| 1. |
- Pazarlis, Konstantinos, MD, 1983-
(författare)
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On the Diagnosis and Treatment of Lumbar Spinal Stenosis
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Lumbar spinal stenosis (LSS) is the most common indication for spinal surgery. The aging global population is increasing the demand for strategies that promote physical activity among the elderly. As the prevalence of LSS rises, the condition gains constantly demographic and socioeconomic attention. Until recently, there has been no clear consensus regarding LSS treatment. Further, using electrodiagnostic examinations (EDX) as predictive tools to identify surgical candidates, could lead to a more tailored medical approach. Methodological issues in previous studies have left some questions unanswered. The necessity of extensive surgery for LSS remains a topic of debate among spinal surgeons, which this work addressed by analyzing data from 723 patients. Parts of the work aimed to compare surgery and structured non-surgical treatment for LSS (Paper I, II, III). Furthermore, it aimed to investigate, by means of EDX, whether the degree of neurological affection correlates to the surgical outcome of LSS (Paper I, II). Additionally, this work evaluated the radiological outcome for surgical vs non-surgical treatment for LSS in terms of sagittal balance parameters (Paper III, V). Finally, parts of this thesis aimed to confirm findings from previous studies regarding DA and DF for LSS with DS (Paper IV, V). The current thesis is based on two randomized controlled trials and a cohort study: the Uppsala Spinal Stenosis Trial, the Swedish Spinal Stenosis Study, and the Cohort Study on LSS with DS. Patient reported outcome measures from the Swedish National Quality Registry for Spine Surgery (Swespine) were used to collect follow-up data. We concluded that at six months, surgery with decompression leads to superior clinical outcome, compared to structured physical therapy. The improvement is not affected by delay of surgery (Paper II). EDX does not add predictive value when assessing the patients for eligibility before surgery (Paper II). DA improves the spinal sagittal balance, regardless of preoperative DS (Paper III) and provides good two-year clinical outcome in LSS with DS with low rate of complications, and low need for subsequent surgery (Paper IV). New radiological stenosis was less common two years after DA than after DF, in LSS with or without preoperative DS (Paper V).
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| 2. |
- Sundström, Johan, Professor, 1971-, et al.
(författare)
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Risk factors for subarachnoid haemorrhage : a nationwide cohort of 950 000 adults
- 2019
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Ingår i: International Journal of Epidemiology. - : Oxford University Press. - 0300-5771 .- 1464-3685. ; 48:6, s. 2018-2025
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Subarachnoid haemorrhage (SAH) is a devastating disease, with high mortality rate and substantial disability among survivors. Its causes are poorly understood. We aimed to investigate risk factors for SAH using a novel nationwide cohort consortium.METHODS: We obtained individual participant data of 949 683 persons (330 334 women) between 25 and 90 years old, with no history of SAH at baseline, from 21 population-based cohorts. Outcomes were obtained from the Swedish Patient and Causes of Death Registries.RESULTS: During 13 704 959 person-years of follow-up, 2659 cases of first-ever fatal or non-fatal SAH occurred, with an age-standardized incidence rate of 9.0 [95% confidence interval (CI) (7.4-10.6)/100 000 person-years] in men and 13.8 [(11.4-16.2)/100 000 person-years] in women. The incidence rate increased exponentially with higher age. In multivariable-adjusted Poisson models, marked sex interactions for current smoking and body mass index (BMI) were observed. Current smoking conferred a rate ratio (RR) of 2.24 (95% CI 1.95-2.57) in women and 1.62 (1.47-1.79) in men. One standard deviation higher BMI was associated with an RR of 0.86 (0.81-0.92) in women and 1.02 (0.96-1.08) in men. Higher blood pressure and lower education level were also associated with higher risk of SAH.CONCLUSIONS: The risk of SAH is 45% higher in women than in men, with substantial sex differences in risk factor strengths. In particular, a markedly stronger adverse effect of smoking in women may motivate targeted public health initiatives.
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| 3. |
- Titova, Olga E., et al.
