M J Savolainen

University of Oulu, Uleoborg, Northern Ostrobothnia, Finland

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Publications (125)647.2 Total impact

  • J. Hukkanen · J. Rysa · K.A. Makela · K.-H. Herzig · J. Hakkola · M.J. Savolainen
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    ABSTRACT: We recently showed that pregnane X receptor (PXR) agonists cause hyperglycaemia during oral glucose tolerance test (OGTT) in rats and healthy volunteers (Rifa-1 study). We now aimed to determine if the secretion of incretin hormones, especially glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP), are affected by PXR agonists since these gut-secreted hormones are major regulators of postprandial glucose metabolism. The Rifa-2 study had a one-phase, open-label design. Twelve subjects were given 600 mg of rifampicin a day for a week. OGTT with glucose, insulin, and incretin hormone measurements was performed before and after the rifampicin dosing. Incretins and insulin were analysed in previously collected rat OGTT samples after pregnenolone 16α-carbonitrile (PCN) or control treatment for 4 days. Rifampicin treatment did not affect glucose, insulin, GLP-1, GIP, glucagon, and peptide YY levels statistically significantly. Incremental AUCs (AUCincr) of glucose and insulin tended to increase (41% increase in glucose AUCincr, P = 0.21, 95% confidence interval (CI) of the difference -47, 187; 24% increase in insulin AUCincr, P = 0.084, CI of the difference -110, 1493). Glucagon AUC was increased in women (53% increase, P = 0.028) and decreased in men (19% decrease, P < 0.001) after rifampicin dosing. In combined analysis of human Rifa-1 and Rifa-2 studies, glucose AUCincr was elevated by 63% (P = 0.010) and insulin AUCincr by 37% (P = 0.011). PCN increased rat insulin level at 60 min time point but did not affect incretin and insulin AUCs statistically significantly. In conclusion, PXR agonists do not affect the secretion of incretin hormones. The regulation of glucagon secretion by PXR may be sexually dimorphic in humans. The mechanism of disrupted glucose metabolism induced by PXR activation requires further study.
    No preview · Article · Dec 2015
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    ABSTRACT: Non-alcoholic fatty liver disease (NAFLD) and atrial fibrillation (AF) are widespread diseases and have multiple common risk factors and comorbidities. No studies of association between ultrasonography-diagnosed NAFLD and AF exist in other than diabetic population. The goal of this prospective study was to study the value of NAFLD as a predictor of atrial fibrillation. This study had 958 subjects from the OPERA (Oulu Project Elucidating Risk of Atherosclerosis) cohort, and the mean follow-up time was 16.3 years. NAFLD was diagnosed if the subject had fatty liver in ultrasonography and no excess alcohol intake. AF was followed in the National Registers. In this study 249 subjects (26.0%) had NAFLD and 37 (14.9%) of these had AF whereas only 56 (7.9%) of those without NAFLD experienced AF during the follow-up time (p = 0.001). In the multiple Cox regression analysis including potential confounders (age, sex, study group, diabetes, body mass index (BMI), waist circumference, alcohol consumption, smoking, serum alanine aminotransferase concentration (ALT), systolic blood pressure, quick index, left ventricular mass index, left atrial diameter, coronary artery disease (CAD), atrial natriuretic peptide (ANP) and high sensitive C-reactive protein (hs-CRP)), NAFLD remained as an independent predictor of AF (Adjusted OR, 1.88 (95% Confidence interval (CI) 1.03-3.45)). In conclusion, our data shows that NAFLD is independently associated with the risk of AF.
