Publications by authors named "Markku Lehto"

44 Publications

Gastrointestinal manifestations after Roux-en-Y gastric bypass surgery in individuals with and without type 2 diabetes.

Surg Obes Relat Dis 2021 Mar 22;17(3):585-594. Epub 2020 Oct 22.

Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland; Research Unit of Internal Medicine and Biocenter Oulu, University of Oulu, Oulu, Finland. Electronic address:

Background: Roux-en-Y gastric bypass (RYGB) surgery is an effective treatment for obesity, which improves cardiovascular health and reduces the risk of premature mortality. However, some reports have suggested that RYGB may predispose patients to adverse health outcomes, such as inflammatory bowel disease (IBD) and colorectal cancer.

Objectives: The present prospective study aimed to evaluate the impact of RYGB surgery on cardiovascular risk factors and gastrointestinal inflammation in individuals with and without type 2 diabetes (T2D).

Setting: University hospital setting in Finland.

Methods: Blood and fecal samples were collected at baseline and 6 months after surgery from 30 individuals, of which 16 had T2D and 14 were nondiabetics. There were also single study visits for 6 healthy reference patients. Changes in cardiovascular risk factors, serum cholesterol, and triglycerides were investigated before and after surgery. Fecal samples were analyzed for calprotectin, anti-Saccharomyces cerevisiae immunoglobulin A antibodies (ASCA), active lipopolysaccharide (LPS) concentration, short-chain fatty acids (SCFAs), intestinal alkaline phosphatase activity, and methylglyoxal-hydro-imidazolone (MG-H1) protein adducts formation.

Results: After RYGB, weight decreased on average -21.6% (-27.2 ± 7.8 kg), excess weight loss averaged 51%, and there were improvements in cardiovascular risk factors. Fecal calprotectin levels (P < .001), active LPS concentration (P < .002), ASCA (P < .02), and MG-H1 (P < .02) values increased significantly, whereas fecal SCFAs, especially acetate (P < .002) and butyrate (P < .03) levels, were significantly lowered.

Conclusion: The intestinal homeostasis is altered after RYGB, with several fecal markers suggesting increased inflammation; however, clinical significance of the detected changes is currently uncertain. As chronic inflammation may predispose patients to adverse health effects, our findings may have relevance for the suggested association between RYGB and increased risks of incident IBD and colorectal cancer.
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http://dx.doi.org/10.1016/j.soard.2020.10.021DOI Listing
March 2021

Bacterial infections as novel risk factors of severe diabetic retinopathy in individuals with type 1 diabetes.

Br J Ophthalmol 2020 Sep 14. Epub 2020 Sep 14.

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

Background/aims: Diabetic retinopathy (DR) is associated and shares many risk factors with other diabetic complications, including inflammation. Bacterial infections, potent inducers of inflammation have been associated with the development of diabetic complications apart from DR. Our aim was to investigate the association between bacterial infections and DR.

Methods: Adult individuals with type 1 diabetes (n=1043) were recruited from the Finnish Diabetic Nephropathy Study (FinnDiane), a prospective follow-up study. DR was defined as incident severe diabetic retinopathy (SDR), identified as first laser treatment. Data on DR were obtained through fundus photographs and medical records, data on bacterial infections from comprehensive national registries (1 January 1995 to 31 December 2015). Risk factors for DR and serum bacterial lipopolysaccharide (LPS) activity were determined at baseline.

Results: Individuals with incident SDR (n=413) had a higher mean number of antibiotic purchases/follow-up year compared with individuals without incident SDR (n=630) (0.92 [95% CI 0.82 to 1.02] vs 0.67 [0.62-0.73], p=0.02), as well as higher levels of LPS activity (0.61 [0.58-0.65] vs 0.56 [0.54-0.59] EU/mL, p=0.03). Individuals with on average ≥1 purchase per follow-up year (n=269) had 1.5 times higher cumulative incidence of SDR, compared with individuals with <1 purchase (n=774) per follow-up year (52% vs 35%, p<0.001). In multivariable Cox survival models, the mean number of antibiotic purchases per follow-up year as well as LPS activity were risk factors for SDR after adjusting for static confounders (HR 1.16 [1.05-1.27], p=0.002 and HR 2.77 [1.92-3.99], p<0.001, respectively).

Conclusion: Bacterial infections are associated with an increased risk of incident SDR in type 1 diabetes.
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http://dx.doi.org/10.1136/bjophthalmol-2020-316202DOI Listing
September 2020

Relationship between ABO blood groups and cardiovascular disease in type 1 diabetes according to diabetic nephropathy status.

Cardiovasc Diabetol 2020 05 19;19(1):68. Epub 2020 May 19.

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

Background: ABO blood groups have previously been associated with cardiovascular disease (CVD) in the general population. This study aimed to investigate the potential relationship between ABO blood groups and CVD in individuals with type 1 diabetes according to diabetic nephropathy (DN) status.

