Publications by authors named "Mariann I Lassenius"

16 Publications

  • Page 1 of 1

Characteristics and survival trends in Finnish multiple myeloma patients-a nationwide real-world evidence study.

Ann Hematol 2021 Mar 12. Epub 2021 Mar 12.

Department of Hematology, University of Helsinki, Helsinki University Hospital, Helsinki, Finland.

Current understanding of the epidemiology and outcomes for patients with multiple myeloma in Finland is scarce due to lack of comprehensive real-world evidence in clinical practice. The aim of this study was to gain understanding of epidemiological characteristics and treatment and survival outcomes by utilizing multiple real-world data sources with information of adults treated for active multiple myeloma (MM) during years 2005-2016 in Finland. A total of 3851 adult MM patients with C90.0 diagnosis fulfilling all inclusion criteria were included in the analysis. The average myeloma incidence was six cases per 100,000, which slightly increased (p = 0.011) during the follow-up. The age-standardized incidence was three cases per 100,000 in the years 2005-2016. On average, 25% of patients received autologous stem cell transplantation (ASCT), and this proportion increased during the years 2005-2015 from 17 to 30%. The majority of patients under 65 years of age received ASCT treatment (60.5%), whereas only 8.7% of patients 65 years of age or older were treated with ASCT. The net median overall survival improved by approximately 5 months from 2005-2010 (3.44 years) to 2011-2016 (3.89 years); after adjusting for covariates, this presented an annual 4% reduction in the risk of death. Longer median survival and decreased risk of death indicate improved treatment outcomes from 2005 to 2016 among adult MM patients in Finland.
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http://dx.doi.org/10.1007/s00277-021-04481-4DOI Listing
March 2021

Cardiovascular event rates increase after each recurrence and associate with poor statin adherence.

Eur J Prev Cardiol 2020 Jul 7. Epub 2020 Jul 7.

Heart Centre, Turku University Hospital and University of Turku, Finland.

Aims: The study evaluated the quality of cardiovascular prevention in real-world clinical practice. The recurrence of up to five cardiovascular events was assessed, as data on recurrence beyond the first event and interindividual variations in event rates past the second event have been sparse. Low-density lipoprotein cholesterol concentrations and lipid-lowering therapy use were investigated.

Methods: This retrospective register-based study included adult patients with an incident cardiovascular event between 2004 and 2016 treated in the hospital district of southwest Finland. Patients were followed for consecutive cardiovascular events or cardiovascular death, low-density lipoprotein cholesterol and statin purchases. The timing of event recurrence was evaluated, and predictive factors were assessed.

Results: A wide interindividual variation in cardiovascular event recurrence was observed, each additional event caused an increased risk, the median time of recurrence decreased from 7 to one year for the second and fifth event. Event rates increased correspondingly from 12 to 43/100 patient-years and were most pronounced in the first years following the previous event. The low-density lipoprotein cholesterol goal (<1.8 mmol/l) was reached by 18% in the year after the event and statin underuse was associated with an increased risk of recurrence. Six months after the index event high intensity statins were used by only 22% of the cohort.

Conclusion: The study provides new perspectives on individual risk assessment showing that event rates are not stable for all patients but increase 1.2-1.9-fold per consecutive event. The underuse of statins and poor adherence support the identification of these patients for intensified multifactorial preventive measures.
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http://dx.doi.org/10.1177/2047487320904334DOI Listing
July 2020

The Gaucher earlier diagnosis consensus point-scoring system (GED-C PSS): Evaluation of a prototype in Finnish Gaucher disease patients and feasibility of screening retrospective electronic health record data for the recognition of potential undiagnosed patients in Finland.

Mol Genet Metab Rep 2021 Jun 9;27:100725. Epub 2021 Feb 9.

Takeda Oy, Ilmalantori 1, 00101 Helsinki, Finland.

Background: Gaucher disease (GD) is a rare inherited multiorgan disorder, yet a diagnosis can be significantly delayed due to a broad spectrum of symptoms and lack of disease awareness. Recently, the prototype of a GD point-scoring system (PSS) was established by the Gaucher Earlier Diagnosis Consensus (GED-C) initiative, and more recently, validated in Gaucher patients in UK. In our study, the original GED-C PSS was tested in Finnish GD patients. Furthermore, the feasibility of point scoring large electronic health record (EHR) data set by data mining to identify potential undiagnosed GD cases was evaluated.

