6.4% Mono-S), by questionnaires, clinical examinations, blood sampling, and review of medical records. Foot examination included clinical signs of peripheral neuropathy and tests of sensibility with monofilament, tuning fork, and assessments of the vibration perception thresholds (VPT).

    Results

    Peripheral autonomic neuropathy (PAN) as judged by two or more signs of dysfunction was the most common and affected 43%. The prevalence of peripheral sensory neuropathy (PSN) was 15% by monofilament, 24% by tuning fork, and 28% by VPT expressed as ZscoreVPT ≥2.0 S.D. Twenty-nine percent had a VPT ≥25 V. Signs of peripheral motor neuropathy (PMN) affected 15%.

    Peripheral neuropathy, at least one variable, affected 67%, whereas 25% were affected by more than one variable of neuropathy, i.e., polyneuropathy. Exclusion of other identified causes for neuropathy than diabetes reduced the prevalence of diabetic polyneuropathy to 23%.

    Concurrent diabetic complications were 29% for retinopathy, 14% for incipient nephropathy, and 8% for overt nephropathy. The prevalence of macrovascular complications was 62% for CVD, 26% for PVD, and 11% for cerebrovascular lesion (CVL).

    Conclusion

    Peripheral neuropathy was common in this representative type 2 diabetes population. Clinical signs of PAN were the most frequent followed by diminished perception of vibration and touch.

  • 18. Langlet, Fanny
    et al.
    Tarbier, Marcel
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Haeusler, Rebecca A.
    Camastra, Stefania
    Ferrannini, Eleuterio
    Friedländer, Marc R.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Accili, Domenico
    microRNA-205-5p is a modulator of insulin sensitivity that inhibits FOXO function2018In: Molecular metabolism, ISSN 2212-8778, Vol. 17, p. 49-60Article in journal (Refereed)
    Abstract [en]

    Objectives: Hepatic insulin resistance is a hallmark of type 2 diabetes and obesity. Insulin receptor signaling through AKT and FOXO has important metabolic effects that have traditionally been ascribed to regulation of gene expression. However, whether all the metabolic effects of FOXO arise from its regulation of protein-encoding mRNAs is unknown. Methods: To address this question, we obtained expression profiles of FOXO-regulated murine hepatic microRNAs (miRNAs) during fasting and refeeding using mice lacking Foxo1, 3a, and 4 in liver (L-Foxo1,3a, 4). Results: Out of 439 miRNA analyzed, 175 were differentially expressed in Foxo knockouts. Their functions were associated with insulin, Wnt, Mapk signaling, and aging. Among them, we report a striking increase of miR-205-5p expression in L-Foxo1,3a,4 knockouts, as well as in obese mice. We show that miR-205-5p gain-of-function increases AKT phosphorylation and decreases SHIP2 in primary hepatocytes, resulting in FOXO inhibition. This results in decreased hepatocyte glucose production. Consistent with these observations, miR-205-5p gain-of-function in mice lowered glucose levels and improved pyruvate tolerance. Conclusions: These findings reveal a homeostatic miRNA loop regulating insulin signaling, with potential implications for in vivo glucose metabolism.

  • 19.
    Lasselin, Julie
    et al.
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Magne, Eric
    Beau, Cédric
    Ledaguenel, Patrick
    Dexpert, Sandra
    Aubert, Agnès
    Layé, Sophie
    Capuron, Lucile
    Adipose inflammation in obesity: relationship with circulating levels of inflammatory markers and association with surgery-induced weight loss.2014In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 99, no 1, p. E53-E61Article in journal (Refereed)
    Abstract [en]

    CONTEXT: The inflammatory state of the adipose tissue is believed to contribute to systemic low-grade inflammation in obesity.

    OBJECTIVE: This study assessed the relationship between adipose and circulating inflammatory markers as well as the influence of adipose inflammation on bariatric surgery-induced weight reduction.

    DESIGN: This was a cross-sectional and longitudinal study (up to 14 mo).

    SETTING: The study was conducted in the digestive/bariatric surgery department of the Tivoli and Jean Villar clinics, Bordeaux, France.

    PATIENTS: Thirty-seven obese patients [body mass index (BMI)>35-40 kg/m2)] seeking bariatric surgery were included. Twenty-eight of them were successively followed up at 1-3 months after surgery and 25 between 6 and 14 months after surgery.

    MAIN OUTCOME MEASURES: Fasting serum samples were collected before surgery to assess concentrations of inflammatory markers. Samples of visceral adipose tissue were extracted during surgery and gene expression of cytokines and immune cell markers were evaluated using quantitative RT-PCR. Pre- and postsurgery weight and BMI were collected.

    RESULTS: Gene expression of several cytokines were strongly intercorrelated in the visceral adipose tissue. Adipose expression of macrophage and T cell markers were related to adipose expression of TNF-α and IL-1 receptor antagonist (P<.01) and to systemic levels of TNF-α (P<.01) and IL-6 (P<.05). A higher inflammatory state of the adipose tissue predicted a lower BMI reduction after surgery (P<.05), notably at early stages after surgery.

    CONCLUSIONS: These findings support the involvement of macrophages and T cells in adipose inflammation and provide new information regarding the role of the visceral adipose tissue in the inflammatory state of obesity and its impact on obesity treatment outcomes, such as surgery-induced weight loss.

  • 20. Lennartsson, Anna-Karin
    et al.
    Theorell, Tores
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Rockwood, Alan L.
    Kushnir, Mark M.
    Jonsdottir, Ingibjorg H.
    Perceived stress at work is associated with attenuated DHEA-S response during acute psychosocial stress2013In: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 38, no 9, p. 1650-1657Article in journal (Refereed)
    Abstract [en]

    Background: Dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEA-S) have been suggested to play a protective role during acute psychosocial stress, because they act as antagonists to the effects of the stress hormone cortisol. This study aims to investigate whether prolonged psychosocial stress, measured as perceived stress at work during the past week, is related to the capacity to produce DHEA and DHEA-S during acute psychosocial stress. It also aims to investigate whether prolonged perceived stress affects the balance between production of cortisol and DHEA-S during acute psychosocial stress. Method: Thirty-six healthy subjects (19 men and 17 women, mean age 37 years, SD 5 years), were included. Perceived stress at work during the past week was measured by using the Stress-Energy (SE) Questionnaire. The participants were divided into three groups based on their mean scores; Low stress, Medium stress and High stress. The participants underwent the Trier Social Stress Test (TSST) and blood samples were collected before, directly after the stress test, and after 30 min of recovery. General Linear Models were used to investigate if the Medium stress group and the High stress group differ regarding stress response compared to the Low stress group. Results: Higher perceived stress at work was associated with attenuated DHEA-S response during acute psychosocial stress. Furthermore, the ratio between the cortisol production and the DHEA-S production during the acute stress test were higher in individuals reporting higher perceived stress at work compared to individuals reporting low perceived stress at work. There was no statistical difference in DHEA response between the groups. Conclusions: This study shows that prolonged stress, measured as perceived stress at work during the past week, seems to negatively affect the capacity to produce DHEA-S during acute stress. Given the protective functions of DHEA-S, attenuated DHEA-S production during acute stress may Lead to higher risk for adverse effects on psychological and physiological health, particularly if stress exposure continues.

  • 21. Levie, Deborah
    et al.
    Derakhshan, Arash
    Shu, Huan
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Broeren, Maarten A. C.
    de Poortere, Ralph A.
    Peeters, Robin P.
    Bornehag, Carl-Gustaf
    Demeneix, Barbara
    Korevaar, Tim I. M.
    The Association of Maternal Iodine Status in Early Pregnancy with Thyroid Function in the Swedish Environmental Longitudinal, Mother and Child, Asthma and Allergy Study2019In: Thyroid, ISSN 1050-7256, E-ISSN 1557-9077, Vol. 29, no 11, p. 1660-1668Article in journal (Refereed)
    Abstract [en]

    Background: Severe maternal iodine deficiency can impact fetal brain development through effects on maternal and/or fetal thyroid hormone availability. The effects of mild-to-moderate iodine deficiency on thyroid function are less clear. The aim was to investigate the association of maternal urinary iodine concentration corrected for creatinine (UI/Creat) with thyroid function and autoantibodies in a mild-to-moderate iodine-deficient pregnant population.

    Methods: This study was embedded within the Swedish Environmental Longitudinal, Mother and child, Asthma and allergy (SELMA) study. Clinical reference ranges were determined by the 2.5th and 97.5th population-based percentile cutoffs. The associations of UI/Creat with thyrotropin (TSH), free thyroxine (fT4), free triiodothyronine (fT3), total T4 (TT4), and total T3 (TT3) were studied using multivariable linear regression in thyroid peroxidase antibody (TPOAb)-negative women. The association of UI/Creat with TPOAb and thyroglobulin antibody (TgAb) positivity was analyzed using multivariable logistic regression.