Methods: Adults with type 1 diabetes (4531 individuals) from the FinnDiane Study were evaluated. DN was determined by two out of three measurements of urinary albumin excretion rate. Albuminuria was defined as an excretion rate above 20 µg/min. CVD events were identified by linking the data with the Finnish Care Register for Health Care and the Finnish Cause of Death Register. Follow-up ranged from the baseline visit until a CVD event, death or the end of 2017. The impact of ABO blood groups on CVD risk was estimated by multivariable Cox-regression analyses adjusted for traditional risk factors.

Results: At baseline, the median age was 38.5 (IQR 29.2-47.9) years, 47.5% were female and median duration of diabetes was 20.9 (11.4-30.7) years. There were 893 incident ischemic heart disease (IHD) events, 301 ischemic strokes (IS), and 415 peripheral artery disease (PAD) events during a median follow up of 16.5 (IQR 12.8-18.6) years. The A blood group showed the highest risk of IHD versus the O blood group, when microalbuminuria was present. Comparing the population with microalbuminuria with those with normoalbuminuria, only the A blood group elevated the risk of IHD. This increased risk was neither explained by the FUT2 secretor phenotype nor by the A-genotype distribution. The risk of IS or PAD was no different among the ABO blood groups regardless of diabetic nephropathy stage.

Conclusion: The A blood group is a risk factor for IHD in individuals with type 1 diabetes and microalbuminuria.
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http://dx.doi.org/10.1186/s12933-020-01038-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7238526PMC
May 2020

Decreased plasma kallikrein activity is associated with reduced kidney function in individuals with type 1 diabetes.

Diabetologia 2020 07 8;63(7):1349-1354. Epub 2020 Apr 8.

Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, Haartmaninkatu 8, 00290, Helsinki, Finland.

Aims/hypothesis: Plasma kallikrein is the central mediator of the plasma kallikrein-kinin system, which is involved both in vascular control and thrombin formation cascades. The plasma kallikrein-kinin system has also been considered protective in pathological conditions, but the impact of plasma kallikreins on diabetic nephropathy remains unknown. The objective of this cross-sectional study was to explore the association of plasma kallikrein with diabetic nephropathy.

Methods: We measured plasma kallikrein activity in 295 individuals with type 1 diabetes at various stages of diabetic nephropathy, and we tested the genetic association between the plasma kallikrein-kinin system and kidney function in 4400 individuals with type 1 diabetes.

Results: Plasma kallikrein activity was associated with diabetes duration (p < 0.001) and eGFR (p < 0.001), and plasma kallikrein activity was lower with more advanced diabetic nephropathy, being lowest in individuals on dialysis. The minor alleles of the KNG1 rs5030062 and rs710446 variants, which have previously been associated with increased plasma pre-kallikrein and/or factor XI (FXI) protein levels, were associated with higher eGFR (rs5030062 β = 0.03, p = 0.01; rs710446 β = 0.03, p = 0.005) in the FinnDiane cohort of 4400 individuals with type 1 diabetes.

Conclusions/interpretation: Plasma kallikrein activity and genetic variants known to increase the plasma kallikrein level are associated with higher eGFR in individuals with type 1 diabetes, suggesting that plasma kallikrein might have a protective effect in diabetic nephropathy.
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http://dx.doi.org/10.1007/s00125-020-05144-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7286847PMC
July 2020

Serum lipopolysaccharide neutralizing capacity in ischemic stroke.

PLoS One 2020 21;15(2):e0228806. Epub 2020 Feb 21.

Department of Neurology, Helios Klinikum Schleswig, Schleswig, Germany.

Introduction: Periodontitis is associated with increased serum lipopolysaccharide (LPS) activity, which may be one mechanism linking periodontitis with the risk of cardiovascular diseases. As LPS-carrying proteins including lipoproteins modify LPS-activity, we investigated the determinants of serum LPS-neutralizing capacity (LPS-NC) in ischemic stroke. The association of LPS-NC and Aggregatibacter actinomycetemcomitans, a major microbial biomarker in periodontitis, was also investigated.

Materials And Methods: The assay to measure LPS-NC was set up by spiking serum samples with E. coli LPS. The LPS-NC, LPS-binding protein (LBP), soluble CD14 (sCD14), lipoprotein profiles, apo(lipoprotein) A-I, apoB, and phospholipid transfer protein (PLTP) activity, were determined in 98 ischemic stroke patients and 100 age- and sex-matched controls. Serum and saliva immune response to A. actinomycetemcomitans, its concentration in saliva, and serotype-distribution were examined.