(författare)
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Comprehensive analyses of circulating cardiometabolic proteins and objective measures of fat mass
- 2023
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Ingår i: International Journal of Obesity. - : Springer Nature. - 1476-5497 .- 0307-0565. ; 47:11, s. 1043-1049
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Tidskriftsartikel (refereegranskat)abstract
- Background: The underlying molecular pathways for the effect of excess fat mass on cardiometabolic diseases is not well understood. Since body mass index is a suboptimal measure of body fat content, we investigated the relationship of fat mass measured by dual-energy X-ray absorptiometry with circulating cardiometabolic proteins. Methods: We used data from a population-based cohort of 4950 Swedish women (55–85 years), divided into discovery and replication samples; 276 proteins were assessed with three Olink Proseek Multiplex panels. We used random forest to identify the most relevant biomarker candidates related to fat mass index (FMI), multivariable linear regression to further investigate the associations between FMI characteristics and circulating proteins adjusted for potential confounders, and principal component analysis (PCA) for the detection of common covariance patterns among the proteins. Results: Total FMI was associated with 66 proteins following adjustment for multiple testing in discovery and replication multivariable analyses. Five proteins not previously associated with body size were associated with either lower FMI (calsyntenin-2 (CLSTN2), kallikrein-10 (KLK10)), or higher FMI (scavenger receptor cysteine-rich domain-containing group B protein (SSC4D), trem-like transcript 2 protein (TLT-2), and interleukin-6 receptor subunit alpha (IL-6RA)). PCA provided an efficient summary of the main variation in FMI-related circulating proteins involved in glucose and lipid metabolism, appetite regulation, adipocyte differentiation, immune response and inflammation. Similar patterns were observed for regional fat mass measures. Conclusions: This is the first large study showing associations between fat mass and circulating cardiometabolic proteins. Proteins not previously linked to body size are implicated in modulation of postsynaptic signals, inflammation, and carcinogenesis.
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| 4. |
- Zheng, Rui, 1990-
(författare)
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Metabolomics, body composition and fracture
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In this thesis, I evaluated the impact of pre-centrifugation sample management on the plasma metabolome, providing verification for the protocol used in a study where I applied metabolomics to better understand the role of body composition in fracture occurrence using a large population-based cohort. In paper 1, I applied untargeted liquid chromatography-mass spectrometry (LC-MS) metabolomics analysis to plasma samples (n = 471) from healthy donors to predict and evaluate the effect of pre-centrifugation temperature and delay time on metabolomics data using a combination of random forest and generalized linear models. I found that delayed treatment (up to 210 min) of blood samples can induce variation to the plasma metabolome at all three temperatures (4, 25 and 37 °C) and thus blood samples should be managed as expediently as possible, preferably at room temperature. Metabolite panels were constructed and validated to predict the pre-centrifugation management conditions of plasma samples.In paper 2, I used a full cohort of men and women (n = 44,366), and a subcohort of women (n = 5022) to investigate the associations between anthropometrics or body composition and fracture risk. I found that lower body mass index (BMI), prior loss of BMI and higher central obesity were associated with increased risks of fracture. The joint analysis revealed that prior gain of BMI was protective against fracture only in individuals with normal weight. The associations between lean mass index (LMI) or fat mass index (FMI) and fracture risk were heavily dependent on bone mineral density (BMD) in the study population. Based on findings of paper 2, a metabolome-wide association of LMI, FMI and BMD was conducted in the subcohort. Metabolites associated with at least one body composition outcome were then associated with hip fracture risk, resulting in the discovery of twenty-three metabolites of interest. Network analysis of these hip fracture-related metabolites highlighted the important role of lysoglycerophospholipids in the skeletomuscular-adipose crosstalk. Mendelian randomization analyses suggested several causal associations between these hip fracture-related metabolites and body composition measures or bone-related clinical biomarkers.In summary, metabolites can reflect perturbations induced by pre-centrifugation management of samples and thus provide valuable information of sample quality. To optimally prevent fractures at older age, low BMI, prior BMI loss and central obesity should be avoided. Metabolites reflecting differences in, and crosstalk of skeletomuscular-adipose tissues may contribute to a further understanding of fracture occurrence and discoveries of actionable targets for prevention.
