| 4981. |
- Karlsson, Cecilia, 1983-
(författare)
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Insulin Signalling in Human Adipocytes and its Interplay with beta-Adrenergic Control of Lipolysis
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The prevalence of obesity has over the last 40 years nearly tripled and obesity is one of the major risk factors of developing type 2 diabetes. Type 2 diabetes was formerly called adultonset diabetes but today, probably due to the rise in childhood obesity, it is also seen in children and adolescents. Type 2 diabetes is diagnosed when the body no longer can control the glucose levels in the blood. This is due to an insulin resistant state in the insulin responding tissues, liver, adipose and muscle and insufficient production of insulin in the pancreas. However, in spite of extensive research the mechanisms behind insulin resistance is still not known.The adipose tissue is believed to play a major role in the development of whole body insulin resistance. Adipocytes are the most important sites for storage of the high energy containing triacylglycerols. Insulin stimulation causes the adipocyte to increase the uptake of glucose and to reduce lipolysis: the hydrolysis of triacylglycerol and release of glycerol and fatty acids. The insulin signalling network is complex with numerous proteins involved. These signaling proteins not only transmit the insulin signal but also create negative and positive feedbackloops and induce cross talk between different parts of the network and with the signalling of other hormones. One important positive feedback in insulin signalling is the mTORC1 mediated feedback to phosphorylation of IRS1 at serine 307. In paper I we found that in human adipocytes this feedback is not likely catalysed by the assumed kinase S6K1. However we find an immunoprecipitate of mTOR to contain a ser307 phosphorylating kinase.Scaffolding proteins serve as docking sites for several proteins to promote protein-protein interactions that facilitate signal transduction. In paper II we demonstrate the existence of the scaffolding protein IQGAP1 in human adipocytes and that the expression of IQGAP1 is downregulated in type 2 diabetes. We reveal that IQGAP1 co-localises with caveolae, invaginations of the plasma membrane where the insulin receptor is situated, and that this interaction is increased upon insulin stimulation.In paper III we focus on the control of lipolysis, and sought to understand the interplay between insulin and beta-adrenergic stimulation. We demonstrated that the re-esterification of fatty acids is downregulated in type 2 diabetes causing an increased release of fatty acids from the cells. We showed that beta-adrenergic stimulation with isoproterenol induced a negative feedback via PKA/Epac1 -> PI3K -> PKB -> PDE3B that reduced the cAMP levels and thereby also reduced lipolysis. We also showed that insulin, in addition to its well-known anti-lipolytic effect, at high concentrations had a positive effect on lipolysis. In conclusion we reveal an intricate control of the stimulation as well as the inhibition of lipolysis induced by both isoproterenol and insulin.
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| 4982. |
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| 4983. |
- Karlsson, Jan, 1950-, et al.
(författare)
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Effects on body weight, eating behavior, and quality of life of a low-energy diet combined with behavioral group treatment of persons with class II or III obesity : A 2-year pilot study
- 2021
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Ingår i: Obesity Science & Practice. - : John Wiley & Sons. - 2055-2238. ; 7:1, s. 4-13
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Obesity is associated with reduced health-related quality of life (HRQoL). Outcomes of nonsurgical weight loss treatment on HRQoL are inconsistent and it is unclear how much weight reduction, or what type of treatment, is required for significant improvements. This study aimed to evaluate the effects of a lifestyle intervention program on weight, eating behaviors, and HRQoL, and to describe participants' experiences of treatment.Methods: This 2-year intervention trial in persons with class II or III obesity comprised a 3-month liquid low-energy diet (880 kcal/d) followed by a 3-month reintroduction to regular foods, combined with behavioral group treatment.Results: Fifty-five participants (73% women) were included, mean (SD) age 43.2 (12.4) years, and mean body mass index 42.0 (6.0) kg/m(2). Mean weight loss at 6, 12, and 24 months was 18.9%, 13.7%, and 7.2%, respectively. Short- and long-term effects on eating behavior were favorable. Twelve of 14 HRQoL domains were improved at 6 months, compared to eight domains at 12 months. After 24 months, 2 of 14 domains, physical and psychosocial functioning, were improved. The treatment program was well accepted by the participants.Conclusions: Substantial weight loss after 6 months was associated with extensive improvements in HRQoL, comprising the physical, psychosocial, and mental domains. Significant weight regain was observed between 6 and 24 months follow-up. Modest weight loss after 24 months was associated with moderate improvement in physical functioning and large improvement in psychosocial functioning. The effect on psychosocial functioning is most likely related to both weight loss and behavioral treatment.