    Preview · Article · Nov 2015 · PLoS ONE
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    Full-text · Dataset · Mar 2015

  • No preview · Article · Aug 2014 · Atherosclerosis
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    ABSTRACT: Background/objectives: Few studies have used biomarkers of whole-grain intake to study its relation to glucose metabolism. We aimed to investigate the association between plasma alkylresorcinols (AR), a biomarker of whole-grain rye and wheat intake, and glucose metabolism in individuals with metabolic syndrome (MetS). Subjects/methods: Participants were 30-65 years of age, with body mass index 27-40 kg/m(2) and had MetS without diabetes. Individuals were recruited through six centers in the Nordic countries and randomized to a healthy Nordic diet (ND, n=96), rich in whole-grain rye and wheat, or a control diet (n=70), for 18-24 weeks. In addition, associations between total plasma AR concentration and C17:0/C21:0 homolog ratio as an indication of the relative whole-grain rye intake, and glucose metabolism measures from oral glucose tolerance tests were investigated in pooled (ND+control) regression analyses at 18/24 weeks. Results: ND did not improve glucose metabolism compared with control diet, but the AR C17:0/C21:0 ratio was inversely associated with fasting insulin concentrations (P=0.002) and positively associated with the insulin sensitivity indices Matsuda ISI (P=0.026) and disposition index (P=0.022) in pooled analyses at 18/24 weeks, even after adjustment for confounders. The AR C17:0/C21:0 ratio was not significantly associated with insulin secretion indices. Total plasma AR concentration was not related to fasting plasma glucose or fasting insulin at 18/24 weeks. Conclusions: The AR C17:0/C21:0 ratio, an indicator of relative whole-grain rye intake, is associated with increased insulin sensitivity in a population with MetS.
    Full-text · Article · Feb 2014 · European journal of clinical nutrition
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    ABSTRACT: It is becoming increasingly recognised that early-life nutritional, metabolic and environmental factors can have a long term impact on the early onset of obesity, type 2 diabetes and cardiovascular diseases. Numerous experimental and epidemiological observations support the concept that an individual's response to its adult life-style and nutritional environment depends not only on their genetic susceptibility but also their previous early-life experiences. The current research challenge is to determine the primary pathways contributing to "non- or epi-genetic" causes of excess adult weight gain and adiposity. Evidence from the fields of genetic epidemiology, life-course modelling and diet-induced fetal programming all support a role for the FTO gene in this complex biological interaction. It may provide a missing link in the developmental regulation of energy metabolism. Our review therefore considers the role of the FTO gene in the early-life determination of body weight, body composition and energy balance. We will summarise current knowledge on FTO biology combining human genetic epidemiology, molecular models and findings from animal studies. Notably, we will focus on the role of FTO in energy balance in humans, the importance of FTO polymorphisms in childhood growth and the impact of fetal nutrition. Ultimately we propose a new hypothesis for future research designed to understand the role of FTO in setting gene expression in metabolically active tissues. This article is protected by copyright. All rights reserved.
    Full-text · Article · Nov 2013 · Acta Physiologica
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    ABSTRACT: Purpose To study the association of potential key single-nucleotide polymorphisms with the short-term anatomic response to bevacizumab treatment in exudative age-related macular degeneration (AMD). Methods Clinical data of 96 bevacizumab-treated exudative age-related macular degeneration patients were analyzed retrospectively. Blood DNA was collected. Based on the disappearance of intra- or subretinal fluid in optical coherence tomography, patients were graded as responders, partial responders, or nonresponders after 3 initial treatment visits and a median time of 3.5 months. Representative single-nucleotide polymorphisms of interleukin 8, vascular endothelial growth factor, erythropoietin, complement factor H, complement component C3, and LOC387715 genes were analysed. Results Interleukin 8 promoter polymorphism −251A/T,conferring a more acitve interleuking-8 system, was significantly associated with persisting fluid in optical coherence tomography. The A allele was more frequent in nonresponders than in responders (P = 0.033). In multivariate modeling, the AA genotype of −251A/T (P = 0.043) and occult (P = 0.042) or predominantly classic (P = 0.040) lesions predicted a poorer outcome. Conclusion The interleukin -8 pathway may modulate the early anatomic response to anti-VEGF treatment in AMD. A possible activation of interleukin -8 production in patients may represent a compensatory mechanism to chronic blockade of VEGF signalling in AMD lesions
    No preview · Article · Aug 2013 · Acta ophthalmologica