Methods: This biobank study was conducted in collaboration with two Finnish biobanks. Five previously diagnosed Finnish GD patients and ~ 170,000 adult biobank subjects were included in the study. The original PSS was locally adjusted due to data availability issues and applied to the Finnish EHR data representing special health care recordings.

Results: All GD patients had high levels of the biomarker lyso-Gb1 and deleterious mutations. One patient was a compound heterozygote with a novel variant, potentially pathogenic mutation. Finnish EHR data allowed the retrospective assessment of 27-30 of the 32 original GED-C signs/co-variables. Total point scores of GD patients were high but variable, 6-18.5 points per patient (based on the available data on 28-29 signs/co-variables per patient). All GD patients had been recorded with anaemia while only three patients had a record of splenomegaly. 0.72% of biobank subjects were assigned at least 6 points but none of these potential "GD suspects" had a point score as high as 18.5. Splenomegaly had been recorded for 0.25% of biobank subjects and was associated with variable point score distribution and co-occurring ICD-10 diagnoses.

Discussion: This study provides an indicative GED-C PSS score range for confirmed GD patients, also representing potential mild cases, and demonstrates the feasibility of scoring Finnish EHR data by data mining in order to screen for undiagnosed GD patients. Further prioritisation of the "GD suspects" with more developed algorithms and data-mining approaches is needed.

Funding: This study was funded by Shire (now part of Takeda).
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http://dx.doi.org/10.1016/j.ymgmr.2021.100725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7875822PMC
June 2021

Cardiovascular event rates increase after each recurrence and associate with poor statin adherence.

Eur J Prev Cardiol 2020 Feb 3:2047487320904334. Epub 2020 Feb 3.

Heart Centre, Turku University Hospital and University of Turku, Finland.

Aims: The study evaluated the quality of cardiovascular prevention in real-world clinical practice. The recurrence of up to five cardiovascular events was assessed, as data on recurrence beyond the first event and interindividual variations in event rates past the second event have been sparse. Low-density lipoprotein cholesterol concentrations and lipid-lowering therapy use were investigated.

Methods: This retrospective register-based study included adult patients with an incident cardiovascular event between 2004 and 2016 treated in the hospital district of southwest Finland. Patients were followed for consecutive cardiovascular events or cardiovascular death, low-density lipoprotein cholesterol and statin purchases. The timing of event recurrence was evaluated, and predictive factors were assessed.

Results: A wide interindividual variation in cardiovascular event recurrence was observed, each additional event caused an increased risk, the median time of recurrence decreased from 7 to one year for the second and fifth event. Event rates increased correspondingly from 12 to 43/100 patient-years and were most pronounced in the first years following the previous event. The low-density lipoprotein cholesterol goal (<1.8 mmol/l) was reached by 18% in the year after the event and statin underuse was associated with an increased risk of recurrence. Six months after the index event high intensity statins were used by only 22% of the cohort.

Conclusion: The study provides new perspectives on individual risk assessment showing that event rates are not stable for all patients but increase 1.2-1.9-fold per consecutive event. The underuse of statins and poor adherence support the identification of these patients for intensified multifactorial preventive measures.
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http://dx.doi.org/10.1177/2047487320904334DOI Listing
February 2020

Burden of migraine in Finland: multimorbidity and phenotypic disease networks in occupational healthcare.

J Headache Pain 2020 Jan 31;21(1). Epub 2020 Jan 31.

Terveystalo Biobank Finland, Turku, Finland.

Background: Migraine is a complex neurological disorder with high co-existing morbidity burden. The aim of our study was to examine the overall morbidity and phenotypic diseasome for migraine among people of working age using real world data collected as a part of routine clinical practice.

Methods: Electronic medical records (EMR) of patients with migraine (n = 17,623) and age- and gender matched controls (n = 17,623) were included in this retrospective analysis. EMRs were assessed for the prevalence of ICD-10 codes, those with at least two significant phi correlations, and a prevalence >2.5% in migraine patients were included to phenotypic disease networks (PDN) for further analysis. An automatic subnetwork detection algorithm was applied in order to cluster the diagnoses within the PDNs. The diagnosis-wise connectivity based on the PDNs was compared between migraine patients and controls to assess differences in morbidity patterns.