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| 5. |
- Brüggemann, Anders
(författare)
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Hip Revision Surgery : Identification of Genetic Markers and Evaluation of Novel Treatment Strategies
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Total hip arthroplasty (THA) is, despite its overall good outcome, for some patients followed by hip revision surgery. This seems in parts to be because of genetic susceptibility to revision surgery. The most common reason for revision surgery is aseptic loosening followed by periprosthetic joint infection and dislocation. Cups made of porous tantalum (TM cups) were thought to be favorable in revision surgery to address aseptic loosening, but they seem to confer an increased risk of dislocation. The effectiveness and biocompatibility in vivo of TM cups have not been researched. Dual mobility cups (DMCs) with two articulating surfaces are proposed to prevent dislocation to a higher degree than standard polyethylene liners.Our hypotheses were that TM cups are superior to their historical treatment alternative in terms of re-revision rates; that the combination of DMC cemented into TM cups would decrease the risk for dislocation after revision surgery; that tantalum ion liberation is marginal after the use of TM cups; and that certain risk genes are associated with an increased risk for revision surgery after total joint arthroplasty.Studies I&II were register-based cohort studies comparing the implant survival of TM cups and conventional acetabular reinforcement rings (study I), and the combination of TM cups/DMC with TM cups/standard polyethylene liners (study II). We found that TM cups perform equally well as reinforcement rings, but that the two implants differ in their failure mechanisms. Cementing a DMC into TM cups adequately addressed the issue of recurrent dislocation. In study III we investigated whether tantalum ion liberation does occur after implantation of a TM cups and how this affects patients’ immunological response by comparison of three groups: primary non-tantalum THA, primary tantalum THA and revision tantalum THA. We found the highest concentration of tantalum ions in the revision cases, yet tantalum ions were not associated with an immunological response, and we found no signs of alteration in the investigated lymphocyte subsets. Study IV aimed to identify possible risk genes for revision surgery after total hip or knee replacement by a genome wide association study. We found six significant risk genes for the endpoint revision surgery for any reason, and three for the endpoint revision due to aseptic loosening. We found a variety of suggestive risk genes within the region coding for the ABO-system.In conclusion, the novel treatment options TM cups and DMC show good results in hip revision surgery, but longer follow-up is warranted. The use of porous tantalum seems not to be associated with the immunological activation that can be observed in metallosis. The risk for revision surgery is associated with certain risk genes.
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| 6. |
- Byberg, Liisa, et al.
(författare)
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Total mortality after changes in leisure time physical activity in 50 year old men : 35 year follow-up of population based cohort
- 2009
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Ingår i: British Journal of Sports Medicine. - : BMJ Publishing Group Ltd. - 0306-3674 .- 1473-0480. ; 338, s. b688-
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To examine how change in level of physical activity after middle age influences mortality and to compare it with the effect of smoking cessation.Design: Population based cohort study with follow-up over 35 years.Setting: Municipality of Uppsala, Sweden.Participants: 2205 men aged 50 in 1970-3 who were reexamined at ages 60, 70, 77, and 82 years.Main Outcome Measure: Total (all cause) mortality.Results: The absolute mortality rate was 27.1, 23.6, and 18.4 per 1000 person years in the groups with low, medium, and high physical activity, respectively. The relative rate reduction attributable to high physical activity was 32% for low and 22% for medium physical activity. Men who increased their physical activity level between the ages of 50 and 60 continued to have a higher mortality rate during the first five years of follow-up (adjusted hazard ratio 2.64, 95% confidence interval 1.32 to 5.27, compared with unchanged high physical activity). After 10 years of follow-up their increased physical activity was associated with reduced mortality to the level of men with unchanged high physical activity (1.10, 0.87 to 1.38). The reduction in mortality associated with increased physical activity (0.51, 0.26 to 0.97, compared with unchanged low physical activity) was similar to that associated with smoking cessation (0.64, 0.53 to 0.78, compared with continued smoking).Conclusions: Increased physical activity in middle age is eventually followed by a reduction in mortality to the same level as seen among men with constantly high physical activity. This reduction is comparable with that associated with smoking cessation
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| 7. |
- Folkersen, Lasse, et al.
(författare)
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Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals.
- 2020
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Ingår i: Nature metabolism. - : Springer Science and Business Media LLC. - 2522-5812. ; 2:10, s. 1135-1148
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Tidskriftsartikel (refereegranskat)abstract
- Circulating proteins are vital in human health and disease and are frequently used as biomarkers for clinical decision-making or as targets for pharmacological intervention. Here, we map and replicate protein quantitative trait loci (pQTL) for 90 cardiovascular proteins in over 30,000 individuals, resulting in 451 pQTLs for 85 proteins. For each protein, we further perform pathway mapping to obtain trans-pQTL gene and regulatory designations. We substantiate these regulatory findings with orthogonal evidence for trans-pQTLs using mouse knockdown experiments (ABCA1 and TRIB1) and clinical trial results (chemokine receptors CCR2 and CCR5), with consistent regulation. Finally, we evaluate known drug targets, and suggest new target candidates or repositioning opportunities using Mendelian randomization. This identifies 11 proteins with causal evidence of involvement in human disease that have not previously been targeted, including EGF, IL-16, PAPPA, SPON1, F3, ADM, CASP-8, CHI3L1, CXCL16, GDF15 and MMP-12. Taken together, these findings demonstrate the utility of large-scale mapping of the genetics of the proteome and provide a resource for future precision studies of circulating proteins in human health.
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| 8. |
- Laszkowska, M., et al.