    Results: Urinary iodine and thyroid function were measured at a median (95% range) gestational age of 10 (6-14) weeks in 2009 women. The median (95% range) UI/Creat was 85 mu g/g (36-386) and the UI/Creat was below 150 mu g/g in 80.1% of women. Reference ranges did not differ substantially by UI/Creat. A lower UI/Creat was associated with a lower TSH (p = 0.027), a higher TT4 (p = 0.032), and with a corresponding trend toward slightly higher fT4 (p = 0.081), fT3 (p = 0.079), and TT3 (p = 0.10). UI/Creat was not associated with the fT4/fT3 (p = 0.94) or TT4/TT3 ratios (p = 0.63). Women with a UI/Creat of 150-249 mu g/g had the lowest prevalence of TPOAb positivity (6.1%), while women with a UI/Creat of <150 mu g/g had a higher prevalence (11.0%, odds ratio [OR] confidence interval [95% CI] 1.84 [1.07-3.20], p = 0.029). Women with a UI/Creat >= 500 mu g/g showed the highest prevalence and a higher risk of TPOAb positivity, however, only a small proportion of women had such a UI/Creat (12.5%, OR, [95% CI] 2.36 [0.54-10.43], p = 0.26).

    Conclusions: We could not identify any meaningful differences in thyroid function reference ranges. Lower iodine availability was associated with a slightly lower TSH and a higher TT4. Women with adequate iodine intake had the lowest risk of TPOAb positivity.

  • 22.
    Luijten, Ineke H. N.
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Feldmann, Helena M.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    von Essen, Gabriella
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Cannon, Barbara
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Nedergaard, Jan
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    In the absence of UCP1-mediated diet-induced thermogenesis, obesity is augmented even in the obesity-resistant 129S mouse strain2019In: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 316, no 5, p. E729-E740Article in journal (Refereed)
    Abstract [en]

    The attractive tenet that recruitment and activation of brown adipose tissue (BAT) and uncoupling protein 1 (UCP1) could counteract the development of obesity and its comorbidities in humans has been experimentally corroborated mainly by experiments demonstrating that UCP1-ablated mice on a C57B1/6 background (exempt from thermal stress) become more obese when fed a high-fat diet. However, concerns may be raised that this outcome of UCP1 ablation is restricted to this very special inbred and particularly obesity-prone mouse strain. Therefore, we have examined to which degree UCP1 ablation has similar metabolic effects in a mouse strain known to be obesity resistant: the 129S strain. For this, male 129S2/sv or 129SV/Pas mice and corresponding UCP1-knockout mice were fed chow or a high-fat or a cafeteria diet for 4 w.k. The absence of UCP1 augmented obesity (weight gain, body fat mass, %body fat, fat depot size) in high-fat diet- and cafeteria-fed mice, with a similar or lower food intake, indicating that, when present, UCP1 indeed decreases metabolic efficiency. The increased obesity was due to a decrease in energy expenditure. The consumption of a high-fat or cafeteria diet increased total BAT UCP1 protein levels in wild-type mice, and correspondingly. high-fat diet and cafeteria diet-fed mice demonstrated increased norepinephrine-induced oxygen consumption. There was a positive correlation between body fat and total BAT UCP1 protein content. No evidence for diet-induced adrenergic thermogenesis was found in UCP1-ablated mice. Thus, the obesity-reducing effect of UCP1 is not restricted to a particular, and perhaps not representative, mouse strain.

  • 23.
    Marseglia, Anna
    et al.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Fratiglioni, Laura
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Stockholm Gerontology Research Center, Sweden.
    Kalpouzos, Grégoria
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Wang, Rui
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Bäckman, Lars
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Xu, Weili
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Tianjin Medical University, China.
    Prediabetes and diabetes accelerate cognitive decline and predict microvascular lesions: A population-based cohort study2019In: Alzheimer's & Dementia, ISSN 1552-5260, E-ISSN 1552-5279, Vol. 15, no 1, p. 25-33Article in journal (Refereed)
    Abstract [en]

    Introduction: The impact of prediabetes and diabetes on cognitive decline and the potential underlying mechanisms remain unclear. We investigated whether prediabetes and diabetes accelerate cognitive decline and brain aging, and the initial pathological changes linked to microvascular processes.

    Methods: Nine-year longitudinal data from the Swedish National Study on Aging and Care-Kungsholmen (n = 2746, age >= 60 years) and the magnetic resonance imaging subsample (n = 455) were used. Cognitive function was assessed with Mini-Mental State Examination. Brain magnetic resonance imaging markers included total brain tissue, white matter, gray matter, white matter hyperintensities, and hippocampal volumes.

    Results: Compared with diabetes-free status, prediabetes and diabetes were independently associated with accelerated cognitive decline. Prediabetes was cross-sectionally associated with smaller total brain tissue volume (P < .01), particularly smaller white matter volume. Diabetes was associated with larger white matter hyperintensities volume. Longitudinally, diabetes was associated with faster white matter hyperintensities accumulation. No associations between prediabetes or diabetes and hippocampal volume were found.

    Discussion: Diabetes and prediabetes accelerate cognitive decline and might predict microvascular lesions among dementia-free older adults.

  • 24.
    Marseglia, Anna
    et al.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Wang, Hui-Xin
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Rizzuto, Debora
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Fratiglioni, Laura
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Stockholm Gerontology Research Center, Sweden.
    Xu, Weili
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Tianjin Medical University, China.
    Participating in Mental, Social, and Physical Leisure Activities and Having a Rich Social Network Reduce the Incidence of Diabetes-Related Dementia in a Cohort of Swedish Older Adults2019In: Diabetes Care, ISSN 0149-5992, E-ISSN 1935-5548, Vol. 42, no 2, p. 232-239Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE

    The effect of a healthy lifestyle on diabetes-related dementia remains unknown. We examined whether an active lifestyle and rich social network may counteract the increased risk of dementia in people with diabetes.

    RESEARCH DESIGN AND METHODS

    Dementia-free older adults from the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K) (n = 2,650) were followed up for 10 years. Diabetes was ascertained on the basis of medical history, medication use, medical records, or glycated hemoglobin (HbA(1c)) 6.5% and prediabetes as HbA(1c) between 5.7 and 6.5%. Dementia was diagnosed by specialists following standard criteria. An active lifestyle was defined as a moderate to high (vs. low) level of engagement in leisure activities or a rich social network (having moderate to rich [vs. poor] social connections and support). Hazard ratios (HRs) of dementia risk were derived from Cox regression models.

    RESULTS

    There were 246 incident dementia cases during follow-up. Those with diabetes (n = 243), but not those with prediabetes (n = 921), had greater risk of dementia (adjusted HR 2.0 [95% CI 1.4-2.9]) than diabetes-free participants. Participants with diabetes but low level of engagement in leisure activities (HR 4.2 [95% CI 2.2-8.2]) or a poor social network (HR 3.4 [95% CI 1.9-6.1]) had greater dementia risk than diabetes-free participants with moderate to high levels of leisure activity engagement or a moderate to rich social network. In participants with diabetes, an active lifestyle (high level of engagement in leisure activities or a rich social network) was associated with less of a raised risk (HR 1.9 [95% CI 1.1-3.4]).

    CONCLUSIONS

    An active and socially integrated lifestyle may significantly counteract the detrimental effect of diabetes on dementia risk.

  • 25.
    Marseglia, Anna
    et al.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Xu, Weili
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Tianjin Medical University, China.
    Fratiglioni, Laura
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Stockholm Gerontology Research Center, Sweden.
    Fabbri, Cristina
    Berendsen, Agnes A. M.
    Bialecka-Debek, Agata
    Jennings, Amy
    Gillings, Rachel
    Meunier, Nathalie
    Caumon, Elodie
    Fairweather-Tait, Susan
    Pietruszka, Barbara
    De Groot, Lisette C. P. G. M.
    Santoro, Aurelia
    Franceschi, Claudio
    Effect of the NU-AGE Diet on Cognitive Functioning in Older Adults: A Randomized Controlled Trial2018In: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 9, article id 349Article in journal (Refereed)
    Abstract [en]

    Background: Findings from animal and epidemiological research support the potential neuroprotective benefits from healthy diets. However, to establish diet neuroprotective causal relations, evidence from dietary intervention studies is needed. NU-AGE is the first multicenter intervention assessing whether a diet targeting health in aging can counteract the age-related physiological changes in different organs, including the brain. In this study, we specifically investigated the effects of NU-AGE's dietary intervention on age related cognitive decline.

    Materials and Methods: NU-AGE randomized trial (NCT01754012, clinicaltrials.gov) included 1279 relatively healthy older-adults, aged 65-79 years, from five European centers. Participants were randomly allocated into two groups: control (n = 638), following a habitual diet; and, intervention (n = 641), given individually tailored dietary advice (NU-AGE diet). Adherence to the NU-AGE diet was measured over follow-up, and categorized into tertiles (low, moderate, high). Cognitive function was ascertained at baseline and at 1-year follow-up with the Consortium to Establish a Registry for Alzheimer's Disease (CERAD)-Neuropsychological Battery and five additional domain-specific single cognitive tests. The raw scores from the CERAD subtests [excluding the Mini-Mental State Examination (MMSE)] and the single tests were standardized into Z-scores. Global cognition (measured with MMSE and CERAD total score), and five cognitive domains (perceptual speed, executive function, episodic memory, verbal abilities, and constructional praxis) were created. Cognitive changes as a function of the intervention were analyzed with multivariable mixed effects models.