Results: The mean number of diagnoses per patient was increased 1.7-fold in migraine compared to controls. Altogether 1337 different ICD-10 codes were detected in EMRs of migraine patients. Monodiagnosis was present in 1% and 13%, and the median number of diagnoses was 12 and 6 in migraine patients and controls. The number of significant phi-correlations was 2.3-fold increased, and cluster analysis showed more clusters in those with migraine vs. controls (9 vs. 6). For migraine, the PDN was larger and denser and exhibited one large cluster containing fatigue, respiratory, sympathetic nervous system, gastrointestinal, infection, mental and mood disorder diagnoses. Migraine patients were more likely affected by multiple conditions compared to controls, even if no notable differences in morbidity patterns were identified through connectivity measures. Frequencies of ICD-10 codes on a three character and block level were increased across the whole diagnostic spectrum in migraine.

Conclusions: Migraine was associated with an increased multimorbidity, evidenced by multiple different approaches in the study. A systematic increase in the morbidity across the whole spectrum of ICD-10 coded diagnoses, and when interpreting PDNs, were detected in migraine patients. However, no specific diagnoses explained the morbidity. The results reflect clinical praxis, but also undoubtedly, the pathophysiological phenotypes related to migraine, and emphasize the importance of better understanding migraine-related morbidity.
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http://dx.doi.org/10.1186/s10194-020-1077-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6995206PMC
January 2020

Forced Vital Capacity (FVC) decline, mortality and healthcare resource utilization in idiopathic pulmonary fibrosis.

Eur Clin Respir J 2020 17;7(1):1702618. Epub 2019 Dec 17.

Hospital administration, Tampere University Hospital, Tampere, Finland.

: Potential care implications of antifibrotic reimbursement restrictions were studied by forced vital capacity (FVC) decline, mortality and specialty care related healthcare resource utilization in patients with idiopathic pulmonary fibrosis (IPF). : IPF patients were identified from the electronic medical records of the Hospital District of Southwest Finland between 2005 and 2017. Text-mining was used for patient identification to exclude other interstitial lung diseases (ILD) from the cohort. FVC reimbursement restriction (FVC 50-90%) was used for stratification. : Out of all patients with ILD, 27% (N = 266) were identified to have IPF. At baseline, 24% presented with FVC>90% and 63% with FVC 50-90% predicted. FVC at diagnosis did not improve during the study period. Median survival decreased by severity from 6.7 years in FVC>90% at baseline to 0.7 years in patient with FVC<50% predicted. In the FVC>90% group, 14% died before a change in FVC category could be noted. Overall, 4.7 million euro worth of specialty care resources were spent on IPF patients. The highest cost driver was inpatient days. : IPF is associated with a high burden of disease, and reimbursement restrictions are in conflict with early care. As there are antifibrotic treatment options for IPF patients, early diagnosis is important.
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http://dx.doi.org/10.1080/20018525.2019.1702618DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6968594PMC
December 2019

The Burden Of Chronic Obstructive Pulmonary Disease (COPD) In Finland: Impact Of Disease Severity And Eosinophil Count On Healthcare Resource Utilization.

Int J Chron Obstruct Pulmon Dis 2019 25;14:2409-2421. Epub 2019 Oct 25.

Division of Medicine, Department of Pulmonary Diseases, Turku University Hospital, Turku, Finland.

Purpose: The burden associated with chronic obstructive pulmonary disease (COPD) is substantial. The objectives of this study were to describe healthcare resource utilization (HCRU) and HCRU-associated costs in patients with COPD in Finland, according to disease severity and blood eosinophil count (BEC).

Patients And Methods: This non-interventional, retrospective registry study (GSK ID: HO-17-17558) utilized data from the specialist care hospital register. Data extraction was from first hospital visit with a COPD diagnosis (index date) from January 1, 2004 until December 31, 2015 or death. Patients (aged >18 years with ≥1 report of post-bronchodilation forced expiratory volume in 1 s (FEV)/forced vital capacity (FVC) ratio <0.7) were categorized as having non-severe or severe COPD (FEV >50% or ≤50% of reference, respectively). Patients who were initially non-severe but progressed to severe were classified as having progressing COPD. Patients without spirometry registry data were classified as having clinically verified COPD. Patients were grouped according to BEC (≥300 cells/μL, <300 cells/μL or BEC unknown). HCRU, estimated associated costs and mortality were evaluated according to COPD severity and BEC.