(författare)
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Systematic review with meta-analysis : the prevalence of coeliac disease in patients with osteoporosis
- 2018
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Ingår i: Alimentary Pharmacology and Therapeutics. - : Blackwell Publishing. - 0269-2813 .- 1365-2036. ; 48:6, s. 590-597
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Forskningsöversikt (refereegranskat)abstract
- Background: Earlier studies have produced highly varying risk estimates for the prevalence of coeliac disease (CD) in osteoporosis.Aims: To investigate the prevalence of CD among individuals with osteoporosis.Methods: We conducted a systematic review of articles published in PubMed, Medline or EMBASE through May 2017 to identify studies looking at prevalence of CD in patients with osteoporosis. Search terms included "coeliac disease" combined with fractures, bone disease, bone density, densitometry, "osteoporos", "osteomal", "osteodys" or "dexa" or "dxa" or "skelet". Non-English papers with English-language abstracts were included. We used fixed-effects inverse variance-weighted models, and tested heterogeneity through subgroup analysis as well as through meta-regression.Results: We identified eight relevant studies, comprising data from 3188 individuals with osteoporosis. Of these, 59 individuals (1.9%) had CD. A weighted pooled analysis demonstrated biopsy-confirmed CD in 1.6% (95% CI=1.1%-2.0%) of individuals with osteoporosis. The heterogeneity was moderate (I-2=40.1%), and influenced by the underlying CD prevalence in the general population. After adding four studies (n=814) with CD defined as positive tissue transglutaminase or endomysial antibodies, the pooled prevalence was comparable (1.6%; 95% CI=1.2%-2.0%).Conclusions: About 1 in 62 individuals with osteoporosis, or 1.6%, have biopsy-verified CD. This prevalence is comparable to that in the general population. These findings argue against routinely screening patients with osteoporosis for CD, which is contrary to current guideline recommendations. Additional studies are needed to determine the true utility of such screening programs.
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| 9. |
- Lind, Lars, et al.
(författare)
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On the association between body fat and left ventricular mass
- 2019
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Ingår i: Journal of Hypertension. - 0263-6352 .- 1473-5598. ; 37:8, s. 1699-1704
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: As intervention studies have shown a reduction in body weight to be paralleled with a reduction in left ventricular mass (LVM), we quantified a hypothesized causal relationship between fat mass and LVM, and how much of these effects that was mediated by blood pressure (BP), diabetes and adipokines. Also visceral and subcutaneous adipose tissue (VAT and SAT) were explored in the same fashion.Methods: In the Prospective Study of the Vasculature in Uppsala Seniors study (n = 1016, 50% women, all aged 70 years), LVM was measured by echocardiography (indexed for lean mass, LVMI), fat and lean mass by dual-energy X-ray. VAT and SAT were measured by abdominal MRI (in n = 275).Results: In a structural equation model adjusting for sex, the total effect of fat mass on LVMI was large (standardized coefficient 0.280, P = 3.2 × 10−15, 95% confidence interval 0.210–0.349). Out of the total effect of fat mass on LVMI, 29.0% was mediated by BP and glucose (P = 2.4 × 10−12). The BP pathway was most important, mediating 24.4% of the total effect of fat mass on LVMI (P = 4.6 × 10−7), while the glucose pathway accounted for 4.6% (P = 0.033). The association of VAT with LVMI (0.202, P = 2.4 × 10−4) was slightly weaker than that of SAT with LVMI (0.283, P = 1.0 × 10−6). Of several measured adipokines, leptin was a significant mediator of the effect of fat mass on LVMI (P = 3.0 × 10−3).Conclusion: One-third of the hypothesized association between body fat and LVMI was mediated by BP and glucose in this population-based cohort. Leptin was also an important mediator. Visceral adipose tissue was not more closely related to LVMI than subcutaneous abdominal fat.
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| 10. |
- Lind, Lars, et al.