Results: LPS-NC values ranged between 51-83% in the whole population. Although several of the LPS-NC determinants differed significantly between cases and controls (PLTP, sCD14, apoA-I, HDL-cholesterol), the levels did not (p = 0.056). The main determinants of LPS-NC were i) triglycerides (β = -0.68, p<0.001), and ii) HDL cholesterol (0.260, <0.001), LDL cholesterol (-0.265, <0.001), PLTP (-0.196, 0.011), and IgG against A. actinomycetemcomitans (0.174, 0.011). Saliva A. actinomycetemcomitans concentration was higher [log mean (95% CI), 4.39 (2.35-8.19) vs. 10.7 (5.45-21) genomes/ml, p = 0.023) and serotype D more frequent (4 vs. 0%, p = 0.043) in cases than controls. Serotypeablity or serotypes did not, however, relate to the LPS-NC.

Conclusion: Serum LPS-NC comprised low PLTP-activity, triglyceride and LDL cholesterol concentrations, as well as high HDL cholesterol and IgG against A. actinomycetemcomitans. The present findings let us to conclude that LPS-NC did not associate with stroke.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0228806PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7034831PMC
May 2020

On-line profiling of volatile compounds produced in vitro by pathogenic oral bacteria.

J Breath Res 2019 12 16;14(1):016010. Epub 2019 Dec 16.

Department of Chemistry, University of Helsinki, Helsinki, Finland.

Infections by oral pathogens are one of the most common health problems worldwide. Due to the intimate connection between exhaled breath and the oral cavity, breath analysis could potentially be used to diagnose these infections. However, little is known about the volatile emissions of important oral pathogens that are connected with gingivitis and periodontitis. In this study, we have performed in vitro headspace measurements on four important oral pathogens (P. gingivalis, T. forsythia, P. intermedia and P. nigrescens) using proton transfer reaction time-of-flight mass spectrometry (PTR-TOF-MS). Some of the most abundant compounds produced by the bacteria include hydrogen sulphide, methanethiol, acetone, dimethylsulphide, isoprene, cyclopentanone and indole as tentatively assigned from the mass spectra. Several other abundant mass signals were recorded but the assignment of these is less certain. Some of the bacterial species can be separated from each other by the emitted volatile fingerprints. The results of this study can be used in potential development of a diagnostic breath test for oral infections. In addition, as several of the measured compounds are known to be toxic, the results point to an intriguing possibility of studying the connection between the bacterial virulence and the emitted volatile compounds.
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http://dx.doi.org/10.1088/1752-7163/ab5559DOI Listing
December 2019

Is a Novel Susceptibility Gene for Diabetic Retinopathy in Type 1 Diabetes.

Diabetes 2019 11 22;68(11):2165-2174. Epub 2019 Aug 22.

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

Diabetic retinopathy is a common diabetes complication that threatens the eyesight and may eventually lead to acquired visual impairment or blindness. While a substantial heritability has been reported for proliferative diabetic retinopathy (PDR), only a few genetic risk factors have been identified. Using genome-wide sib pair linkage analysis including 361 individuals with type 1 diabetes, we found suggestive evidence of linkage with PDR at chromosome 10p12 overlapping the gene (logarithm of odds = 2.73). Evidence of association between variants in and PDR was also found in association analysis of 4,005 individuals with type 1 diabetes with an odds ratio of 0.83 and value of 8.6 × 10 for rs11014284. Sequencing of revealed two coding variants, R476C/rs202152674 and S502L/rs137886839. is abundantly expressed in retinal cells and encodes the β2 subunit of the L-type calcium channel. Blocking vascular endothelial growth factor (VEGF) by intravitreous anti-VEGF injections is a promising clinical therapy to treat PDR. Our data show that L-type calcium channels regulate VEGF expression and secretion from retinal pigment epithelial cells (ARPE19) and support the role of via regulation of VEGF in the pathogenesis of PDR. However, further genetic and functional studies are necessary to consolidate the findings.
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http://dx.doi.org/10.2337/db19-0130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6804633PMC
November 2019

Gain-of-function CEBPE mutation causes noncanonical autoinflammatory inflammasomopathy.

J Allergy Clin Immunol 2019 11 13;144(5):1364-1376. Epub 2019 Jun 13.

Adult Immunodeficiency Unit, Infectious Diseases, Inflammation Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Rare Diseases Center and Pediatric Research Center, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. Electronic address:

Background: CCAAT enhancer-binding protein epsilon (C/EBPε) is a transcription factor involved in late myeloid lineage differentiation and cellular function. The only previously known disorder linked to C/EBPε is autosomal recessive neutrophil-specific granule deficiency leading to severely impaired neutrophil function and early mortality.

Objective: The aim of this study was to molecularly characterize the effects of C/EBPε transcription factor Arg219His mutation identified in a Finnish family with previously genetically uncharacterized autoinflammatory and immunodeficiency syndrome.

Methods: Genetic analysis, proteomics, genome-wide transcriptional profiling by means of RNA-sequencing, chromatin immunoprecipitation (ChIP) sequencing, and assessment of the inflammasome function of primary macrophages were performed.