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    ABSTRACT: Background: Different healthy food patterns may modify cardiometabolic risk. We investigated the effects of an isocaloric healthy Nordic diet on insulin sensitivity, lipid profile, blood pressure and inflammatory markers in people with metabolic syndrome. Methods: We conducted a randomized dietary study lasting for 18-24 weeks in individuals with features of metabolic syndrome (mean age 55 years, BMI 31.6 kg m(-2) , 67% women). Altogether 309 individuals were screened, 200 started the intervention after 4-week run-in period, and 96 (proportion of dropouts 7.9%) and 70 individuals (dropouts 27%) completed the study, in the Healthy diet and Control diet groups, respectively. Healthy diet included whole-grain products, berries, fruits and vegetables, rapeseed oil, three fish meals per week and low-fat dairy products. An average Nordic diet served as a Control diet. Compliance was monitored by repeated 4-day food diaries and fatty acid composition of serum phospholipids. Results: Body weight remained stable, and no significant changes were observed in insulin sensitivity or blood pressure. Significant changes between the groups were found in non-HDL cholesterol (-0.18, mmol L(-1) 95% CI -0.35; -0.01, P = 0.04), LDL to HDL cholesterol (-0.15, -0.28; -0.00, P = 0.046) and apolipoprotein B to apolipoprotein A1 ratios (-0.04, -0.07; -0.00, P = 0.025) favouring the Healthy diet. IL-1 Ra increased during the Control diet (difference -84, -133; -37 ng L(-1) , P = 0.00053). Intakes of saturated fats (E%, beta estimate 4.28, 0.02; 8.53, P = 0.049) and magnesium (mg, -0.23, -0.41; -0.05, P = 0.012) were associated with IL-1 Ra. Conclusions: Healthy Nordic diet improved lipid profile and had a beneficial effect on low-grade inflammation.
    Full-text · Article · Feb 2013 · Journal of Internal Medicine
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    ABSTRACT: Circulating cholesterol (C) and triglyceride (TG) levels are associated with vascular injury in type 1 diabetes (T1DM). Lipoproteins are responsible for transporting lipids, and alterations in their subclass distributions may partly explain the increased mortality in individuals with T1DM. A cohort of 3544 individuals with T1DM was recruited by the nationwide multicentre FinnDiane Study Group. At baseline, six very low-density lipoprotein VLDL, one intermediate-density lipoprotein IDL, three low-density lipoprotein LDL and four higher high-density lipoprotein HDL subclasses were quantified by proton nuclear magnetic resonance spectroscopy. At follow-up, the baseline data were analysed for incident micro- or macroalbuminuria (117 cases in 5.3 years), progression from microalbuminuria (63 cases in 6.1 years), progression from macroalbuminuria (109 cases in 5.9 years) and mortality (385 deaths in 9.4 years). Univariate associations were tested by age-matched cases and controls and multivariate lipoprotein profiles were analysed using the self-organizing map (SOM). TG and C levels in large VLDL were associated with incident albuminuria, TG and C in medium VLDL were associated with progression from microalbuminuria, and TG and C in all VLDL subclasses were associated with mortality. Large HDL-C was inversely associated with mortality. Three extreme phenotypes emerged from SOM analysis: (i) low C (<3% mortality), (ii) low TG/C ratio (6% mortality), and (iii) high TG/C ratio (40% mortality) in all subclasses. TG–C imbalance is a general lipoprotein characteristic in individuals with T1DM and high vascular disease risk.
    No preview · Article · Dec 2012 · Journal of Internal Medicine
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    ABSTRACT: Background/aim: Inflammatory markers have been observed in proliferative diabetic retinopathy (PDR). We assessed vitreous concentrations of adhesion molecules and cytokines in PDR and non-diabetic controls and plasma concentrations to differentiate local inflammation from the breakdown of the blood-retina barrier. Methods: 38 patients with PDR and 16 controls with macular hole or epiretinal membrane underwent vitrectomy. Vitreous and plasma soluble adhesion molecules [sE-selectin, intercellular adhesion molecule (sICAM)-1 and -3, platelet-endothelial cell adhesion molecule (sPECAM)-1, sP-selectin, vascular cell adhesion molecule (sVCAM)-1] and cytokines [interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12 (p70), tumour necrosis factor-α and -β, γ-interferon] were detected by the multiplex assay. Results: Levels of IL-6 and IL-8 were 26-fold (p = 0.001) and 6-fold higher (p = 0.001) in vitreous than in plasma in PDR. Vitreous IL-10 (p = 0.004), sPECAM-1, sE-selectin, sICAM-1 and sVCAM-1 were higher in PDR than controls (p = 0.001 for all). Adhesion molecule concentrations in vitreous in PDR were less than 10% of those in plasma. IL-10 was lower in vitreous than plasma (3.0 vs. 12.8 pg/ml, p = 0.007), and the vitreous IL-10/IL-8 ratio was significantly lower in PDR than in controls (0.10 vs. 0.55 pg/ml, p = 0.003). Conclusion: The elevated IL-6 and IL-8 levels in vitreous, but not in plasma, are evidence favouring local over systemic inflammation in PDR. Furthermore, there was imbalance between inflammatory and anti-inflammatory cytokines in the vitreous.