Results: There were 9042 patients with COPD; 340 non-severe, 326 progressing, 394 severe, and 7982 clinically verified. BEC was available for 31.8% of patients. The mean follow-up time was 3.7-6.5 years in the classified patient-groups. All-cause mortality was 46% during follow-up. Severe COPD was associated with more COPD-related HCRU and higher mortality than non-severe COPD. Patients with BEC ≥300 cells/μL had higher overall HCRU but improved survival compared with those with BEC <300 cells/μL. Overall direct costs were similar across COPD severity categories, 3300-3900€/patient-year, although COPD-related costs were higher in patients with severe versus non-severe COPD.

Conclusion: This study demonstrated a substantial burden associated with severe and/or eosinophilic COPD for patients in Finland.
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http://dx.doi.org/10.2147/COPD.S222581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6818542PMC
April 2020

Burden of migraine in Finland: health care resource use, sick-leaves and comorbidities in occupational health care.

J Headache Pain 2019 Feb 12;20(1):13. Epub 2019 Feb 12.

Terveystalo Biobank Finland, Humalistonkatu 7B, 20100, Turku, Finland.

Background: The highest prevalence of migraine is detected among people who are of working age. The aim of this study was to assess the burden of migraine in an occupational health care setting using real world data collected as a part of routine clinical practice.

Methods: This retrospective register study included migraineurs using occupational health care at the private health care provider Terveystalo. An age and gender matched control population was established for comparison. Electronic medical records were assessed for overall and migraine related health care visits, sick-leaves and comorbidities. Stratification to acute and prophylactic treatment groups along with prophylactic treatment lines was based on prescriptions.

Results: Among the 369,383 individuals in the study cohort, 7.4% women and 2.1% men were identified having a diagnosis of migraine. Prophylactic medication was prescribed to 13% of migraine patients and exclusively acute medication to 37%. Although migraine related visits and sick-leave days were significantly lower than overall visits or sick-leave days, both increased by prophylactic treatment line. The number of visits rose from 13.8 to 26.2 and sick-leave days from 16.8 to 30.4 per patient-year, in those without prophylaxis vs. ≥3 prophylactic treatments. Moreover, migraine patients had 1.7-fold increase in visits and 1.8-fold increase in sick leave days on average per patient-year, when compared to the control population. Depression and anxiety were 1.8-fold more common among patients with migraine, and the frequency also increase by treatment line.

Conclusions: Migraine burden increased by each failed treatment line and was associated with increased comorbidity. In addition, migraine patients had significantly higher extent of visits and sick-leave days as well as extent of comorbidities when compared to their age- and gender-matched counterparts.
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http://dx.doi.org/10.1186/s10194-019-0964-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6734482PMC
February 2019

Dietary patterns reflecting healthy food choices are associated with lower serum LPS activity.

Sci Rep 2017 07 26;7(1):6511. Epub 2017 Jul 26.

Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland.

Gram-negative bacteria-derived lipopolysaccharides (LPS) are associated with various negative health effects. Whether diet is associated with LPS, is an understudied phenomenon. We investigated the association between diet and serum LPS activity in 668 individuals with type 1 diabetes in the FinnDiane Study. Serum LPS activity was determined using the Limulus Amoebocyte Lysate assay. Diet was assessed with a food frequency questionnaire (FFQ) section of a diet questionnaire and a food record. The food record was used to calculate energy, macronutrient, and fibre intake. In a multivariable model, energy, macronutrient, or fibre intake was not associated with the LPS activity. Using factor analysis, we identified seven dietary patterns from the FFQ data ("Sweet", "Cheese", "Fish", "Healthy snack", "Vegetable", "Traditional", and "Modern"). In a multivariable model, higher factor scores of the Fish, Healthy snack, and Modern patterns predicted lower LPS activity. The validity of the diet questionnaire was also investigated. The questionnaire showed reasonable relative validity against a 6-day food record. The two methods classified participants into the dietary patterns better than expected by chance. In conclusion, healthy dietary choices, such as consumption of fish, fresh vegetables, and fruits and berries may be associated with positive health outcomes by reducing systemic endotoxaemia.
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http://dx.doi.org/10.1038/s41598-017-06885-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5529547PMC
July 2017

Endotoxins are associated with visceral fat mass in type 1 diabetes.