Results: Studies revealed a novel mechanism of genome-wide gain-of-function that dysregulated transcription of 464 genes. Mechanisms involved dysregulated noncanonical inflammasome activation caused by decreased association with transcriptional repressors, leading to increased chromatin occupancy and considerable changes in transcriptional activity, including increased expression of NLR family, pyrin domain-containing 3 protein (NLRP3) and constitutively expressed caspase-5 in macrophages.

Conclusion: We describe a novel autoinflammatory disease with defective neutrophil function caused by a homozygous Arg219His mutation in the transcription factor C/EBPε. Mutated C/EBPε acts as a regulator of both the inflammasome and interferome, and the Arg219His mutation causes the first human monogenic neomorphic and noncanonical inflammasomopathy/immunodeficiency. The mechanism, including widely dysregulated transcription, is likely not unique for C/EBPε. Similar multiomics approaches should also be used in studying other transcription factor-associated diseases.
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http://dx.doi.org/10.1016/j.jaci.2019.06.003DOI Listing
November 2019

The Gut-Kidney Axis: Putative Interconnections Between Gastrointestinal and Renal Disorders.

Front Endocrinol (Lausanne) 2018 19;9:553. Epub 2018 Sep 19.

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

Diabetic kidney disease (DKD) is a devastating condition associated with increased morbidity and premature mortality. The etiology of DKD is still largely unknown. However, the risk of DKD development and progression is most likely modulated by a combination of genetic and environmental factors. Patients with autoimmune diseases, like type 1 diabetes, inflammatory bowel disease, and celiac disease, share some genetic background. Furthermore, gastrointestinal disorders are associated with an increased risk of kidney disease, although the true mechanisms have still to be elucidated. Therefore, the principal aim of this review is to evaluate the impact of disturbances in the gastrointestinal tract on the development of renal disorders.
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http://dx.doi.org/10.3389/fendo.2018.00553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6157406PMC
September 2018

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

Septin 7 reduces nonmuscle myosin IIA activity in the SNAP23 complex and hinders GLUT4 storage vesicle docking and fusion.

Exp Cell Res 2017 Jan 20;350(2):336-348. Epub 2016 Dec 20.

Department of Pathology, University of Helsinki, 00014 Helsinki, Finland. Electronic address:

Glomerular epithelial cells, podocytes, are insulin responsive and can develop insulin resistance. Here, we demonstrate that the small GTPase septin 7 forms a complex with nonmuscle myosin heavy chain IIA (NMHC-IIA; encoded by MYH9), a component of the nonmuscle myosin IIA (NM-IIA) hexameric complex. We observed that knockdown of NMHC-IIA decreases insulin-stimulated glucose uptake into podocytes. Both septin 7 and NM-IIA associate with SNAP23, a SNARE protein involved in GLUT4 storage vesicle (GSV) docking and fusion with the plasma membrane. We observed that insulin decreases the level of septin 7 and increases the activity of NM-IIA in the SNAP23 complex, as visualized by increased phosphorylation of myosin regulatory light chain. Also knockdown of septin 7 increases the activity of NM-IIA in the complex. The activity of NM-IIA is increased in diabetic rat glomeruli and cultured human podocytes exposed to macroalbuminuric sera from patients with type 1 diabetes. Collectively, the data suggest that the activity of NM-IIA in the SNAP23 complex plays a key role in insulin-stimulated glucose uptake into podocytes. Furthermore, we observed that septin 7 reduces the activity of NM-IIA in the SNAP23 complex and thereby hinders GSV docking and fusion with the plasma membrane.
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http://dx.doi.org/10.1016/j.yexcr.2016.12.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5243148PMC
January 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

Combined immunodeficiency and hypoglycemia associated with mutations in hypoxia upregulated 1.

J Allergy Clin Immunol 2017 04 29;139(4):1391-1393.e11. Epub 2016 Nov 29.

Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden; Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland; Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland; Center for Innovative Medicine, Karolinska Institutet, Huddinge, Sweden.

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http://dx.doi.org/10.1016/j.jaci.2016.09.050DOI Listing
April 2017

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

Detection of hydrogen cyanide from oral anaerobes by cavity ring down spectroscopy.

Sci Rep 2016 Mar 4;6:22577. Epub 2016 Mar 4.

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

Hydrogen cyanide (HCN) has been recognized as a potential biomarker for non-invasive diagnosis of Pseudomonas aeruginosa infection in the lung. However, the oral cavity is a dominant production site for exhaled HCN and this contribution can mask the HCN generated in the lung. It is thus important to understand the sources of HCN production in the oral cavity. By screening of oral anaerobes for HCN production, we observed that the genus of Porphyromonas, Prevotella and Fusobacterium generated low levels of HCN in vitro. This is the first study to show that oral anaerobes are capable of producing HCN in vitro. Further investigations were conducted on the species of P. gingivalis and we successfully detected HCN production (0.9-10.9 ppb) in the headspace of three P. gingivalis reference strains (ATCC 33277, W50 and OMG 434) and one clinical isolate. From P. gingivalis ATCC 33277 and W50, a strong correlation between HCN and CO2 concentrations (rs = 0.89, p < 0.001) was observed, indicating that the HCN production of P. gingivalis might be connected with the bacterial metabolic activity. These results indicate that our setup could be widely applied to the screening of in vitro HCN production by both aerobic and anaerobic bacteria.
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http://dx.doi.org/10.1038/srep22577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4778072PMC
March 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

Bacterial infections in patients with type 1 diabetes: a 14-year follow-up study.