    Results: After the 1-year follow-up, 571 (89.1%) controls and 573 (89.8%) from the intervention group participated in the post-intervention assessment. Both control and intervention groups showed improvements in global cognition and in all cognitive domains after 1 year, but differences in cognitive changes between the two groups were not statistically significant. However, participants with higher adherence to the NU-AGE diet showed statistically significant improvements in global cognition [beta 0.20 (95%CI 0.004, 0.39), p-value = 0.046] and episodic memory [beta 0.15 (95%Cl 0.02, 0.28), p-value = 0.025] after 1 year, compared to those adults with lower adherence.

    Discussion: High adherence to the culturally adapted, individually tailored, NU-AGE diet could slow down age-related cognitive decline, helping to prevent cognitive impairment and dementia.

  • 26.
    Marseglia, Anna
    et al.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Italian National Council Research (CNR), Italy.
    Xu, Weili
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Rizzuto, Debora
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Ferrari, Camilla
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). University of Florence, Italy.
    Whisstock, Christine
    Brocco, Enrico
    Fratiglioni, Laura
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Stockholm Gerontology Research Center, Sweden.
    Crepaldi, Gaetano
    Maggi, Stefania
    Cognitive functioning among patients with diabetic foot2014In: Journal of diabetes and its complications, ISSN 1056-8727, E-ISSN 1873-460X, Vol. 28, no 6, p. 863-868Article in journal (Refereed)
    Abstract [en]

    Aims: Using diabetic foot (OF) as an indicator of severe diabetes, we aimed to investigate the cognitive profile of OF patients and the relations between cognitive functioning and both diabetes complications and comorbidities. Methods: Dementia-free patients with DF aged 30-90 (n = 153) were assessed through medical records and a cognitive battery. Information on diabetes complications and comorbidities was collected via interview; glycated hemoglobin (HbA1c) was tested. Data were analyzed using robust logistic or quantile regression adjusted for potential confounders. Results: The mean Mini-Mental Examination (MMSE) score of patients was 24.6 (SD = 3.6), and 40% had global cognitive dysfunction (MMSE <= 24). Among elderly patients (aged >= 65), MMSE impairment was related to amputation (OR 3.59, 95% CI 1.07-12.11). Episodic memory impairment was associated with foot amputation (OR 4.13, 95% CI 1.11-1528) and microvascular complications (OR 9.68, 95% CI 1.67-56.06). Further, elderly patients with HbA1c <7% had increased odds of psychomotor slowness (OR 7.75, 95% CI 1.55-38.73) and abstract reasoning impairment (OR 4.49, 95% CI: 1.15-17.46). However, such significant associations were not shown in adult patients aged <65. Conclusion: Amputation, microvascular diseases and glycemic control were associated with impaired global cognitive function and its domains among patients aged >= 65.

  • 27. Merlin, Jon
    et al.
    Sato, Masaaki
    Chia, Ling Yeong
    Fahey, Richard
    Pakzad, Mohsen
    Nowell, Cameron J.
    Summers, Roger J.
    Bengtsson, Tore
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Evans, Bronwyn A.
    Hutchinson, Dana S.
    Rosiglitazone and a beta(3)-Adrenoceptor Agonist Are Both Required for Functional Browning of White Adipocytes in Culture2018In: Frontiers in Endocrinology, ISSN 1664-2392, E-ISSN 1664-2392, Vol. 9, article id 249Article in journal (Refereed)
    Abstract [en]

    The recruitment of brite (or beige) adipocytes has been advocated as a means to combat obesity, due to their ability to phenotypically resemble brown adipocytes (BA). Lineage studies indicate that brite adipocytes are formed by differentiation of precursor cells or by direct conversion of existing white adipocytes, depending on the adipose depot examined. We have systematically compared the gene expression profile and a functional output (oxygen consumption) in mouse adipocytes cultured from two contrasting depots, namely interscapular brown adipose tissue, and inguinal white adipose tissue (iWAT), following treatment with a known browning agent, the peroxisome proliferator-activated receptor (PPAR gamma) activator rosiglitazone. Prototypical BA readily express uncoupling protein (UCP)1, and upstream regulators including the beta(3)-adrenoceptor and transcription factors involved in energy homeostasis. Adipocytes from inguinal WAT display maximal UCP1 expression and mitochondrial uncoupling only when treated with a combination of the PPAR. activator rosiglitazone and a beta(3)-adrenoceptor agonist. In conclusion, brite adipocytes are fully activated only when a browning agent (rosiglitazone) and a thermogenic agent (beta(3)-adrenoceptor agonist) are added in combination. The presence of rosiglitazone throughout the 7-day culture period partially masks the effects of beta(3)-adrenoceptor signaling in inguinal white adipocyte cultures, whereas including rosiglitazone only for the first 3 days promotes robust beta(3)-adrenoceptor expression and provides an improved window for detection of beta(3)-adrenoceptor responses.

  • 28.
    Nässel, Dick R.
    et al.
    Stockholm University, Faculty of Science, Department of Zoology.
    Kubrak, Olga I.
    Stockholm University, Faculty of Science, Department of Zoology.
    Liu, Yiting
    Stockholm University, Faculty of Science, Department of Zoology.
    Luo, Jiangnan
    Stockholm University, Faculty of Science, Department of Zoology.
    Lushchak, Oleh V.
    Stockholm University, Faculty of Science, Department of Zoology.
    Factors that regulate insulin producing cells and their output in Drosophila2013In: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 4, article id 252Article, review/survey (Refereed)
    Abstract [en]

    Insulin-like peptides (ILPs) and growth factors (IGFs) not only regulate development, growth, reproduction, metabolism, stress resistance, and lifespan, but also certain behaviors and cognitive functions. ILPs, IGFs, their tyrosine kinase receptors and downstream signaling components have been largely conserved over animal evolution. Eight ILPs have been identified in Drosophila (DILP1-8) and they display cell and stage-specific expression patterns. Only one insulin receptor, dInR, is known in Drosophila and most other invertebrates. Nevertheless, the different DILPs are independently regulated transcriptionally and appear to have distinct functions, although some functional redundancy has been revealed. This review summarizes what is known about regulation of production and release of DILPs in Drosophila with focus on insulin signaling in the daily life of the fly. Under what conditions are DILP-producing cells (IPCs) activated and which factors have been identified in control of IPC activity in larvae and adult flies? The brain IPCs that produce DILP2, 3 and 5 are indirectly targeted by DILP6 and a leptin-like factor from the fat body, as well as directly by a few neurotransmitters and neuropeptides. Serotonin, octopamine, GABA, short neuropeptide F (sNPF), corazonin and tachykinin-related peptide have been identified in Drosophila as regulators of IPCs. The GABAergic cells that inhibit IPCs and DILP release are in turn targeted by a leptin-like peptide (unpaired 2) from the fat body, and the IPC-stimulating corazonin/sNPF neurons may be targeted by gut-derived peptides. We also discuss physiological conditions under which IPC activity may be regulated, including nutritional states, stress and diapause induction.

  • 29.
    Nässel, Dick R.
    et al.
    Stockholm University, Faculty of Science, Department of Zoology.
    Williams, Michael J.
    Cholecystokinin-like peptide (DSK) in Drosophila, not only for satiety signaling2014In: Frontiers in Endocrinology, ISSN 1664-2392, E-ISSN 1664-2392, Vol. 5, article id 219Article, review/survey (Refereed)
    Abstract [en]

    Cholecystokinin (CCK) signaling appears well conserved over evolution. In Drosophila, the CCK-like sulfakinins (DSKs) regulate aspects of gut function, satiety and food ingestion, hyperactivity and aggression, as well as escape-related locomotion and synaptic plasticity during neuromuscular junction development. Activity in the DSK-producing neurons is regulated by octopamine. We discuss mechanisms behind CCK function in satiety, aggression, and locomotion in some detail and highlight similarities to mammalian CCK signaling.

  • 30. Oliveira, A.J.
    et al.
    Rostila, Mikael
    Stockholm University, Faculty of Social Sciences, Centre for Health Equity Studies (CHESS).
    Lopes, C.S.
    Monteiro Ponce de Leon, A.
    The influence of social relationships on obesity: sex differences in a longitudinal study2013In: Obesity, ISSN 1930-7381, E-ISSN 1930-739X, Vol. 21, no 8, p. 1540-1547Article in journal (Refereed)
    Abstract [en]

    Objective: To investigate the effect of five dimensions of social relationships on obesity and potential sex differences in these associations.

    Design and Methods: This study used longitudinal data from the Swedish Level of Living Surveys (LNU) in 1991 and 2000. The sample included 3,586 individuals. The dimensions of social relationships examined in this study include emotional support, frequency of visiting friends, marital status, marital status changes, and a Social Relationships Index (SRI). Obesity status was based on BMI (kg/m(2)) and calculated with self-reported measurements. The association between social relationships and the incidence of obesity after 9 years of follow-up was evaluated through Poisson regressions.Results: After controlling for confounders, we found that the lack of emotional support (RR = 1.98; 95% CI, 1.1-4.6) influenced the incidence of obesity among men. In addition, men with the lowest levels of SRI (RR = 2.22; 95% CI, 1.1-4.4) had an increased risk of being obese. Among women, SRI was not significantly associated with obesity. Women who changed their marital status from married to unmarried had lower risk of obesity (RR = 0.39; 95% CI, 0.2-0.9).