Sci Rep 2016 12 13;6:38887. Epub 2016 Dec 13.

Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland.

Bacterial lipopolysaccharides (LPS), potent inducers of inflammation, have been associated with chronic metabolic disturbances. Obesity is linked to dyslipidemia, increased body adiposity, and endotoxemia. We investigated the cross-sectional relationships between serum LPS activity and body adiposity as well as inflammation in 242 subjects with type 1 diabetes. Body fat distribution was measured by DXA and serum LPS activity by the limulus amebocyte lysate end-point assay. Since no interaction between visceral fat mass and sex was observed, data were pooled for the subsequent analyses. LPS was independently associated with visceral fat mass, when adjusted for traditional risk factors (age, sex, kidney status, hsCRP, insulin sensitivity). In the multivariate analysis, serum LPS activity and triglyceride concentrations had a joint effect on visceral fat mass, independent of these factors alone. A combination of high LPS and high hsCRP concentrations was also observed in those with the largest visceral fat mass. In conclusion, high serum LPS activity levels were associated with visceral fat mass in subjects with type 1 diabetes strengthening its role in the development of central obesity, inflammation and insulin resistance.
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http://dx.doi.org/10.1038/srep38887DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5153626PMC
December 2016

Local TNF causes NFATc1-dependent cholesterol-mediated podocyte injury.

J Clin Invest 2016 09 2;126(9):3336-50. Epub 2016 Aug 2.

High levels of circulating TNF and its receptors, TNFR1 and TNFR2, predict the progression of diabetic kidney disease (DKD), but their contribution to organ damage in DKD remains largely unknown. Here, we investigated the function of local and systemic TNF in podocyte injury. We cultured human podocytes with sera collected from DKD patients, who displayed elevated TNF levels, and focal segmental glomerulosclerosis (FSGS) patients, whose TNF levels resembled those of healthy patients. Exogenous TNF administration or local TNF expression was equally sufficient to cause free cholesterol-dependent apoptosis in podocytes by acting through a dual mechanism that required a reduction in ATP-binding cassette transporter A1-mediated (ABCA1-mediated) cholesterol efflux and reduced cholesterol esterification by sterol-O-acyltransferase 1 (SOAT1). TNF-induced albuminuria was aggravated in mice with podocyte-specific ABCA1 deficiency and was partially prevented by cholesterol depletion with cyclodextrin. TNF-stimulated free cholesterol-dependent apoptosis in podocytes was mediated by nuclear factor of activated T cells 1 (NFATc1). ABCA1 overexpression or cholesterol depletion was sufficient to reduce albuminuria in mice with podocyte-specific NFATc1 activation. Our data implicate an NFATc1/ABCA1-dependent mechanism in which local TNF is sufficient to cause free cholesterol-dependent podocyte injury irrespective of TNF, TNFR1, or TNFR2 serum levels.
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http://dx.doi.org/10.1172/JCI85939DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5004940PMC
September 2016

Cyclin-dependent kinase 2 protects podocytes from apoptosis.

Sci Rep 2016 Feb 15;6:21664. Epub 2016 Feb 15.

Department of Pathology, University of Helsinki, 00290 Helsinki, Finland.

Loss of podocytes is an early feature of diabetic nephropathy (DN) and predicts its progression. We found that treatment of podocytes with sera from normoalbuminuric type 1 diabetes patients with high lipopolysaccharide (LPS) activity, known to predict progression of DN, downregulated CDK2 (cyclin-dependent kinase 2). LPS-treatment of mice also reduced CDK2 expression. LPS-induced downregulation of CDK2 was prevented in vitro and in vivo by inhibiting the Toll-like receptor (TLR) pathway using immunomodulatory agent GIT27. We also observed that CDK2 is downregulated in the glomeruli of obese Zucker rats before the onset of proteinuria. Knockdown of CDK2, or inhibiting its activity with roscovitine in podocytes increased apoptosis. CDK2 knockdown also reduced expression of PDK1, an activator of the cell survival kinase Akt, and reduced Akt phosphorylation. This suggests that CDK2 regulates the activity of the cell survival pathway via PDK1. Furthermore, PDK1 knockdown reduced the expression of CDK2 suggesting a regulatory loop between CDK2 and PDK1. Collectively, our data show that CDK2 protects podocytes from apoptosis and that reduced expression of CDK2 associates with the development of DN. Preventing downregulation of CDK2 by blocking the TLR pathway with GIT27 may provide a means to prevent podocyte apoptosis and progression of DN.
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http://dx.doi.org/10.1038/srep21664DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4753499PMC
February 2016