BMJ Open Diabetes Res Care 2015 5;3(1):e000067. Epub 2015 Mar 5.

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

Objective: This study explored the annual occurrence/incidence of bacterial infections, and their association with chronic hyperglycemia and diabetic nephropathy, in patients with type 1 diabetes.

Design: In a register-based follow-up study, we investigated the frequency of bacterial infections in patients with type 1 diabetes (n=4748) and age-matched and sex-matched non-diabetic control (NDC) subjects (n=12 954) using nationwide register data on antibiotic drug prescription purchases and hospital discharge diagnoses, collected between 1996 and 2009. Diabetic nephropathy was classified based on the urinary albumin excretion rate (AER).

Results: The hospitalization rate due to bacterial infections was higher in patients with diabetes compared with NDCs (rate ratio (RR) 2.30 (95% CI 2.11 to 2.51)). The rate correlated with the severity of diabetic nephropathy: RR for microalbuminuria was 1.23 (0.94 to 1.60), 1.97 (1.49 to 2.61) for macroalbuminuria, 11.2 (8.1 to 15.5) for dialysis, and 6.72 (4.92 to 9.18) for kidney transplant as compared to patients with diabetes and normal AER. The annual number of antibiotic purchases was higher in patients with diabetes (1.00 (1.00 to 1.01)) as compared with NDCs (0.47 (0.46 to 0.47)), RR=1.71 (1.65 to 1.77). Annual antibiotic purchases were 1.18-fold more frequent in patients with microalbuminuria, 1.29-fold with macroalbuminuria, 2.43-fold with dialysis, and 2.74-fold with kidney transplant as compared to patients with normal AER. Each unit of increase in glycated hemoglobin was associated with a 6-10% increase in the number of annual antibiotic purchases.

Conclusions: The incidence of bacterial infections was significantly higher in patients with type 1 diabetes compared with age-matched and sex-matched NDC subjects, and correlated with the severity of diabetic nephropathy in inpatient and outpatient settings.
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http://dx.doi.org/10.1136/bmjdrc-2014-000067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4352693PMC
March 2015

Endotoxemia, nutrition, and cardiometabolic disorders.

Acta Diabetol 2015 Apr 19;52(2):395-404. Epub 2014 Oct 19.

Institute of Dentistry, University of Helsinki, Biomedicum 1, P.O. Box 63, 00014, Helsinki, Finland,

Aims: Circulating lipopolysaccharides (LPSs), associated with both infection and inflammation, may arise from the gastrointestinal tract microbiota, and the levels may be affected by daily nutrition. We investigated whether nutrient intake affects the association of serum LPS activity with prevalent obesity, metabolic syndrome (MetS), diabetes, and coronary heart disease (CHD) and with the risk of incident CHD events.

Methods: The nutrition cohort (n = 2,452, mean age ± SD, 52.2 ± 10.1 years) of the FINRISK 1997 Study was followed up for 10 years. Information on macronutrient intake at baseline was collected from 24-h dietary recall. Serum endotoxin activities were determined by the Limulus amebocyte lysate assay.

Results: LPS activity was associated directly with the total energy intake and indirectly with carbohydrate intake in lean, healthy subjects. High LPS was significantly associated with prevalent obesity, MetS, diabetes, and CHD events, independently of established risk factors, CRP, and total energy or nutrient intake. The ORs (95 % CI) were 1.49 (1.21-1.85, p < 0.001, Q2-4 vs. Q1) for obesity, 2.56 (1.97-3.32, p < 0.001, Q2-4 vs. Q1) for MetS, 1.94 (1.06-3.52, p = 0.031, Q2-4 vs. Q1) for CHD, and 1.01 (1.00-1.01, p = 0.032, LPS unit) for diabetes. In the follow-up, high LPS was significantly associated with the risk of CHD events with a hazard ratio of 1.88 (1.13-3.12, p = 0.013, Q2-4 vs. Q1). This association was independent of baseline established risk factors, diet, obesity, MetS, and diabetes.

Conclusion: A high serum LPS activity is strongly associated with cardiometabolic disorders, which supports the role of bacterial infections and immune response in their etiology.
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http://dx.doi.org/10.1007/s00592-014-0662-3DOI Listing
April 2015

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

Sphingomyelinase-like phosphodiesterase 3b expression levels determine podocyte injury phenotypes in glomerular disease.