    Conclusions: This study provides evidence for the effect of social relationships on the incidence of obesity, with significant differences by sex.

  • 31.
    Olsson, Lisa
    et al.
    Stockholm University, Faculty of Social Sciences, Centre for Health Equity Studies (CHESS).
    Grill, Valdemar
    Midthjell, Kristian
    Ahlbom, Anders
    Andersson, Tomas
    Carlsson, Sofia
    Mortality in Adult-Onset Autoimmune Diabetes Is Associated With Poor Glycemic Control Results from the HUNT Study2013In: Diabetes Care, ISSN 0149-5992, E-ISSN 1935-5548, Vol. 36, no 12, p. 3971-3978Article in journal (Refereed)
    Abstract [en]

    OBJECTIVEKnowledge on mortality in autoimmune diabetes with adult onset is limited. We compared mortality in adult-onset autoimmune diabetes and type 2 diabetes, taking into account metabolic risk factors, HbA(1c), lifestyle, and socioeconomic factors.RESEARCH DESIGN AND METHODSParticipants of the population-based HUNT2 Study (second survey of the Norwegian HelseUndersOkelsen i Nord-TrOndelag Study; n = 64,264) were followed up prospectively for mortality in the Cause of Death Registry (1995-2009). Diabetes with onset 35 years was classified as autoimmune diabetes in adults if anti-GAD was positive (n = 208) and as type 2 diabetes if anti-GAD was negative (n = 2,425). Hazard ratios (HRs) of mortality from all-causes, cardiovascular disease (CVD), and ischemic heart disease (IHD) were calculated using the Cox proportional hazards model.RESULTSPrevalence of the metabolic syndrome was lower in autoimmune diabetes than in type 2 diabetes (55 vs. 77%, P < 0.001). Still, autoimmune diabetes was associated with an increased risks of mortality from all-causes (HR 1.55 [95% CI 1.25-1.92]), CVD (1.87 [1.40-2.48]), and IHD (2.39 [1.57-3.64]), equally high as in type 2 diabetes in analyses where individuals without diabetes were used as the reference group. The increased risk was not explained by overweight, lifestyle, socioeconomic position, or presence of the metabolic syndrome. Excess mortality was primarily observed in individuals with elevated HbA(1c).CONCLUSIONSMortality in autoimmune diabetes was as high as in type 2 diabetes, despite a more favorable baseline metabolic risk profile. Excess risk was associated with poor glycemic control. The results from this study, the largest so far on mortality in autoimmune diabetes in adults, underscore the importance of optimal treatment modalities to improve survival in adult-onset autoimmune diabetes.

  • 32. Pettersson-Klein, A. T.
    et al.
    Izadi, M.
    Ferreira, D. M. S.
    Cervenka, I.
    Correia, J. C.
    Martinez-Redondo, V.
    Southern, M.
    Cameron, M.
    Kamenecka, T.
    Agudelo, L. Z.
    Porsmyr-Palmertz, M.
    Martens, Ulf
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Lundgren, Bo
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Otrocka, M.
    Jenmalm-Jensen, A.
    Griffin, P. R.
    Ruas, J. L.
    Small molecule PGC-1 alpha 1 protein stabilizers induce adipocyte Ucp1 expression and uncoupled mitochondrial respiration2018In: Molecular metabolism, ISSN 2212-8778, Vol. 9, p. 28-42Article in journal (Refereed)
    Abstract [en]

    Objective: The peroxisome proliferator-activated receptor-gamma coactivator-1 alpha 1 (PGC-1 alpha 1) regulates genes involved in energy metabolism. Increasing adipose tissue energy expenditure through PGC-1 alpha 1 activation is potentially beneficial for systemic metabolism. Pharmacological PGC-1 alpha 1 activators could be valuable tools in the fight against obesity and metabolic disease. Finding such compounds has been challenging partly because PGC-1 alpha 1 is a transcriptional coactivator with no known ligand-binding properties. While, PGC-1 alpha 1 activation is regulated by several mechanisms, protein stabilization is a crucial limiting step due to its short half-life under unstimulated conditions.

    Methods: We designed a cell-based high-throughput screening system to identify PGC-1 alpha 1 protein stabilizers. Positive hits were tested for their ability to induce endogenous PGC-1 alpha 1 protein accumulation and activate target gene expression in brown adipocytes. Select compounds were analyzed for their effects on global gene expression and cellular respiration in adipocytes.

    Results: Among 7,040 compounds screened, we highlight four small molecules with high activity as measured by: PGC-1 alpha 1 protein accumulation, target gene expression, and uncoupled mitochondrial respiration in brown adipocytes.

    Conclusions: We identify compounds that induce PGC-1 alpha 1 protein accumulation and show that this increases uncoupled respiration in brown adipocytes. This screening platform establishes the foundation for a new class of therapeutics with potential use in obesity and associated disorders.

  • 33. Qi, Xiuying
    et al.
    Sun, Jing
    Wang, Jing
    Wang, Peizhong Peter
    Xu, Zhongliang
    Murphy, Madonna
    Jia, Junting
    Wang, Jianhua
    Xie, Yun
    Xu, Weili
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Prevalence and Correlates of Latent Autoimmune Diabetes in Adults in Tianjin, China A population-based cross-sectional study2011In: Diabetes Care, ISSN 0149-5992, E-ISSN 1935-5548, Vol. 34, no 1, p. 66-70Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Data on latent autoimmune diabetes in adults (LADA) from population-based studies are sparse. We sought to investigate the prevalence and correlates of LADA. RESEARCH DESIGN AND METHODS: A total of 8,109 participants, who were aged >= 15 years and living in Tianjin, China, were assessed to identify individuals with type 2 diabetes (American Diabetes Association Criteria, 1997) and further to detect patients with LADA. LADA was ascertained by 1) the presence of type 2 diabetes and age >= 35 years, 2) the lack of a requirement for insulin at least 6 months after the diagnosis of type 2 diabetes, and 3) serum GAD antibody positivity. Data were analyzed using multinomial logistic regression with adjustment for potential confounders. RESULTS: Of all participants, 498 (6.1%) were patients with type 2 diabetes. Of them, 46 (9.2%) were found to have LADA. The prevalence of LADA was 0.6% (46 of 8,109), and tended to increase with age up to 50-59 years in all participants. The odds ratios (95% CI) of LADA related to hypertension, family history of diabetes, waist-to-hip ratio >= 0.85, and major stressful events were 1.93 (1.02-3.65), 17.59 (9.08-34.06), 5.37 (2.31-12.49), and 4.09 (1.75-9.52), respectively. CONCLUSIONS: The prevalence of LADA is similar to 9% in patients with type 2 diabetes. Hypertension, family history of diabetes, central obesity, and major stressful events may be associated with the occurrence of LADA.

  • 34. Robson-Doucette, Christine A.
    et al.
    Sultan, Sobia
    Allister, Emma M.
    Wikström, Jakob D.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Koshkin, Vasilij
    Bhatacharjee, Alpana
    Prentice, Kacey J.
    Sereda, Samuel B.
    Shirihai, Orian S.
    Wheeler, Michael B.
    beta-Cell Uncoupling Protein 2 Regulates Reactive Oxygen Species Production, Which Influences Both Insulin and Glucagon Secretion2011In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 60, no 11, p. 2710-2719Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE-The role of uncoupling protein 2 (UCP2) in pancreatic beta-cells is highly debated, partly because of the broad tissue distribution of UCP2 and thus limitations of whole-body UCP2 knockout mouse models. To investigate the function of UCP2 in the beta-cell, beta-cell-specific UCP2 knockout mice (UCP2BKO) were generated and characterized. RESEARCH DESIGN AND METHODS-UCP2BKO mice were generated by crossing loxUCP2 mice with mice expressing rat insulin promoter-driven Cre recombinase. Several in vitro and in vivo parameters were measured, including respiration rate, mitochondrial membrane potential, islet ATP content, reactive oxygen species (ROS) levels, glucose-stimulated insulin secretion (GSIS), glucagon secretion, glucose and insulin tolerance, and plasma hormone levels. RESULTS-UCP2BKO beta-cells displayed mildly increased glucose-induced mitochondrial membrane hyperpolarization but unchanged rates of uncoupled respiration and islet ATP content. UCP2BKO islets had elevated intracellular ROS levels that associated with enhanced GSIS. Surprisingly, UCP2BKO mice were glucose-intolerant, showing greater alpha-cell area, higher islet glucagon content, and aberrant ROS-dependent glucagon secretion under high glucose conditions. CONCLUSIONS-Using a novel beta-cell-specific UCP2K0 mouse model, we have shed light on UCP2 function in primary beta-cells. UCP2 does not behave as a classical metabolic uncoupler in the beta-cell, but has a more prominent role in the regulation of intracellular ROS levels that contribute to GSIS amplification. In addition, beta-cell UCP2 contributes to the regulation of intraislet ROS signals that mediate changes in alpha-cell morphology and glucagon secretion. Diabetes 60:2710-2719, 2011