    No preview · Article · Dec 2012 · Ophthalmic Research

  • No preview · Article · Sep 2012 · Fertility and Sterility
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    ABSTRACT: Objective: Acute alcohol exposure induces malformation and malfunction of placenta-yolk sac tissues in rodents, reducing the labyrinth zone in the placenta and altering the permeability and fluidity of the cell membrane. During normal mouse placentation the cells line up in an optimal way to form a hemotrichorial placenta where layers II and III are connected through gap junctions. These act as molecular sieves that limit the passage of large molecules. PlGF is a developmentally regulated protein that controls the passage of molecules in the vasculosyncytial membranes and media of large blood vessels in the placental villi. In addition to the chorioallontoic placenta, rodents also have another type of placenta that consists of Reichert's membrane within the trophoblast cell layer on the maternal side and the parietal endodermal cells on the embryonic site. This forms a separate materno-fetal transport system. We study here whether alcohol affects these two placental barriers, leading to placental malfunction that in turn diminishes the nutrient supply to the embryo. Study design: CD-1 mice received two intraperitoneal injections of 3 g/kg ethanol at 4 h intervals at 8.75 days post coitum (dpc). The placentas were collected on 9.5, 11.5 and 14.5 dpc and used for histopathological protein studies. Hemotrichorial cell layer structure interactions through connective tissue and gap junction were analyzed by electron microscopy. The permeability of the feto-maternal barrier was visualized with Evans Blue. Results: VEGF, a permeability inducer, was found to be up-regulated in the mouse placenta after acute alcohol exposure, and permeability was also affected by altered structures in the barriers that separate the feto-maternal blood circulation which destroyed the gap junctions in the hemotrichorial cell layer, reduced the thickness of Reichert's membrane and interfered with with Reichert's trophoblast/Reichert's parietal interaction. These defects together could have caused the permeability malfunction of the placenta-yolk sac tissues as visualized and quantified here by Evans Blue leakage. Conclusions: An altered PlGF/VEGF ratio together with barrier malformation may contribute to placental malfunction by altering the permeability of the feto-maternal barriers. Further studies are needed in order to show whether premature permeability is involved in the intrauterine growth restriction observed in human FAS embryos.
    No preview · Article · Aug 2012 · Placenta
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    ABSTRACT: Accumulating evidence suggests that serum lipids are associated with cognitive decline and dementias. However, majority of the existing information concerns only serum total cholesterol (TC) and data at the level of lipoprotein fractions and subclasses is limited. The aim of this study was to explore the levels and trends of main cholesterol and triglyceride measures and eight lipoprotein subclasses during normal aging and the development of mild cognitive impairment by following a group of elderly for six years. Longitudinal. City of Kuopio, Finland. 45 elderly individuals of which 20 developed mild cognitive impairment (MCI) during the follow-up. On each visit participants underwent an extensive neuropsychological and clinical assessment. Lipoprotein levels were measured via 1H NMR from native serum samples. Serum cholesterol and many primarily cholesterol-associated lipoprotein measures clearly decreased in MCI while the trends were increasing for those elderly people who maintained normal cognition. These findings suggest that a decreasing trend in serum cholesterol measures in elderly individuals may suffice as an indication for more detailed inspection for potential signs of cognitive decline.