J Am Soc Nephrol 2015 Jan 12;26(1):133-47. Epub 2014 Jun 12.

Department of Medicine, Division of Nephrology and Hypertension, Peggy and Harold Katz Family Drug Discovery Center and Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, Florida;

Diabetic kidney disease (DKD) is the most common cause of ESRD in the United States. Podocyte injury is an important feature of DKD that is likely to be caused by circulating factors other than glucose. Soluble urokinase plasminogen activator receptor (suPAR) is a circulating factor found to be elevated in the serum of patients with FSGS and causes podocyte αVβ3 integrin-dependent migration in vitro. Furthermore, αVβ3 integrin activation occurs in association with decreased podocyte-specific expression of acid sphingomyelinase-like phosphodiesterase 3b (SMPDL3b) in kidney biopsy specimens from patients with FSGS. However, whether suPAR-dependent αVβ3 integrin activation occurs in diseases other than FSGS and whether there is a direct link between circulating suPAR levels and SMPDL3b expression in podocytes remain to be established. Our data indicate that serum suPAR levels are also elevated in patients with DKD. However, unlike in FSGS, SMPDL3b expression was increased in glomeruli from patients with DKD and DKD sera-treated human podocytes, where it prevented αVβ3 integrin activation by its interaction with suPAR and led to increased RhoA activity, rendering podocytes more susceptible to apoptosis. In vivo, inhibition of acid sphingomyelinase reduced proteinuria in experimental DKD but not FSGS, indicating that SMPDL3b expression levels determined the podocyte injury phenotype. These observations suggest that SMPDL3b may be an important modulator of podocyte function by shifting suPAR-mediated podocyte injury from a migratory phenotype to an apoptotic phenotype and that it represents a novel therapeutic glomerular disease target.
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http://dx.doi.org/10.1681/ASN.2013111213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4279736PMC
January 2015

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

Effects of a single bout of interval hypoxia on cardiorespiratory control in patients with type 1 diabetes.

Diabetes 2013 Dec 3;62(12):4220-7. Epub 2013 Jun 3.

Department of Sport Science, Medical Section, University of Innsbruck, Innsbruck, Austria.

Hypoxemia is common in diabetes, and reflex responses to hypoxia are blunted. These abnormalities could lead to cardiovascular/renal complications. Interval hypoxia (IH) (5-6 short periods of hypoxia each day over 1-3 weeks) was successfully used to improve the adaptation to hypoxia in patients with chronic obstructive pulmonary disease. We tested whether IH over 1 day could initiate a long-lasting response potentially leading to better adaptation to hypoxia. In 15 patients with type 1 diabetes, we measured hypoxic and hypercapnic ventilatory responses (HCVRs), ventilatory recruitment threshold (VRT-CO2), baroreflex sensitivity (BRS), blood pressure, and blood lactate before and after 0, 3, and 6 h of a 1-h single bout of IH. All measurements were repeated on a placebo day (single-blind protocol, randomized sequence). After IH (immediately and after 3 h), hypoxic and HCVR increased, whereas the VRT-CO2 dropped. No such changes were observed on the placebo day. Systolic and diastolic blood pressure increased, whereas blood lactate decreased after IH. Despite exposure to hypoxia, BRS remained unchanged. Repeated exposures to hypoxia over 1 day induced an initial adaptation to hypoxia, with improvement in respiratory reflexes. Prolonging the exposure to IH (>2 weeks) in type 1 diabetic patients will be a matter for further studies.
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http://dx.doi.org/10.2337/db13-0167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3837073PMC
December 2013

New susceptibility loci associated with kidney disease in type 1 diabetes.

PLoS Genet 2012 Sep 20;8(9):e1002921. Epub 2012 Sep 20.

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

Diabetic kidney disease, or diabetic nephropathy (DN), is a major complication of diabetes and the leading cause of end-stage renal disease (ESRD) that requires dialysis treatment or kidney transplantation. In addition to the decrease in the quality of life, DN accounts for a large proportion of the excess mortality associated with type 1 diabetes (T1D). Whereas the degree of glycemia plays a pivotal role in DN, a subset of individuals with poorly controlled T1D do not develop DN. Furthermore, strong familial aggregation supports genetic susceptibility to DN. However, the genes and the molecular mechanisms behind the disease remain poorly understood, and current therapeutic strategies rarely result in reversal of DN. In the GEnetics of Nephropathy: an International Effort (GENIE) consortium, we have undertaken a meta-analysis of genome-wide association studies (GWAS) of T1D DN comprising ~2.4 million single nucleotide polymorphisms (SNPs) imputed in 6,691 individuals. After additional genotyping of 41 top ranked SNPs representing 24 independent signals in 5,873 individuals, combined meta-analysis revealed association of two SNPs with ESRD: rs7583877 in the AFF3 gene (P = 1.2 × 10(-8)) and an intergenic SNP on chromosome 15q26 between the genes RGMA and MCTP2, rs12437854 (P = 2.0 × 10(-9)). Functional data suggest that AFF3 influences renal tubule fibrosis via the transforming growth factor-beta (TGF-β1) pathway. The strongest association with DN as a primary phenotype was seen for an intronic SNP in the ERBB4 gene (rs7588550, P = 2.1 × 10(-7)), a gene with type 2 diabetes DN differential expression and in the same intron as a variant with cis-eQTL expression of ERBB4. All these detected associations represent new signals in the pathogenesis of DN.
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http://dx.doi.org/10.1371/journal.pgen.1002921DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3447939PMC
September 2012