High-fat meals induce systemic cytokine release without evidence of endotoxemia-mediated cytokine production from circulating monocytes or myeloid dendritic cells.

Acta Diabetol 2015 Apr 3;52(2):315-22. Epub 2014 Sep 3.

Folkhälsan Research Center, Biomedicum Helsinki (Room C317b), Haartmaninkatu 8, 00290, Helsinki, Finland.

Aims: Dietary fats have been shown to promote the translocation of bacterial endotoxins from the gut into circulation, which may induce systemic inflammation and modulate the inflammatory response of circulating immune cells. The aim of this study was to determine the effect of the postprandial milieu on inflammation and the inflammatory response of antigen presenting cells in the context of type 1 diabetes (T1D).

Materials And Methods: Eleven patients with T1D and eleven nondiabetic controls were recruited as part of the FinnDiane study and given two fatty meals during 1 day. Cytokine responses in monocytes and myeloid dendritic cells (mDCs) as well as serum lipopolysaccharide activity levels, triglyceride concentrations and cytokine concentrations were measured from fasting and postprandial blood samples.

Results: Postprandially, patients with T1D and controls showed significant increases in eight inflammatory cytokines (IL-6, TNF-α, IL-1β, IFN-α, IL-10, IFN-γ, IL-12 and MIP-1β) without concomitant increase in serum LPS activity. Serum cytokine production was similar in both groups. No postprandial change was seen in the IL-6, TNF-α or IL-1β production of mDCs or monocytes. At fasting, diabetic mDCs exhibited higher LPS-induced IL-6 and IL-1β production than controls.

Conclusions: Acute high-fat meals increase circulating cytokines but have no effect on serum lipopolysaccharide activity levels or cytokine production in circulating mDCs or monocytes. Our results suggest that postprandial increase in serum cytokine levels is neither mediated by circulating endotoxins nor the activation of circulating innate cells. The production of high-fat meal-induced inflammatory markers is most likely regulated at the tissue level.
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http://dx.doi.org/10.1007/s00592-014-0641-8DOI Listing
April 2015

Patients with type 1 diabetes show signs of vascular dysfunction in response to multiple high-fat meals.

Nutr Metab (Lond) 2014 13;11:28. Epub 2014 Jun 13.

Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum, Helsinki, Finland ; Department of Medicine, Division of Nephrology, Helsinki University Central Hospital, Helsinki, Finland ; Diabetes & Obesity Research Program, Research Program's Unit, University of Helsinki, Helsinki, Finland.

Background: A high-fat diet promotes postprandial systemic inflammation and metabolic endotoxemia. We investigated the effects of three consecutive high-fat meals on endotoxemia, inflammation, vascular function, and postprandial lipid metabolism in patients with type 1 diabetes.

Methods: Non-diabetic controls (n = 34) and patients with type 1 diabetes (n = 37) were given three high-caloric, fat-containing meals during one day. Blood samples were drawn at fasting (8:00) and every two hours thereafter until 18:00. Applanation tonometry was used to assess changes in the augmentation index during the investigation day.

Results: Three consecutive high-fat meals had only a modest effect on serum LPS-activity levels and inflammatory markers throughout the day in both groups. Of note, patients with type 1 diabetes were unable to decrease the augmentation index in response to the high-fat meals. The most profound effects of the consecutive fat loads were seen in chylomicron and HDL-metabolism. The triglyceride-rich lipoprotein remnant marker, apoB-48, was elevated in patients compared to controls both at fasting (p = 0.014) and postprandially (p = 0.035). The activities of the HDL-associated enzymes PLTP (p < 0.001), and CETP (p = 0.007) were higher and paraoxonase (PON-1) activity, an anti-oxidative enzyme bound to HDL, decreased in patients with type 1 diabetes (p = 0.027).