    No preview · Article · Jul 2012 · The Journal of Nutrition Health and Aging
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    ABSTRACT: International Journal of Obesity is a monthly, multi-disciplinary forum for papers describing basic, clinical and applied studies in biochemistry, genetics and nutrition, together with molecular, metabolic, psychological and epidemiological aspects of obesity and related disorders
    Full-text · Article · Jun 2012 · International journal of obesity (2005)
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    ABSTRACT: OBJECTIVE: Ascending aortic aneurysms result from a degenerative process in the aortic wall, characterized by the loss of smooth muscle cells and elastic fibers. We hypothesized that there would be changes in plasma protein and aortic tissue messenger RNA levels of osteopontin, matrix metalloproteinase type 2, matrix metalloproteinase type 9, and tissue inhibitor of matrix metalloproteinases type 1 in ascending aortic aneurysm samples. METHODS: Plasma, aortic tissue, and aortic mRNA samples were collected from patients with an ascending aortic aneurysm or an abdominal aortic aneurysm and from control individuals. Plasma protein levels of osteopontin, matrix metalloproteinase (MMP) types 2 and 9, and tissue inhibitor of matrix metalloproteinases type 1 were determined by quantitative sandwich enzyme-linked immunosorbent assay. Aortic mRNA levels of these same proteins were analyzed with the quantitative real-time polymerase chain reaction (RT-PCR) method and protein levels from the aortic tissues were assayed by immunostaining. Quantitative RT-PCR results were estimated by the normalized expression method (ΔΔCt). RESULTS: Plasma protein levels were significantly elevated for osteopontin, MMP-2, and MMP-9 in the samples of ascending and abdominal aortic aneurysm group compared with controls. Plasma protein levels of MMP-9 were higher in the nonoperated compared with the operated ascending aortic aneurysm group. Aortic osteopontin, MMP-2, and MMP-9 mRNA levels were increased for ascending aortic aneurysm samples. CONCLUSIONS: This study reveals an important role of osteopontin, MMP-2 and MMP-9 in the development of ascending and abdominal aortic aneurysm.
    No preview · Article · May 2012 · The Journal of thoracic and cardiovascular surgery
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    ABSTRACT: Having demonstrated short-term weight loss with liraglutide in this group of obese adults, we now evaluate safety/tolerability (primary outcome) and long-term efficacy for sustaining weight loss (secondary outcome) over 2 years. A randomized, double-blind, placebo-controlled 20-week study with 2-year extension (sponsor unblinded at 20 weeks, participants/investigators at 1 year) in 19 European clinical research centers. A total of 564 adults (n=90-98 per group; body mass index 30-40 kg m(-2)) enrolled, 398 entered the extension and 268 completed the 2-year trial. Participants received diet (500 kcal deficit per day) and exercise counseling during 2-week run-in, before being randomly assigned (with a telephone or web-based system) to once-daily subcutaneous liraglutide (1.2, 1.8, 2.4 or 3.0 mg, n=90-95), placebo (n=98) or open-label orlistat (120 mg × 3, n=95). After 1 year, liraglutide/placebo recipients switched to liraglutide 2.4 mg, then 3.0 mg (based on 20-week and 1-year results, respectively). The trial ran from January 2007-April 2009 and is registered with Clinicaltrials.gov, number NCT00480909. From randomization to year 1, liraglutide 3.0 mg recipients lost 5.8 kg (95% confidence interval 3.7-8.0) more weight than those on placebo and 3.8 kg (1.6-6.0) more than those on orlistat (P0.0001; intention-to-treat, last-observation-carried-forward). At year 2, participants on liraglutide 2.4/3.0 mg for the full 2 years (pooled group, n=184) lost 3.0 kg (1.3-4.7) more weight than those on orlistat (n=95; P<0.001). Completers on liraglutide 2.4/3.0 mg (n=92) maintained a 2-year weight loss of 7.8 kg from screening. With liraglutide 3.0 mg, 20-week body fat decreased by 15.4% and lean tissue by 2.0%. The most frequent drug-related side effects were mild to moderate, transient nausea and vomiting. With liraglutide 2.4/3.0 mg, the 2-year prevalence of prediabetes and metabolic syndrome decreased by 52 and 59%, with improvements in blood pressure and lipids. Liraglutide is well tolerated, sustains weight loss over 2 years and improves cardiovascular risk factors.