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| 4984. |
- Karlsson, L., et al.
(författare)
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Persistence with denosumab and persistence with oral bisphosphonates for the treatment of postmenopausal osteoporosis : a retrospective, observational study, and a meta-analysis
- 2015
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Ingår i: Osteoporosis International. - : Springer Science and Business Media LLC. - 0937-941X .- 1433-2965. ; 26:10, s. 2401-2411
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Tidskriftsartikel (refereegranskat)abstract
- The Summary The objectives of this study were to estimate persistence with denosumab and put these results in context by conducting a review of persistence with oral bisphosphonates. Persistence with denosumab was found to be higher than with oral bosphosphonates. Purpose This study had two objectives: to analyse persistence in Swedish women initiating denosumab for treatment of postmenopausal osteoporosis (PMO) and to put these findings in context by conducting a literature review and meta-analysis of persistence data for oral bisphosphonates. Methods The study used the Swedish Prescribed Drug Register and included women aged at least 50 years initiating denosumab between May 2010 and July 2012. One injection of denosumab was defined as 6-month persistence. Women were considered persistent for another 6 months if they filled their next prescription within 6 months + 56 days and survival analysis applied to the data. A literature search was conducted in PubMed to identify retrospective studies of persistence with oral bisphosphonates and pooled persistence estimates were calculated using a random-effects model. Results The study identified 2,315 women who were incident denosumab users. Mean age was 74 years and 61 % had been previously treated for PMO. At 12 and 24 months, persistence with denosumab was 83 % (95 % CI, 81-84 %) and 62 % (95 % CI, 60-65 %), respectively. The literature search identified 40 articles for inclusion in the meta-analysis. At 12 and 24 months, persistence with oral bisphosphonates ranged from 10 % to 78 % and from 16 % to 46 %, with pooled estimates of 45 % and 30 %, respectively. Conclusion These data from the Swedish Prescribed Drug Register and literature review suggest that persistence was higher with denosumab than with oral bisphosphonates.
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| 4985. |
- Karlsson, Magnus, et al.
(författare)
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International and ethnic variability of falls in older men
- 2014
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Ingår i: Scandinavian journal of public health. - : SAGE Publications. - 1651-1905 .- 1403-4948. ; 42:2, s. 194-200
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Tidskriftsartikel (refereegranskat)abstract
- Aims: Fallers and especially recurrent fallers are at high risk for injuries. The aim of this study was to evaluate fall epidemiology in older men with special attention to the influence of age, ethnicity and country of residence. Methods: 10,998 men aged 65 years or above recruited in Hong Kong, the United States (US) and Sweden were evaluated in a cross-sectional retrospective study design. Self-reported falls and fractures for the preceding 12 months were registered through questionnaires. Group comparisons were done by chi-square test or logistic regression. Results: The proportion of fallers among the total population was 16.5% in ages 65-69, 24.8% in ages 80-84 and 43.2% in ages above 90 (P <0.001). The corresponding proportions of recurrent fallers in the same age groups were 6.3%, 10.1% and 18.2%, respectively (P <0.001), and fallers with fractures 1.0%, 2.3% and 9.1%, respectively (P <0.001). The proportion of fallers was highest in the US, intermediate in Sweden and lowest in Hong Kong (in most age groups P <0.05). The proportion of fallers among white men in the US was higher than in white men in Sweden (all comparable age groups P <0.01) but there were no differences in the proportion of fallers in US men with different ethnicity. Conclusions: The proportion of fallers in older men is different in different countries, and data in this study corroborate with the view that society of residence influences fall prevalence more than ethnicity.
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| 4986. |
- Karlsson, Magnus, et al.
(författare)
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Physical activity as a strategy to reduce the risk of osteoporosis and fragility fractures.