Conclusions: In response to high-fat meals, early signs of vascular dysfunction alongside accumulation of chylomicron remnants, higher augmentation index, and decreased PON-1 activity were observed in patients with type 1 diabetes. The high-fat meals had no significant impact on postprandial LPS-activity in non-diabetic subjects or patients with type 1 diabetes suggesting that metabolic endotoxemia may be more central in patients with chronic metabolic disturbances such as obesity, type 2 diabetes, or diabetic kidney disease.
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http://dx.doi.org/10.1186/1743-7075-11-28DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4067102PMC
June 2014

Cyclodextrin protects podocytes in diabetic kidney disease.

Diabetes 2013 Nov 8;62(11):3817-27. Epub 2013 Jul 8.

Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida.

Diabetic kidney disease (DKD) remains the most common cause of end-stage kidney disease despite multifactorial intervention. We demonstrated that increased cholesterol in association with downregulation of ATP-binding cassette transporter ABCA1 occurs in normal human podocytes exposed to the sera of patients with type 1 diabetes and albuminuria (DKD(+)) when compared with diabetic patients with normoalbuminuria (DKD(-)) and similar duration of diabetes and lipid profile. Glomerular downregulation of ABCA1 was confirmed in biopsies from patients with early DKD (n = 70) when compared with normal living donors (n = 32). Induction of cholesterol efflux with cyclodextrin (CD) but not inhibition of cholesterol synthesis with simvastatin prevented podocyte injury observed in vitro after exposure to patient sera. Subcutaneous administration of CD to diabetic BTBR (black and tan, brachiuric) ob/ob mice was safe and reduced albuminuria, mesangial expansion, kidney weight, and cortical cholesterol content. This was followed by an improvement of fasting insulin, blood glucose, body weight, and glucose tolerance in vivo and improved glucose-stimulated insulin release in human islets in vitro. Our data suggest that impaired reverse cholesterol transport characterizes clinical and experimental DKD and negatively influences podocyte function. Treatment with CD is safe and effective in preserving podocyte function in vitro and in vivo and may improve the metabolic control of diabetes.
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http://dx.doi.org/10.2337/db13-0399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3806621PMC
November 2013

Bacterial endotoxin activity in human serum is associated with dyslipidemia, insulin resistance, obesity, and chronic inflammation.

Diabetes Care 2011 Aug 2;34(8):1809-15. Epub 2011 Jun 2.

Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, Finland.

Objective: To investigate whether bacterial lipopolysaccharide (LPS) activity in human serum is associated with the components of the metabolic syndrome (MetS) in type 1 diabetic patients with various degrees of kidney disease and patients with IgA glomerulonephritis (IgAGN).

Research Design And Methods: Serum LPS activity was determined with the Limulus Amoebocyte Lysate chromogenic end point assay in type 1 diabetic patients with a normal albumin excretion rate (n = 587), microalbuminuria (n = 144), macroalbuminuria (n = 173); patients with IgAGN (n = 98); and in nondiabetic control subjects (n = 345). The relationships of the LPS/HDL ratio and MetS-associated variables were evaluated with Pearson correlation.

Results: The MetS was more prevalent in type 1 diabetic patients (48%) than in patients with IgAGN (15%). Diabetic patients with macroalbuminuria had a significantly higher serum LPS/HDL ratio than patients with IgAGN. In the normoalbuminuric type 1 diabetic group, patients in the highest LPS/HDL quartile were diagnosed as having the MetS three times more frequently than patients in the lowest quartile (69 vs. 22%; P < 0.001). High LPS activity was associated with higher serum triglyceride concentration, earlier onset of diabetes, increased diastolic blood pressure, and elevated urinary excretion of monocyte chemoattractant protein-1.

Conclusions: High serum LPS activity is strongly associated with the components of the MetS. Diabetic patients with kidney disease seem to be more susceptible to metabolic endotoxemia than patients with IgAGN. Bacterial endotoxins may thus play an important role in the development of the metabolic and vascular abnormalities commonly seen in obesity and diabetes-related diseases.
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http://dx.doi.org/10.2337/dc10-2197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3142060PMC
August 2011