Systemic exposure to Pseudomonal bacteria: a potential link between type 1 diabetes and chronic inflammation.

Acta Diabetol 2013 Jun 5;50(3):351-61. Epub 2012 Aug 5.

Biomedicum Helsinki, Folkhälsan Institute of Genetics, Folkhälsan Research Center/FinnDiane, Haartmaninkatu 8, 00290, Helsinki, Finland.

Bacterial endotoxins have been associated with chronic inflammation and the development and progression of diabetic nephropathy. We hypothesized that subjects with high serum lipopolysaccharide activity also carry remains of bacterial DNA in their system. Serum-derived bacterial DNA clones were isolated and identified from 10 healthy controls and 14 patients with type 1 diabetes (T1D) using universal primers targeted to bacterial 16S rDNA. A total of 240 clones representing 35 unique bacterial species were isolated and identified. A significant proportion of the isolated bacteria could be assigned to our living environment. Proteobacteria was by far the most prevalent phylum among the samples. Notably, the patients had significantly higher frequencies of Stenotrophomonas maltophilia clones in their sera compared to the healthy controls. Real-time PCR analysis of S. maltophilia and Pseudomonas aeruginosa flagellin gene copy number in the human leukocyte DNA fraction revealed that the overall Pseudomonal bacterial load was higher in older patients with T1D. Serum IgA- and IgG-antibody levels against Pseudomonal bacteria Delftia acidovorans, P. aeruginosa, and S. maltophilia were also determined in 200 healthy controls and 200 patients with T1D. The patients had significantly higher serum levels of IgA antibodies against all three Pseudomonal bacteria. Additionally, the IgA antibodies against Pseudomonal bacteria correlated significantly with serum C-reactive protein. These findings indicate that recurrent or chronic Pseudomonal exposure may increase susceptibility to chronic inflammation in patients with T1D.
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http://dx.doi.org/10.1007/s00592-012-0421-2DOI Listing
June 2013

OSBP-related protein 8 (ORP8) regulates plasma and liver tissue lipid levels and interacts with the nucleoporin Nup62.

PLoS One 2011 15;6(6):e21078. Epub 2011 Jun 15.

Department of Biology, Jinan University, Guangzhou, China.

We earlier identified OSBP-related protein 8 (ORP8) as an endoplasmic reticulum oxysterol-binding protein implicated in cellular lipid homeostasis. We now investigated its action in hepatic cells in vivo and in vitro. Adenoviral overexpression of ORP8 in mouse liver induced a decrease of cholesterol, phospholipids, and triglycerides in serum (-34%, -26%, -37%, respectively) and liver tissue (-40%, -12%, -24%), coinciding with reduction of nuclear (n)SREBP-1 and -2 and mRNA levels of their target genes. Consistently, excess ORP8 reduced nSREBPs in HuH7 cells, and ORP8 overexpression or silencing by RNA interference moderately suppressed or induced the expression of SREBP-1 and SREBP-2 target genes, respectively. In accordance, cholesterol biosynthesis was reduced by ORP8 overexpression and enhanced by ORP8 silencing in [(3)H]acetate pulse-labeling experiments. ORP8, previously shown to bind 25-hydroxycholesterol, was now shown to bind also cholesterol in vitro. Yeast two-hybrid, bimolecular fluorescence complementation (BiFC), and co-immunoprecipitation analyses revealed the nuclear pore component Nup62 as an interaction partner of ORP8. Co-localization of ORP8 and Nup62 at the nuclear envelope was demonstrated by BiFC and confocal immunofluorescence microscopy. Furthermore, the impact of overexpressed ORP8 on nSREBPs and their target mRNAs was inhibited in cells depleted of Nup62. Our results reveal that ORP8 has the capacity to modulate lipid homeostasis and SREBP activity, probably through an indirect mechanism, and provide clues of an entirely new mode of ORP action.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0021078PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3115989PMC
November 2011

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

Endotoxemia is associated with an increased risk of incident diabetes.

Diabetes Care 2011 Feb;34(2):392-7

Institute of Dentistry, University of Helsinki, Helsinki, Finland.