- 2012
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Ingår i: International Journal of Endocrinology and Metabolism. - : Briefland. - 1726-913X .- 1726-9148. ; 10:3, s. 527-536
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Tidskriftsartikel (refereegranskat)abstract
- Childhood and adolescence are critical periods for the skeleton. Mechanical load has then been shown to be one of the best stimuli to enhance not only bone mass, but also structural skeletal adaptations, as both contributing to bone strength. Exercise prescription also includes a window of opportunity to improve bone strength in the late pre- and early peri-pubertal period. There is some evidence supporting the notion that skeletal gains obtained by mechanical load during growth are maintained at advanced age despite a reduction of physical activity in adulthood. The fact that former male athletes have a lower fracture risk than expected in their later years does not oppose the view that physical activity during growth and adolescence is important and it should be supported as one feasible strategy to reduce the future incidence of fragility fractures.
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| 4987. |
- Karlsson, Sofia A., et al.
(författare)
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Association between refill adherence to lipid-lowering medications and the risk of cardiovascular disease and mortality in Swedish patients with type 2 diabetes mellitus: a nationwide cohort study.
- 2018
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Ingår i: BMJ open. - : BMJ. - 2044-6055. ; 8:3
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Tidskriftsartikel (refereegranskat)abstract
- To analyse the association between refill adherence to lipid-lowering medications, and the risk of cardiovascular disease (CVD) and mortality in patients with type 2 diabetes mellitus.Cohort study.National population-based cohort of Swedish patients with type 2 diabetes mellitus.86 568 patients aged ≥18 years, registered with type 2 diabetes mellitus in the Swedish National Diabetes Register, who filled at least one prescription for lipid-lowering medication use during 2007-2010, 87% for primary prevention.Refill adherence of implementation was assessed using the medication possession ratio (MPR), representing the proportion of days with medications on hand during an 18-month exposure period. MPR was categorised by five levels (≤20%, 21%-40%, 41%-60%, 61%-80% and >80%). Patients without medications on hand for ≥180 days were defined as non-persistent. Risk of CVD (myocardial infarction, ischaemic heart disease, stroke and unstable angina) and mortality by level of MPR and persistence was analysed after the exposure period using Cox proportional hazards regression and Kaplan-Meier, adjusted for demographics, socioeconomic status, concurrent medications and clinical characteristics.The hazard ratios for CVD ranged 1.33-2.36 in primary prevention patients and 1.19-1.58 in secondary prevention patients, for those with MPR ≤80% (p<0.0001). The mortality risk was similar regardless of MPR level. The CVD risk was 74% higher in primary prevention patients and 33% higher in secondary prevention patients, for those who were non-persistent (p<0.0001). The mortality risk was 6% higher in primary prevention patients and 18% higher in secondary prevention patients, for non-persistent patients (p<0.0001).Higher refill adherence to lipid-lowering medications was associated with lower risk of CVD in primary and secondary prevention patients with type 2 diabetes mellitus.
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| 4988. |
- Karlsson, Sofia A., et al.
(författare)
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Prescription of lipid-lowering medications for patients with type 2 diabetes mellitus and risk-associated LDL cholesterol: a nationwide study of guideline adherence from the Swedish National Diabetes Register.
- 2018
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Ingår i: BMC health services research. - : Springer Science and Business Media LLC. - 1472-6963. ; 18:1
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Tidskriftsartikel (refereegranskat)abstract
- Management of type 2 diabetes mellitus (T2DM) encompasses intensive glycaemic control, along with treatment of comorbidities and complications to handle the increased risk of cardiovascular disease (CVD). Improved control of LDL-cholesterol (LDL-C) with lipid-lowering medications is associated with reduced CVD risk in T2DM patients. Thus, treatment guidelines recommend lipid-lowering medications for T2DM patients with LDL-C above risk-associated thresholds. This study aimed to assess healthcare provider adherence to guidelines regarding lipid-lowering medication prescription among T2DM patients and to analyse factors associated with lipid-lowering medication prescription.Observations in 2007 - 2014 for T2DM patients age ≥ 18 were collected from the Swedish National Diabetes Register. Observations were excluded if they lacked information about LDL-C, lipid-lowering medication prescription or CVD. Observations with established CVD were attributed to secondary prevention; remaining observations were attributed to primary prevention. The analyses included primary and secondary prevention observations with LDL-C above risk-associated thresholds (LDL-C ≥ 2.5 mmol/l and LDL-C ≥ 1.8 mmol/l respectively). Guideline adherence was analysed as the probability of prescribing lipid-lowering medications using mixed-effect model regression adjusted for potential confounders. Factors associated with prescribing lipid-lowering medications were analysed for patient and healthcare provider characteristics using mixed-effect model regression and odds ratio.A total of 1,204,376 observations from 322,046 patients reported by 1352 healthcare providers were included. Primary prevention accounted for 63%; 52% were men, mean age was 64 and mean LDL-C was 3.4 mmol/l. For secondary prevention, 60% were men, mean age was 72 and mean LDL-C was 2.7 mmol/l. During 2007-2014, guideline adherence ranged from 36 to 47% for primary prevention and 59 to 69% for secondary prevention. In general, concomitant prescription of diabetes medications, antiplatelets and antihypertensives along with smoking and specialised care were associated with higher prescription of lipid-lowering medications. Patients age ≥ 80 were associated with lower prescription of lipid-lowering medications. Higher prescription was associated with longer diabetes duration in primary prevention and men in secondary prevention.Adherence to treatment guidelines levelled off after an initial increase in both prevention groups. Lipid-lowering medication prescription was based on individualised CVD risk.