  • 35.
    Sato, Masaaki
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Monash University, Australia.
    Dehvari, Nodi
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Öberg, Anette I.
    Dallner, Olof S.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. The Rockefeller University, USA.
    Sandström, Anna L.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Olsen, Jessica M.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Csikasz, Robert I.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Summers, Roger J.
    Hutchinson, Dana S.
    Bengtsson, Tore
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Improving type 2 diabetes through a distinct adrenergic signaling pathway involving mTORC2 that mediates glucose uptake in skeletal muscle2014In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 63, no 12, p. 4115-4129Article in journal (Refereed)
    Abstract [en]

    There is an increasing worldwide epidemic of type 2 diabetes that poses major health problems. We have identified a novel physiological system that increases glucose uptake in skeletal muscle but not in white adipocytes. Activation of this system improves glucose tolerance in Goto-Kakizaki rats or mice fed a high-fat diet, which are established models for type 2 diabetes. The pathway involves activation of β2-adrenoceptors that increase cAMP levels and activate cAMP-dependent protein kinase, which phosphorylates mammalian target of rapamycin complex 2 (mTORC2) at S2481. The active mTORC2 causes translocation of GLUT4 to the plasma membrane and glucose uptake without the involvement of Akt or AS160. Stimulation of glucose uptake into skeletal muscle after activation of the sympathetic nervous system is likely to be of high physiological relevance because mTORC2 activation was observed at the cellular, tissue, and whole-animal level in rodent and human systems. This signaling pathway provides new opportunities for the treatment of type 2 diabetes.

  • 36. Scott, Robert A.
    et al.
    Scott, Laura J.
    Maegi, Reedik
    Marullo, Letizia
    Gaulton, Kyle J.
    Kaakinen, Marika
    Pervjakova, Natalia
    Pers, Tune H.
    Johnson, Andrew D.
    Eicher, John D.
    Jackson, Anne U.
    Ferreira, Teresa
    Lee, Yeji
    Ma, Clement
    Steinthorsdottir, Valgerdur
    Thorleifsson, Gudmar
    Qi, Lu
    Van Zuydam, Natalie R.
    Mahajan, Anubha
    Chen, Han
    Almgren, Peter
    Voight, Ben F.
    Grallert, Harald
    Mueller-Nurasyid, Martina
    Ried, Janina S.
    Rayner, Nigel W.
    Robertson, Neil
    Karssen, Lennart C.
    Van Leeuwen, Elisabeth M.
    Willems, Sara M.
    Fuchsberger, Christian
    Kwan, Phoenix
    Teslovich, Tanya M.
    Chanda, Pritam
    Li, Man
    Lu, Yingchang
    Dina, Christian
    Thuillier, Dorothee
    Yengo, Loic
    Jiang, Longda
    Sparso, Thomas
    Kestler, Hans A.
    Chheda, Himanshu
    Eisele, Lewin
    Gustafsson, Stefan
    Frånberg, Mattias
    Stockholm University, Faculty of Science, Numerical Analysis and Computer Science (NADA). Stockholm University, Science for Life Laboratory (SciLifeLab).
    Strawbridge, Rona J.
    Benediktsson, Rafn
    Hreidarsson, Astradur B.
    Kong, Augustine
    Sigurdsson, Gunnar
    Kerrison, Nicola D.
    Luan, Jian'an
    Liang, Liming
    Meitinger, Thomas
    Roden, Michael
    Thorand, Barbara
    Esko, Tonu
    Mihailov, Evelin
    Fox, Caroline
    Liu, Ching-Ti
    Rybin, Denis
    Isomaa, Bo
    Lyssenko, Valeriya
    Tuomi, Tiinamaija
    Couper, David J.
    Pankow, James S.
    Grarup, Niels
    Have, Christian T.
    Jorgensen, Marit E.
    Jorgensen, Torben
    Linneberg, Allan
    Cornelis, Marilyn C.
    Van Dam, Rob M.
    Hunter, David J.
    Kraft, Peter
    Sun, Qi
    Edkins, Sarah
    Owen, Katharine R.
    Perry, John R. B.
    Wood, Andrew R.
    Zeggini, Eleftheria
    Tajes-Fernandes, Juan
    Abecasis, Goncalo R.
    Bonnycastle, Lori L.
    Chines, Peter S.
    Stringham, Heather M.
    Koistinen, Heikki A.
    Kinnunen, Leena
    Sennblad, Bengt
    Muehleisen, Thomas W.
    Noethen, Markus M.
    Pechlivanis, Sonali
    Baldassarre, Damiano
    Gertow, Karl
    Humphries, Steve E.
    Tremoli, Elena
    Klopp, Norman
    Meyer, Julia
    Steinbach, Gerald
    Wennauer, Roman
    Eriksson, Johan G.
    Mannisto, Satu
    Peltonen, Leena
    Tikkanen, Emmi
    Charpentier, Guillaume
    Eury, Elodie
    Lobbens, Stephane
    Gigante, Bruna
    Leander, Karin
    McLeod, Olga
    Bottinger, Erwin P.
    Gottesman, Omri
    Ruderfer, Douglas
    Blueher, Matthias
    Kovacs, Peter
    Tonjes, Anke
    Maruthur, Nisa M.
    Scapoli, Chiara
    Erbel, Raimund
    Joeckel, Karl-Heinz
    Moebus, Susanne
    De Faire, Ulf
    Hamsten, Anders
    Stumvoll, Michael
    Deloukas, Panagiotis
    Donnelly, Peter J.
    Frayling, Timothy M.
    Hattersley, Andrew T.
    Ripatti, Samuli
    Salomaa, Veikko
    Pedersen, Nancy L.
    Boehm, Bernhard O.
    Bergman, Richard N.
    Collins, Francis S.
    Mohlke, Karen L.
    Tuomilehto, Jaakko
    Hansen, Torben
    Pedersen, Oluf
    Barroso, Ines
    Lannfelt, Lars
    Ingelsson, Erik
    Lind, Lars
    Lindgren, Cecilia M.
    Cauchi, Stephane
    Froguel, Philippe
    Loos, Ruth J. F.
    Balkau, Beverley
    Boeing, Heiner
    Franks, Paul W.
    Gurrea, Aurelio Barricarte
    Palli, Domenico
    Van der Schouw, Yvonne T.
    Altshuler, David
    Groop, Leif C.
    Langenberg, Claudia
    Wareham, Nicholas J.
    Sijbrands, Eric
    Van Duijn, Cornelia M.
    Florez, Jose C.
    Meigs, James B.
    Boerwinkle, Eric
    Gieger, Christian
    Strauch, Konstantin
    Metspalu, Andres
    Morris, Andrew D.
    Palmer, Colin N. A.
    Hu, Frank B.
    Thorsteinsdottir, Unnur
    Stefansson, Kari
    Dupuis, Josee
    Morris, Andrew P.
    Boehnke, Michael
    McCarthy, Mark I.
    Prokopenko, Inga
    An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans2017In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 66, no 11, p. 2888-2902Article in journal (Refereed)
    Abstract [en]

    To characterize type 2 diabetes (T2D)-associated variation across the allele frequency spectrum, we conducted a meta-analysis of genome-wide association data from 26,676 T2D case and 132,532 control subjects of European ancestry after imputation using the 1000 Genomes multiethnic reference panel. Promising association signals were followed up in additional data sets (of 14,545 or 7,397 T2D case and 38,994 or 71,604 control subjects). We identified 13 novel T2D-associated loci (P < 5 x 10(-8)), including variants near the GLP2R, GIP, and HLA-DQA1 genes. Our analysis brought the total number of independent T2D associations to 128 distinct signals at 113 loci. Despite substantially increased sample size and more complete coverage of low-frequency variation, all novel associations were driven by common single nucleotide variants. Credible sets of potentially causal variants were generally larger than those based on imputation with earlier reference panels, consistent with resolution of causal signals to common risk haplotypes. Stratification of T2D-associated loci based on T2D-related quantitative trait associations revealed tissue-specific enrichment of regulatory annotations in pancreatic islet enhancers for loci influencing insulin secretion and in adipocytes, monocytes, and hepatocytes for insulin action-associated loci. These findings highlight the predominant role played by common variants of modest effect and the diversity of biological mechanisms influencing T2D pathophysiology.

  • 37.
    Shang, Ying
    et al.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Marseglia, Anna
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Fratiglioni, Laura
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Stockholm Gerontology Research Center, Sweden.
    Welmer, Anna-Karin
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Karolinska University Hospital, Sweden.
    Wang, Rui
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Wang, Hui-Xin
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Xu, Weili
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Tianjin Medical University, China.
    Natural history of prediabetes in older adults from a population-based longitudinal study2019In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 286, no 3, p. 326-340Article in journal (Refereed)
    Abstract [en]

    Background. The natural history of prediabetes in older adults remains unknown.

    Objectives. To assess the rate at which prediabetes progresses to diabetes, leads to death or reverts to normoglycaemia in older adults and to identify prognostic factors related to different outcomes of prediabetes.