Objective: Diabetes is accompanied with a chronic low-grade inflammation, which may in part be mediated by endotoxins derived from Gram-negative bacteria.

Research Design And Methods: We investigated in a population-based cohort whether endotoxemia is associated with clinically incident diabetes. The serum endotoxin activity was measured by limulus assay from the FINRISK97 cohort comprising 7,169 subjects aged 25-74 years and followed up for 10 years.

Results: Both the subjects with prevalent diabetes (n = 537) and those with incident diabetes (n = 462) had higher endotoxin activity than the nondiabetic individuals (P < 0.001). The endotoxin activity was significantly associated with increased risk for incident diabetes with a hazard ratio 1.004 (95% CI 1.001-1.007; P = 0.019) per unit increase resulting in a 52% increased risk (P = 0.013) in the highest quartile compared with the lowest one. The association was independent of diabetes risk factors: serum lipids, γ-glutamyl transferase, C-reactive protein, BMI, and blood glucose. Furthermore, the association of endotoxemia with an increased risk of incident diabetes was independent of the metabolic syndrome as defined either by the National Cholesterol Educational Program-Adult Treatment Panel III or the International Diabetes Federation. Endotoxin activity was linearly related (P < 0.001) to the number of components of the metabolic syndrome.

Conclusions: Both prevalent and incident diabetes were associated with endotoxemia, which may link metabolic disorders to inflammation. The results suggest that microbes play a role in the pathogenesis of diabetes.
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http://dx.doi.org/10.2337/dc10-1676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3024355PMC
February 2011

Serum lipopolysaccharide activity is associated with the progression of kidney disease in finnish patients with type 1 diabetes.

Diabetes Care 2009 Sep 5;32(9):1689-93. Epub 2009 Jun 5.

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

Objective: The aim of the study was to investigate whether serum lipopolysaccharide (LPS) activities are associated with the progression of kidney disease in patients with type 1 diabetes.

Research Design And Methods: For this prospective study, we chose 477 Finnish patients with type 1 diabetes, who were followed for 6 years. At the baseline visit, 239 patients had a normal albumin excretion rate (normoalbuminuria) and 238 patients had macroalbuminuria. Patients were further divided into nonprogressors and progressors based on their albumin excretion rate at follow-up. Eighty normoalbuminuric patients had developed microalbuminuria, and 79 macroalbuminuric patients had progressed to end-stage renal disease. Serum LPS activity was determined with the Limulus amoebocyte lysate chromogenic end point assay.

Results: Serum LPS activity was significantly higher in the macroalbuminuric group than in the normoalbuminuric group (P < 0.001). Notably, normoalbuminuric progressor patients had a significantly higher LPS activity at baseline than normoalbuminuric nonprogressor patients (median 49 [interquartile range 34-87] vs. 39 [29-54] EU/ml; P = 0.001). The normoalbuminuric progressor patients exhibited features of the metabolic syndrome with higher triglyceride concentrations and lower estimated glucose disposal rate. A high LPS-to-HDL ratio was associated with the progression of kidney disease in both groups. Insulin resistance (P < 0.001) and serum LPS activity (P = 0.026) were independent risk factors of disease development, when A1C was removed from the regression analysis.

Conclusions: High serum LPS activity is associated with the development of diabetic nephropathy in Finnish patients with type 1 diabetes.
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http://dx.doi.org/10.2337/dc09-0467DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2732155PMC
September 2009

The R-Ras interaction partner ORP3 regulates cell adhesion.

J Cell Sci 2008 Mar 12;121(Pt 5):695-705. Epub 2008 Feb 12.

Department of Molecular Medicine, National Public Health Institute, Biomedicum, FI-00251 Helsinki, Finland.

Oxysterol-binding protein (OSBP)-related protein 3 (ORP3) is highly expressed in epithelial, neuronal and hematopoietic cells, as well as in certain forms of cancer. We assessed the function of ORP3 in HEK293 cells and in human macrophages. We show that ORP3 interacts with R-Ras, a small GTPase regulating cell adhesion, spreading and migration. Gene silencing of ORP3 in HEK293 cells results in altered organization of the actin cytoskeleton, impaired cell-cell adhesion, enhanced cell spreading and an increase of beta1 integrin activity--effects similar to those of constitutively active R-Ras(38V). Overexpression of ORP3 leads to formation of polarized cell-surface protrusions, impaired cell spreading and decreased beta1 integrin activity. In primary macrophages, overexpression of ORP3 leads to the disappearance of podosomal structures and decreased phagocytotic uptake of latex beads, consistent with a role in actin regulation. ORP3 is phosphorylated when cells lose adhesive contacts, suggesting that it is subject to regulation by outside-in signals mediated by adhesion receptors. The present findings demonstrate a new function of ORP3 as part of the machinery that controls the actin cytoskeleton, cell polarity and cell adhesion.
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http://dx.doi.org/10.1242/jcs.016964DOI Listing
March 2008