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| 4989. |
- Karlsson, Sofia A., et al.
(författare)
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Refill adherence and persistence to lipid-lowering medicines in patients with type 2 diabetes: A nation-wide register-based study.
- 2017
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Ingår i: Pharmacoepidemiology and drug safety. - : Wiley. - 1099-1557 .- 1053-8569. ; 26:10
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Tidskriftsartikel (refereegranskat)abstract
- This study aimed to describe and compare refill adherence and persistence to lipid-lowering medicines in patients with type 2 diabetes by previous cardiovascular disease (CVD).We followed 97 595 patients (58% men; 23% with previous CVD) who were 18 years of age or older when initiating lipid-lowering medicines in 2007-2010 until first fill of multi-dose dispensed medicines, death, or 3 years. Using personal identity numbers, we linked individuals' data from the Swedish Prescribed Drug Register, the Swedish National Diabetes Register, the National Patient Register, the Cause of Death Register, and the Longitudinal Integration Database for Health Insurance and Labour Market Studies. We assessed refill adherence using the medication possession ratio (MPR) and the maximum gap method, and measured persistence from initiation to discontinuation of treatment or until 3 years after initiation. We analyzed differences in refill adherence and persistence by previous CVD in multiple regression models, adjusted for socioeconomic status, concurrent medicines, and clinical characteristics.The mean age of the study population was 64 years, 80% were born in Sweden, and 56% filled prescriptions for diabetes medicines. Mean MPR was 71%, 39% were adherent according to the maximum gap method, and mean persistence was 758 days. Patients with previous CVD showed higher MPR (3%) and lower risk for discontinuing treatment (12%) compared with patients without previous CVD (P < 0.0001).Patients with previous CVD were more likely to be adherent to treatment and had lower risk for discontinuation compared with patients without previous CVD.
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| 4990. |
- Kassem, Ali, et al.
(författare)
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TLR5, a novel mediator of innate immunity-induced osteoclastogenesis and bone loss
- 2015
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Ingår i: Faseb Journal. - : Wiley. - 0892-6638 .- 1530-6860. ; 29:11, s. 4449-4460
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Tidskriftsartikel (refereegranskat)abstract
- Accumulating evidence points to the importance of the innate immune system in inflammation-induced bone loss in infectious and autoimmune diseases. TLRs are well known for being activated by ligands expressed by bacteria, viruses, and fungi. Recent findings indicate that also endogenous ligands in inflammatory processes are important, one being a TLR5 agonist present in synovial fluid from patients with rheumatoid arthritis (RA). We found that activation of TLR5 by its specific ligand, flagellin, caused robust osteoclast formation and bone loss in cultured mouse neonatal parietal bones dependent on increased receptor activator of NF-kappa B ligand (RANKL): osteoprotegerin ratio, with half-maximal stimulation at 0.01 mu g/ml. Flagellin enhanced Rankl mRNA in isolated osteoblasts by a myeloid differentiation primary response gene 88 and NF-kappa B-dependent mechanism. Injection of flagellin locally over skull bones in 5-wk-oldmice resulted in increased mRNA expression of Rankl and osteoclastic genes, robust osteoclast formation, and bone loss. The effects in vitro and in vivo were absent in Tlr5(-/-) mice. These data show that TLR5 is a novel activator of RANKL and osteoclast formation and, therefore, a potential key factor in inflammation-induced bone erosions in diseases like RA, reactive arthritis, and periodontitis. TLR5 might be a promising novel treatment target for prevention of inflammatory bone loss.
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