    Methods. In the Swedish National Study on Aging and Care-Kungsholmen, 2575 diabetes-free participants aged >= 60 years were examined at baseline and followed for up to 12 years. At each wave, diabetes was diagnosed via medical examination, antidiabetic drug use, medical records or glycated haemoglobin (HbA1c) >= 6.5%. Prediabetes was defined as HbA1c >= 5.7% and normoglycaemia as HbA1c <5.7% in diabetes-free participants. Data were analysed with multinomial logistic regression.

    Results. At baseline, 918 (36%) individuals had prediabetes. Of them, 204 (22%) reverted to normoglycaemia (3.4/100 person-years, 95% CI 5.6-12.3), 119 (13%) developed diabetes (2.0/100 person-years, 95% CI 1.7-2.4) and 215 (23%) died (13.0/100 person-years, 95% CI 11.4-14.9) during the 12-year follow-up. The rates of reversion, progression and mortality were higher in the first 6-year than in the second 6-year follow-up, albeit not statistically significant. Lower systolic blood pressure (SBP), absence of heart diseases and weight loss promoted the reversion from prediabetes to normoglycaemia, whilst obesity accelerated its progression to diabetes.

    Conclusions. During a 12-year follow-up, most of older adults with prediabetes remained stable or reverted to normoglycaemia, whereas only one-third developed diabetes or died. Lower SBP, no heart diseases and weight management may promote reversion to normoglycaemia, suggesting possible strategies for achieving normoglycaemia in older adults with prediabetes.

  • 38. Song, Fei
    et al.
    Bao, Cuiping
    Deng, Meiyu
    Xu, Hui
    Fan, Meijuan
    Paillard-Borg, Stephanie
    Xu, Weili
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Tianjin Medical University, China.
    Qi, Xiuying
    The prevalence and determinants of hypothyroidism in hospitalized patients with type 2 diabetes mellitus2017In: Endocrine (Basingstoke), ISSN 1355-008X, E-ISSN 1559-0100, Vol. 55, no 1, p. 188-194Article in journal (Refereed)
    Abstract [en]

    The purpose of this study was to investigate the prevalence of hypothyroidism among hospitalized patients with type 2 diabetes mellitus and its related factors, and to assess the prevalence of macrovascular and microvascular diseases among type 2 diabetes mellitus inpatients with hypothyroidism and euthyroidism. A total of 1662 type 2 diabetes mellitus inpatients hospitalized at the Metabolic Diseases Hospital, Tianjin Medical University from 1 January 2008 to 1 March 2013 were included in this study. Information on demographic and anthropometric factors and additional variables related to hypothyroidism were collected from medical records. Prevalence rates were calculated and standardized using direct method based on the age-specific and sex-specific structure of all participants. Data were analyzed using binary logistic regression with adjustment for potential confounders. The prevalence of hypothyroidism among type 2 diabetes mellitus inpatients was 6.8 %, and 77.0% of the patients with hypothyroidism had subclinical hypothyroidism. The prevalence of hypothyroidism increased with age, and was higher in women (10.8 %) than in men (3.4 %). Older age (odds ratio, 1.74; 95% confidence interval, 1. 05 to 2.89), female gender (odds ratio, 2.02; 95% confidence interval, 1.05 to 3.87), and positive thyroid peroxidase antibody (odds ratio, 4.99; 95% confidence interval, 2.83 to 8.79) were associated with higher odds of hypothyroidism among type 2 diabetes mellitus inpatients. The type 2 diabetes mellitus inpatients with hypothyroidism had higher prevalence of cerebrovascular diseases than those with euthyroidism after adjustment for age and gender. The prevalence of hypothyroidism among type 2 diabetes mellitus inpatients was 6.8 %, and most patients had subclinical hypothyroidism. Older age, female gender, and positive thyroid peroxidase antibody could be indicators for detecting hypothyroidism in type 2 diabetes mellitus inpatients.

  • 39.
    Taloyan, Marina
    et al.
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Saleh-Stattin, Nuha
    Johansson, Sven-Erik
    Agréus, Lars
    Wändell, Per
    Hypertriglyceridemic waist may explain ethnic differences in hypertension among patients with type 2 diabetes in Sweden2012In: BMC Research Notes, ISSN 1756-0500, E-ISSN 1756-0500, Vol. 5, article id 474Article in journal (Refereed)
    Abstract [en]

    Background

    Hypertension is common among persons with type 2 diabetes. The aim of this study was to analyze the association between ethnicity and hypertension prevalence after adjusting for age, sex, Hba1c, total cholesterol, elevated triglycerides and hypertriglyceridemic waist. The study population consisted of 354 primary health care patients diagnosed with type 2 diabetes (173 Assyrians/Syrians and 181 Swedes) residing in Södertälje, Sweden. Unconditional logistic regression was used to analyze the data.

    Results

    Hypertension prevalence was higher among Swedes than Assyrians/Syrians, (77% versus 58%; p = 0.001). In the unadjusted logistic regression model, the odds ratio for hypertension in Swedes was twice as high than that in Assyrians/Syrians (OR = 2.44; 95% CI =1.54-3.86). In the age- and sex-adjusted model, odds ratio of hypertension was 2.25 (95% CI 1.41-3.60). After adjustments for total cholesterol was made, the odds ratio of hypertension decreased slightly to 1.73. When elevated triglycerides and hypertriglyceridemic waist were separately introduced, the odds ratio of hypertension was no longer significant between the ethnic groups (1.60 and 1.43 for triglycerides and hypertriglyceridemic waist respectively). In addition, advanced age – 60–69 years old (OR = 1.80, CI 95% 1.00-3.20) and ≥ 70 years old (OR = 2.88, CI 95% 1.40-5.93), elevated total cholesterol (OR = 1.48, CI 95% 1.12-1.95) and presents of hypertriglyceridemic waist (those with high WC and high TG) were significant confounding factors for the increased risk of hypertension independent of ethnicity.

    Conclusions

    The crude differences in prevalence of hypertension between the Swedes and Assyrians/Syrians in our study population with type 2 diabetes were no longer significant when adjusting for high triglycerides levels or the presence of hypertriglyceridemic waist.

  • 40.
    Theorell, Töres
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Stressens endokrinologi2015In: Endokrinologi / [ed] Sigbritt Werner, Stockholm: Liber, 2015, 3, p. 389-394Chapter in book (Other academic)
  • 41. Virtue, Sam
    et al.
    Feldmann, Helena
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    Christian, Mark
    Tan, Chong Yew
    Masoodi, Mojgan
    Dale, Martin
    Lelliott, Chris
    Burling, Keith
    Campbell, Mark
    Eguchi, Naomi
    Voshol, Peter
    Sethi, Jaswinder K.
    Parker, Malcolm
    Urade, Yoshihiro
    Griffin, Julian L.
    Cannon, Barbara
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    Vidal-Puig, Antonio
    A New Role for Lipocalin Prostaglandin D Synthase in the Regulation of Brown Adipose Tissue Substrate Utilization2012In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 61, no 12, p. 3139-3147Article in journal (Refereed)
    Abstract [en]

    In this study, we define a new role for lipocalin prostaglandin D synthase (L-PGDS) in the control of metabolic fuel utilization by brown adipose tissue (BAT). We demonstrate that L-PGDS expression in BAT is positively correlated with BAT activity, upregulated by peroxisome proliferator activated receptor gamma coactivator 1 alpha or 1 beta and repressed by receptor-interacting protein 140. Under cold-acclimated conditions, mice lacking L-PGDS had elevated reliance on carbohydrate to provide fuel for thermogenesis and had increased expression of genes regulating glycolysis mid de novo lipogenesis in BAT. These transcriptional differences were associated with increased lipid content in BAT and a BAT lipid composition enriched with de novo synthesized lipids. Consistent with the concept that lack of L-PGDS increases glucose utilization, mice lacking L-PGDS had improved glucose tolerance after high-fat, feeding. The improved glucose tolerance appeared to be independent of changes in insulin sensitivity, as insulin levels during the glucose tolerance test and insulin, leptin, and adiponectin levels were unchanged. Moreover, L-PGDS knock-out mice exhibited increased expression of genes involved in thermogenesis and increased norepinephrine-stimulated glucose uptake to BAT, suggesting that sympathetically mediated changes in glucose uptake may have improved glucose tolerance. Taken together, these results suggest that L-PGDS plays an important role in the regulation of glucose utilization in vivo. Diabetes 61:3139-3147, 2012

  • 42.
    von Essen, Gabriella
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Lindsund, Erik
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Cannon, Barbara
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Nedergaard, Jan
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Adaptive facultative diet-induced thermogenesis in wild-type but not in UCP1-ablated mice2017In: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 313, no 5, p. E515-E527Article in journal (Refereed)
    Abstract [en]

    The significance of diet-induced thermogenesis (DIT) for metabolic control is still debated. Although obesogenic diets recruit UCP1 and adrenergically inducible thermogenesis, and although the absence of UCP1 may promote the development of obesity, no actual UCP1-related thermogenesis identifiable as diet-induced thermogenesis has to date been unambiguously demonstrated. Examining mice living at thermoneutrality, we have identified a process of facultative (directly elicited by acute eating), adaptive (magnitude develops over weeks on an obesogenic diet), and fully UCP1-dependent thermogenesis. We found no evidence for UCP1-independent diet-induced thermogenesis. The thermogenesis was proportional to the total amount of UCP1 protein in brown adipose tissue and was not dependent on any contribution of UCP1 in brite/beige adipose tissue, since no UCP1 protein was found there under these conditions. Total UCP1 protein amount developed proportionally to total body fat content. The physiological messenger linking obesity level and acute eating to increased thermogenesis is not known. Thus UCP1-dependent diet-induced thermogenesis limits obesity development during exposure to obesogenic diets but does not prevent obesity as such.