    Full-text · Article · Aug 2011 · International journal of obesity (2005)

  • No preview · Article · Jun 2011 · Atherosclerosis Supplements
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    ABSTRACT: Viruses and bacteria like Chlamydia pneumoniae and Helicobacter pylori have been suggested to have a role in pathogenesis of overweight and obesity. We studied whether C. pneumoniae-specific IgG antibodies are associated with elevated body mass index (BMI), waist and hip circumference, and/or waist-hip ratio (WHR), and whether the risk is more pronounced in the simultaneous presence of an ongoing inflammation as measured by elevated high-sensitive C-reactive protein (hsCRP) levels. Our study population was derived from the Northern Finland Birth Cohort 1966 (NFBC1966), a general population sample of 12,058 live-born children. This cross-sectional study consisted of 5044 persons at 31 years of age. Serum C. pneumoniae IgG titers were measured by microimmunofluorescence test, and hsCRP levels by immunoenzymometric assay. C. pneumoniae IgG positivity (titer ≥ 32), both alone and jointly with elevated hsCRP (≥ 1.64 mg l(-1), an upper quartile), was found to significantly associate with elevated BMI in the whole study population and with elevated hip and waist circumference in women, yet no association with WHR was seen. The analyses were adjusted for sex (when appropriate), smoking, socioeconomic position, glucose, insulin, high- and low-density lipoprotein cholesterols, triglycerides, leukocytes and pulse pressure. These findings suggest that especially in women, persistent C. pneumoniae infection may be associated with overweight/obesity, independently of more traditional risk factors.
    Full-text · Article · Mar 2011 · International journal of obesity (2005)
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    ABSTRACT: The aim of this study was to evaluate differences in body mass index and eating behavior in obese and overweight persons with and without anhedonia during a weight loss intervention study. Psychiatric diagnostics were based on the Structured Clinical Interview for DSM-IV disorders. Eating behavior was assessed by the Three Factor Eating Questionnaire (TFEQ-18) and binge eating by the Binge Eating Scale (BES). Out of 82 participants, 20 (24.4%) reported experiencing anhedonia at least once during the study period. Those suffering from anhedonia scored significantly higher values in BES at baseline and at follow-up. They also reported more uncontrolled and emotional eating at the first follow-up. Overall, persons suffering from anhedonia achieved a poorer outcome in weight loss compared to those without anhedonia. Anhedonia was associated with uncontrolled eating, emotional eating, and binge eating, all of which may have contributed to the poorer outcomes achieved in weight loss.
    Full-text · Article · Dec 2010 · Appetite
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    ABSTRACT: Objective To determine associations of systemic metabolites with subclinical atherosclerosis. Methods 4407 serum samples were measured by nuclear magnetic resonance (NMR) spectroscopy from the Cardiovascular Risk in Young Finns Study, and carotid intima-media thickness (IMT) was assessed by ultrasound. Numerous lipoprotein lipids subclasses as well as low-molecular-weight metabolites were quantified from the NMR data. Results In these young adults (aged 24–45 years) data-driven analysis using self-organising maps showed distinct metabolic phenotypes associated with elevated IMT. The phenotypes were characterised by varying combinations of metabolic disturbances including elevated very-low-density lipoprotin (VLDL) and LDL subclasses, but also several low-molecular-weight metabolites. Results for 6-year incidence of high carotid IMT and IMT progression as shown by discrimination and reclassification will also be discussed. Conclusion The study showed different metabolic phenotypes inherently associated with subclinical atherosclerosis. Prediction of subclinical atherosclerosis was improved by comprehensive metabolic profiling. The findings substantiate developments towards the use of multi-metabolic risk phenotypes in cardiovascular risk assessment.
    Preview · Article · Sep 2010 · Heart (British Cardiac Society)

Publication Stats

4k Citations
647.20 Total Impact Points


  • 1975-2015
    • University of Oulu
      • • Biocenter Oulu
      • • Institute of Clinical Medicine
      • • Department of Internal Medicine
      • • Physics
      • • Department of Medical Biochemistry and Molecular Biology
      Uleoborg, Northern Ostrobothnia, Finland
  • 1982-2013
    • Oulu University Hospital
      • Department of Internal Medicine
      Uleoborg, Oulu, Finland
  • 2001
    • University of the Balearic Islands
      Palma, Balearic Islands, Spain
  • 2000
    • Biocenter Finland
      Helsinki, Uusimaa, Finland
  • 1984
    • Icahn School of Medicine at Mount Sinai
      • Department of Medicine
      Borough of Manhattan, New York, United States