(författare)
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Plasma Protein Profiling of Incident Cardiovascular Diseases : A Multisample Evaluation
- 2023
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Ingår i: CIRCULATION-GENOMIC AND PRECISION MEDICINE. - : Wolters Kluwer. - 2574-8300. ; 16:6
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Proteomic profiling could potentially disclose new pathophysiological pathways for cardiovascular diseases (CVD) and improve prediction at the individual level. We therefore aimed to study the plasma protein profile associated with the incidence of different CVDs.METHODS: Plasma levels of 245 proteins suspected to be linked to CVD or metabolism were measured in 4 Swedish prospective population-based cohorts (SIMPLER [Swedish Infrastructure for Medical Population-Based Life-Course and Environmental Research], ULSAM (Uppsala Longitudinal Study of Adult Men), EpiHealth, and POEM [Prospective Investigation of Obesity, Energy Production, and Metabolism]) comprising 11 869 individuals, free of CVD diagnoses at baseline. Our primary CVD outcome was defined by a combined end point that included either incident myocardial infarction, stroke, or heart failure.RESULTS: Using a discovery/validation approach, 42 proteins were associated with our primary composite end point occurring in 1163 subjects. In separate meta-analyses for each of the 3 CVD outcomes, 49 proteins were related to myocardial infarction, 34 to ischemic stroke, and 109 to heart failure. Thirteen proteins were related to all 3 outcomes. Of those, urokinase plasminogen activator surface receptor, adrenomedullin, and KIM-1 (kidney injury molecule 1) were also related to several markers of subclinical CVD in Prospective Investigation of Obesity, Energy production and Metabolism, reflecting myocardial or arterial pathologies. In prediction analysis, a lasso selection of 11 proteins in ULSAM improved the discrimination of CVD by 3.3% (P<0.0001) in SIMPLER when added to traditional risk factors.CONCLUSIONS: Protein profiling in multiple samples disclosed several new proteins to be associated with subsequent myocardial infarction, stroke, and heart failure, suggesting common pathophysiological pathways for these diseases. KIM-1, urokinase plasminogen activator surface receptor, and adrenomedullin were novel early markers of CVD. A selection of 11 proteins improved the discrimination of CVD.
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| 11. |
- Ludvigsson, Jonas F., 1969-, et al.
(författare)
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Adaptation of the Charlson Comorbidity Index for Register-Based Research in Sweden
- 2021
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Ingår i: Clinical Epidemiology. - : Dove Medical Press Ltd.. - 1179-1349. ; 13, s. 21-41
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Comorbidity indices are often used to measure comorbidities in register-based research. We aimed to adapt the Charlson comorbidity index (CCI) to a Swedish setting.Methods: Four versions of the CCI were compared and evaluated by disease-specific experts.Results: We created a cohesive coding system for CCI to 1) harmonize the content between different international classification of disease codes (ICD-7,8,9,10), 2) delete incorrect codes, 3) enhance the distinction between mild, moderate or severe disease (and between diabetes with and without end-organ damage), 4) minimize duplication of codes, and 5) briefly explain the meaning of individual codes in writing.Conclusion: This work may provide an integrated and efficient coding algorithm for CCI to be used in medical register-based research in Sweden.
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| 12. |
- Mitchell, Adam
(författare)
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Insights into the Effects of Type 2 Diabetes on Bone Health
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Individuals with type 2 diabetes mellitus (T2DM) have an increased risk of hip fracture, despite a stable or even greater bone mineral density (BMD). Bone area is linked to hip fracture risk independent of BMD and smaller bone area has been reported in T2DM subjects at the radius and tibia, but information at the hip is lacking. The Mediterranean diet is associated with a lower risk of hip fracture yet the mechanisms are unclear. The diet’s effect on T2DM status may be a possible mechanism. This thesis aims to discern the effects fasting glucose levels and T2DM have on bone.In paper I, clinical cut offs of fasting glucose used to define T2DM, were used to explore the association with BMD, bone area and bone turnover markers in the Swedish mammography cohort clinical (SMCC) and the Uppsala longitudinal study of adult men (ULSAM). T2DM was associated with greater BMD yet lower bone area at the total hip when compared to those without T2DM. T2DM was also associated with lower levels of bone turnover markers.In paper II, a Mendelian randomisation (MR) study was used to assess the potential causal effects of genetically predicted fasting glucose concentrations on bone area and BMD in partici-pants from SMCC, the prospective investigation in the vasculature of Uppsala seniors (PIVUS) and ULSAM. Results suggest an increase in genetically predicted fasting glucose concentrations may be a causal risk factor for lower bone area and possibly greater BMD.In paper III, the association between T2DM status and change in bone area and BMD over 8 years, was analysed in the SMCC, PIVUS and ULSAM. Those with incident T2DM had a lesser expansion in bone area at the total hip compared to those without T2DM.In paper IV, causal inference mediation analyses were used to estimate the direct effect of Mediterranean diet on the risk of hip fracture and the possible mediating effects of T2DM and BMI in the Swedish mammography cohort (SMC) and the cohort of Swedish men (COSM). Results showed a direct effect of the Mediterranean diet on the risk of hip fracture but ruled out the effects of T2DM and BMI as major mediators.In summary, T2DM and fasting glucose were associated with lower bone area at the hip. This may provide important mechanistic evidence as to why those with T2DM have a greater risk of hip fracture. We cannot rule out mediation or counteracting effects but there is an effect of Medi-terranean diet on hip fracture that does not go through T2DM and BMI.
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