  • 43. Wang, Zhida
    et al.
    Bao, Cuiping
    Su, Cheng
    Xu, Weili
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Luo, Hongbin
    Chen, Liming
    Qi, Xiuying
    Association between diabetes or antidiabetic therapy and lung cancer: A meta-analysis2013In: JOURNAL OF DIABETES INVESTIGATION, ISSN 2040-1116, Vol. 4, no 6, p. 659-666Article in journal (Refereed)
    Abstract [en]

    Aims/IntroductionDiabetes can increase the risk of cancers at several sites, but the association between diabetes and lung cancer remains unclear. We aimed to provide the quantitative estimates for the association between diabetes or antidiabetic treatment and lung cancer risk in the present meta-analysis. Materials and MethodsCohort studies were identified by searching the PubMed database (January 1960 through October 2012) and manually assessing the cited references in the retrieved articles. Study-specific relative risks (RRs) and 95% confidence intervals (CIs) were estimated using a random-effects model. Study quality was assessed using the Newcastle-Ottawa scale. ResultsA total of 19 cohort studies were included in the present meta-analysis. Of these, 14 studies focused on the association between diabetes and lung cancer incidence, and seven studies focused on the association between antidiabetic treatment and lung cancer incidence. Compared with non-diabetic individuals, diabetic patients do not have an increased risk of lung cancer (RR=1.04, 95% CI 0.87-1.24). The association between diabetes and lung cancer remained not statistically significant in subgroup analysis stratified by study characteristics, study quality, diabetes ascertainment or important confounders. A null association between insulin or biguanides therapy and lung cancer risk was found. However, the diabetic patients receiving thiazolidinedione (TZD) treatment had a 20% reduced risk of lung cancer than those without TZD treatment. ConclusionsNo association between diabetes and lung cancer risk was found. However, TZD treatment might reduce lung cancer risk in diabetic patients.

  • 44. Wändell, Per E.
    et al.
    Gigane, Bruna
    Nixon Andreasson, Anna
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Carlsson, Axel C.
    Gender Differences Regarding Novel Biomarkers and Metabolic Risk Factors in Metformin Treated Type 2 Diabetic Patients2012In: The Open Diabetes Journal, ISSN 1876-5246, E-ISSN 1876-5246, Vol. 5, p. 13-19Article in journal (Refereed)
    Abstract [en]

    We aimed to analyze associations between adiponectin, ghrelin and leptin with anthropometric and metabolic markers in men and women with Metformin-treated type 2 diabetes (n=53), recruited from a trial of relaxation therapies. Anthropometrical measures and fasting blood samples were assessed on three occasions: at baseline, and after 10 and 24 weeks: BMI, waist, HbA1c, insulin, glucose, adiponectin, leptin, fasting ghrelin, high sensitivity C-reactive protein (CRP), tumor necrosis factor α (TNF- α) and interleukin 6 (IL-6). HOMA2ir and HOMA2s were calculated from fasting glucose and insulin, and adiponectin/leptin and adiponectin/HOMA2ir ratios were calculated. In men, higher leptin and lower adiponectin/leptin ratio correlated with insulin and insulin resistance, and in women lower ghrelin with insulin and insulin resistance. In multivariate linear regression, higher levels of leptin were associated with insulin resistance among men, but not among women. Among women, insulin resistance was associated with lower adiponectin/leptin ratio and ghrelin. Factor analysis showed that leptin in women was closely related to anthropometric variables, but in men both related to anthropometric and inflammatory variables. Gender differences could indicate different pathophysiologic mechanisms of insulin resistance and type 2 diabetes among men and women, where leptin possibly could be a better marker among men, and ghrelin among women.

  • 45.
    Xu, Weili
    et al.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Caracciolo, Barbara
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Wang, Hui-Xin
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Winblad, Bengt
    Bäckman, Lars
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Qiu, Chengxuan
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Fratiglioni, Laura
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Accelerated progression from mild cognitive impairment to dementia in people with diabetes2010In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 59, no 11, p. 2928-35Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: The effect of diabetes on mild cognitive impairment (MCI) and its conversion to dementia remains controversial. We sought to examine whether diabetes and pre-diabetes are associated with MCI and accelerate the progression from MCI to dementia.

    RESEARCH DESIGN AND METHODS: In the Kungsholmen Project, 963 cognitively intact participants and 302 subjects with MCI (120 with amnestic MCI [aMCI] and 182 with other cognitive impairment no dementia [oCIND]) age ≥ 75 years were identified at baseline. The two cohorts were followed for 9 years to detect the incident MCI and dementia following international criteria. Diabetes was ascertained based on a medical examination, hypoglycemic medication use, and random blood glucose level ≥ 11.0 mmol/l. Pre-diabetes was defined as random blood glucose level of 7.8-11.0 mmol/l in diabetes-free participants. Data were analyzed using standard and time-dependent Cox proportional-hazards models.

    RESULTS: During the follow-up period, in the cognitively intact cohort, 182 people developed MCI (42 aMCI and 140 oCIND), and 212 developed dementia. In the MCI cohort, 155 subjects progressed to dementia, the multi-adjusted hazard ratio (95% CI) of dementia was 2.87 (1.30-6.34) for diabetes, and 4.96 (2.27-10.84) for pre-diabetes. In a Kaplan-Meier survival analysis, diabetes and pre-diabetes accelerated the progression from MCI to dementia by 3.18 years. Diabetes and pre-diabetes were neither cross-sectionally nor longitudinally associated with MCI.

    CONCLUSIONS: Diabetes and pre-diabetes substantially accelerate the progression from MCI to dementia, and anticipate dementia occurrence by more than 3 years in people with MCI. The association of diabetes with the development of MCI is less evident in old people.

  • 46.
    Xu, Weili
    et al.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Tianjin Medical University, China.
    Xu, Zhongliang
    Jia, Junting
    Xie, Yun
    Wang, Hui-Xin
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Qi, Xiuying
    Detection of Prediabetes and Undiagnosed Type 2 Diabetes: A Large Population-Based Study2012In: Canadian Journal of Diabetes, ISSN 1499-2671, Vol. 36, no 3, p. 108-113Article in journal (Refereed)
    Abstract [en]

    Objective: Prediabetes and undiagnosed diabetes have been commonly ignored. We aimed to investigate the prevalence of prediabetes and undiagnosed type 2 diabetes mellitus, and to verify the hypothesis that vascular risk factors (VRFs) may indicate prediabetes and undiagnosed type 2 diabetes.

    Methods: A total of 7567 adults, who were 20 to 79 years of age, and living in Tianjin, China, participated in this study. Type 2 diabetes was assessed based on medical history, hypoglycemic drugs use, fasting plasma glucose level >= 7.0 mmol/L, or postprandial 2-hour plasma glucose level >= 11.1 mmol/L. Undiagnosed type 2 diabetes was defined among subjects with type 2 diabetes when neither a medical history of diabetes nor hypoglycemic drugs use was present. Prediabetes was ascertained as fasting plasma glucose level of 6.1 to 6.9 mmol/L, or postprandial 2-hour plasma glucose level of 7.8 to 11.0 mmol/L (WHO 1999) among diabetes-free participants. Data were analyzed using multinomial logistic regression with adjustment for potential confounders.

    Results: Of all participants, 655 (8.7%) had prediabetes, and 721 (9.5%) were patients with type 2 diabetes, including 321 (4.2%) undiagnosed type 2 diabetes accounting for 44.5% patients with diabetes. The prevalence of prediabetes and undiagnosed type 2 diabetes increased with age, and was higher in women than in men. In a fully adjusted multinomial logistic regression model, hypertension, overweight, obesity, central obesity, and family history of diabetes were significantly associated with prediabetes and undiagnosed diabetes, whereas physical inactivity was independently related to undiagnosed diabetes.

    Conclusion: The prevalence of prediabetes and undiagnosed diabetes is approximately 13%, and almost 45% of patients with diabetes are undiagnosed. VRFs, such as hypertension, high adiposity, and family history of diabetes can be indicators for detecting prediabetes and undiagnosed diabetes.

  • 47. Xu, Z.
    et al.
    Qi, X.
    Dahl, A. K.
    Xu, W.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Tianjin Medical University, China.
    Waist-to-height ratio is the best indicator for undiagnosed Type 2 diabetes2013In: Diabetic Medicine, ISSN 0742-3071, E-ISSN 1464-5491, Vol. 30, no 6, p. e201-E207Article in journal (Refereed)
    Abstract [en]

    Aims

    Early detection of diabetes is important for the prevention of diabetic complications. The best adiposity index for indicating Type 2 diabetes mellitus remains unclear. We aimed to identify the optimal adiposity measure among BMI, waist circumference, waist–hip ratio and waist-to-height ratio to indicate undiagnosed Type 2 diabetes and impaired fasting glucose in Chinese adults.

    Methods

    A total of 7567 participants aged 20–79 years were included in this study. Impaired fasting glucose was defined as a fasting plasma glucose level of 6.1–6.9 mmol/l in participants without diabetes. Undiagnosed Type 2 diabetes was identified as fasting plasma glucose ≥ 7.0 mmol/l when neither a history of diabetes nor use of hypoglycaemic drugs was present. Body weight, height, waist and hip circumferences were measured following standard procedures. Data were analysed using logistic regression and areas under the receiver operating characteristic curves.

    Results

    Of the 7567 participants, 536 were defined as having impaired fasting glucose and 690 were patients with Type 2 diabetes, including 290 (3.8%) persons with undiagnosed diabetes. In multivariate logistic regression, the odds ratios of waist-to-height ratio (≥ 0.5) were stronger than BMI (≥ 24 kg/m2), waist circumference (≥ 85 cm in men and ≥ 80 cm in women) and waist–hip ratio (≥ 0.85) for undiagnosed Type 2 diabetes and impaired fasting glucose. Among the four indices, waist-to-height ratio ≥ 0.5 showed the largest area under the receiver operating characteristic curve for diagnosing undiagnosed Type 2 diabetes (0.725, 95% CI 0.693–0.756) and impaired fasting glucose (0.662, 95% CI 0.638–0.687).

    Conclusions

    By comparison with BMI, waist circumference and waist–hip ratio, waist-to-height ratio ≥ 0.5 may be the best indicator for undiagnosed Type 2 diabetes and impaired fasting glucose.

  • 48. Yan, Xin
    et al.
    Wang, Zhen
    Westberg-Rasmussen, Sidse
    Tarbier, Marcel
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Rathjen, Thomas
    Tattikota, Sudhir G.
    Peck, Bailey C. E.
    Kanke, Matt
    Oxvig, Claus
    Frystyk, Jan
    Starup-Linde, Jakob
    Sethupathy, Praveen
    Friedländer, Marc R.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Gregersen, Søren
    Poy, Matthew N.
    Differential Impact of Glucose Administered Intravenously and Orally on Circulating miR-375 Levels in Human Subjects2017In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 102, no 10, p. 3749-3755Article in journal (Refereed)
    Abstract [en]

    Background

    To date, numerous nucleic acid species have been detected in the systemic circulation including microRNAs (miRNAs); however, their functional role in this compartment remains unclear.

    Objective

    The aim of this study was to determine whether systemic levels of miRNAs abundant in blood, including the neuroendocrine tissue-enriched miR-375, are altered in response to a glucose challenge.

    Design

    Twelve healthy males were recruited for an acute crossover study that consisted of two tests each following an 8-hour fasting period. An oral glucose tolerance test (OGTT) was performed, and blood samples were collected over a 3-hour period. Following a period of at least 1 week, the same participants were administered an isoglycemic intravenous glucose infusion (IIGI) with the same blood-collection protocol.

    Results

    The glucose response curve following the IIGI mimicked that obtained after the OGTT, but as expected, systemic insulin levels were lower during the IIGI compared with the OGTT (P < 0.05). miR-375 levels in circulation were increased only in response to an OGTT and not during an IIGI. In addition, the response to the OGTT also coincided with the transient increase of circulating glucagon-like peptide (GLP)-1, GLP-2, and glucose-dependent insulinotropic polypeptide.

    Conclusions

    The present findings show levels of miR-375 increase following administration of an OGTT and, in light of its enrichment in cells of the gut, suggest that the gastrointestinal tract may play an important role in the abundance and function of this miRNA in the blood.

  • 49. Yang, Rongrong
    et al.
    Pedersen, Nancy L.
    Bao, Cuiping
    Xu, Weige
    Xu, Hui
    Song, Ruixue
    Qi, Xiuying
    Xu, Weili
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Tianjin Medical University, People’s Republic of China.
    Type 2 diabetes in midlife and risk of cerebrovascular disease in late life: a prospective nested case-control study in a nationwide Swedish twin cohort2019In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 62, no 8, p. 1403-1411Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis We aimed to examine the association between midlife type 2 diabetes mellitus and cerebrovascular disease (CBD) in late life, and further to explore whether genetic and early-life familial environmental factors (such as shared childhood socioeconomic status and adolescent environment) play a role in this association.

    Methods In this prospective nested case-control study based on the Swedish Twin Registry, 33,086 twin individuals who were born in 1958 or earlier and were CBD-free before the age of 60 were included. Midlife (40-59 years) type 2 diabetes was ascertained from self-report, the National Patient Registry (NPR) and glucose-lowering medication use. CBD diagnosis (cerebral infarction, occlusion of cerebral arteries, subarachnoid haemorrhage, intracerebral haemorrhage and unspecified CBD) and onset age were identified from the NPR. Late-life CBD was defined as CBD onset age >= 60 years. Generalised estimating equation (GEE) models were used to analyse unmatched case-control data (adjusted for the clustering of twins within a pair). Conditional logistic regression was used in co-twin matched case-control analyses in CBD-discordant twin pairs.

    Results Of all the participants, 1248 (3.8%) had midlife type 2 diabetes and 3121 (9.4%) had CBD in late life. In GEE models adjusted for age, sex, education, BMI, smoking, alcohol consumption, marital status, hypertension and heart disease, the ORs (95% CIs) of type 2 diabetes were 1.29 (1.03, 1.61) for cerebral infarction, 2.03 (1.20, 3.44) for occlusion of cerebral arteries, 0.52 (0.12, 2.21) for subarachnoid haemorrhage and 0.78 (0.45, 1.36) for intracerebral haemorrhage. In multi-adjusted conditional logistic regression, the OR of the type 2 diabetes-cerebral infarction association was 0.96 (0.51, 1.80). The differences in ORs from the GEE and co-twin control analyses were not statistically significant (p=0.780).

    Conclusions/interpretation Midlife type 2 diabetes is significantly associated with increased risk of cerebral infarction and occlusion of cerebral arteries, but not intracerebral haemorrhage or subarachnoid haemorrhage in late life. Genetic and early-life familial environmental factors do not appear to account for the type 2 diabetes-cerebral infarction association, but further clarification is needed.

  • 50.
    Zandawala, Meet
    et al.
    Stockholm University, Faculty of Science, Department of Zoology.
    Tian, Shi
    Elphick, Maurice R.
    The evolution and nomenclature of GnRH-type and corazonin-type neuropeptide signaling systems2018In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 264, p. 64-77Article, review/survey (Refereed)
    Abstract [en]

    Gonadotropin-releasing hormone (GnRH) was first discovered in mammals on account of its effect in triggering pituitary release of gonadotropins and the importance of this discovery was recognized forty years ago in the award of the 1977 Nobel Prize for Physiology or Medicine. Investigation of the evolution of GnRH revealed that GnRH-type signaling systems occur throughout the chordates, including agnathans (e.g. lampreys) and urochordates (e.g. sea squirts). Furthermore, the discovery that adipokinetic hormone (AKH) is the ligand for a GnRH-type receptor in the arthropod Drosophila melanogaster provided evidence of the antiquity of GnRH-type signaling. However, the occurrence of other AKH-like peptides in arthropods, which include corazonin and AKH/corazonin-related peptide (ACP), has complicated efforts to reconstruct the evolutionary history of this family of related neuropeptides. Genome/transcriptome sequencing has revealed that both GnRH-type receptors and corazonin-type receptors occur in lophotrochozoan protostomes (annelids, mollusks) and in deuterostomian invertebrates (cephalochordates, hemichordates, echinoderms). Furthermore, peptides that act as ligands for GnRH-type and corazonin-type receptors have been identified in mollusks. However, what has been lacking is experimental evidence that distinct GnRH-type and corazonin-type peptide-receptor signaling pathways occur in deuterostomes. Importantly, we recently reported the identification of two neuropeptides that act as ligands for either a GnRH-type receptor or a corazonin-type receptor in an echinoderm species - the common European starfish Asterias rubens. Discovery of distinct GnRH-type and corazonin-type signaling pathways in this deuterostomian invertebrate has demonstrated for the first time that the evolutionarily origin of these paralogous systems can be traced to the common ancestor of protostomes and deuterostomes. Furthermore, lineage-specific losses of corazonin signaling (in vertebrates, urochordates and nematodes) and duplication of the GnRH signaling system in arthropods (giving rise to the AKH and ACP signaling systems) and quadruplication of the GnRH signaling system in vertebrates (followed by lineage-specific losses or duplications) accounts for the phylogenetic distribution of GnRH/corazonin-type peptide-receptor pathways in extant animals. Informed by these new insights, here we review the history of research on the evolution of GnRH/corazonin-type neuropeptide signaling. Furthermore, we propose a standardized nomenclature for GnRH/corazonin-type neuropeptides wherein peptides are either named GnRH or corazonin, with the exception of the paralogous GnRH-type peptides that have arisen by gene duplication in the arthropod lineage and which are referred to as AKH (or red pigment concentrating hormone, RCPH, in crustaceans) and ACP.

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