Browsing by Subject "INSULIN SENSITIVITY"

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  • Ottosson-Laakso, Emilia; Tuomi, Tiinamaija; Forsen, Bjorn; Gullstrom, Monika; Groop, Per-Henrik; Groop, Leif; Vikman, Petter (2016)
    Familial renal glycosuria is an inherited disorder resulting in glucose excretion in the urine despite normal blood glucose concentrations. It is most commonly due to mutations in the SLC5A2 gene coding for the glucose transporter SGLT2 in the proximal tubule. Several drugs have been introduced as means to lower glucose in patients with type 2 diabetes targeting SGLT2 resulting in renal glycosuria, but no studies have addressed the potential effects of decreased renal glucose reabsorption and chronic glycosuria on the prevention of glucose intolerance. Here we present data on a large pedigree with renal glycosuria due to two mutations (c.300-303+2del and p.A343V) in the SLC5A2 gene. The mutations, which in vitro affected glucose transport in a cell line model, and the ensuing glycosuria were not associated with better glycemic control during a follow-up period of more than 10 years. One individual, who was compound heterozygous for mutations in the SLC5A2 gene suffered from severe urogenital candida infections and postprandial hypoglycemia. In conclusion, in this family with familial glycosuria we did not find any evidence that chronic loss of glucose in the urine would protect from deterioration of the glucose tolerance over time.
  • Cammarota, Giovanni; Ianiro, Gianluca; Kelly, Colleen R.; Mullish, Benjamin H.; Allegretti, Jessica R.; Kassam, Zain; Putignani, Lorenza; Fischer, Monika; Keller, Josbert J.; Costello, Samuel Paul; Sokol, Harry; Kump, Patrizia; Satokari, Reetta; Kahn, Stacy A.; Kao, Dina; Arkkila, Perttu; Kuijper, Ed J.; Vehreschild, Maria J. G. T.; Pintus, Cristina; Lopetuso, Loris; Masucci, Luca; Scaldaferri, Franco; Terveer, E. M.; Nieuwdorp, Max; Lopez-Sanroman, Antonio; Kupcinskas, Juozas; Hart, Ailsa; Tilg, Herbert; Gasbarrini, Antonio (2019)
    Although faecal microbiota transplantation (FMT) has a well-established role in the treatment of recurrent Clostridioides difficile infection (CDI), its widespread dissemination is limited by several obstacles, including lack of dedicated centres, difficulties with donor recruitment and complexities related to regulation and safety monitoring. Given the considerable burden of CDI on global healthcare systems, FMT should be widely available to most centres. Stool banks may guarantee reliable, timely and equitable access to FMT for patients and a traceable workflow that ensures safety and quality of procedures. In this consensus project, FMT experts from Europe, North America and Australia gathered and released statements on the following issues related to the stool banking: general principles, objectives and organisation of the stool bank; selection and screening of donors; collection, preparation and storage of faeces; services and clients; registries, monitoring of outcomes and ethical issues; and the evolving role of FMT in clinical practice, Consensus on each statement was achieved through a Delphi process and then in a plenary face-to-face meeting. For each key issue, the best available evidence was assessed, with the aim of providing guidance for the development of stool banks in order to promote accessibility to FMT in clinical practice.
  • Huvinen, Emilia; Engberg, Elina; Meinilä, Jelena; Tammelin, Tuija; Kulmala, Janne; Heinonen, Kati; Bergman, Paula; Stach-Lempinen, Beata; Koivusalo, Saila (2020)
    Aim Women with prior gestational diabetes (GDM) are at increased diabetes risk. This study aimed to assess whether lifestyle is associated with glycemic health of high-risk women 5 years postpartum, taking into account the pre-pregnancy BMI. Methods The RADIEL study enrolled before or in early pregnancy 720 women with pre-pregnancy BMI >= 30 kg/m(2)and/or prior GDM. The follow-up visit 5 years postpartum included questionnaires and measurements of anthropometrics, blood pressure, and physical activity (PA) as well as analyses of glucose metabolism, lipids, and inflammatory markers. We measured body composition (Inbody) and calculated a Healthy Food Intake Index (HFII) from Food Frequency Questionnaires (FFQ). ArmBand measured PA, sedentary time, and sleep. To take into account the diverse risk groups of GDM, we divided the women based on pre-pregnancy BMI over/under 30 kg/m(2). Results Altogether 348 women attended the follow-up. The obese and non-obese women showed similar prevalence of glycemic abnormalities, 13% and 19% (p = 0.139). PA levels were higher among the non-obese women (p <0.05), except for step count, and their HFII was higher compared to the obese women (p = 0.033). After adjusting for age, education, and GDM history, PA and HFII were associated with glycemic health only among obese women. When both lifestyle factors were in the same model, only PA remained significant. PA associated with other markers of metabolic health also among the non-obese women, excluding HbA1c. Conclusion Lifestyle 5 years postpartum was associated with better glycemic health only among the obese high-risk women. PA, however, is essential for the metabolic health of all high-risk women.
  • Slopien, Radoslaw; Wender-Ozegowska, Ewa; Rogowicz-Frontczak, Anita; Meczekalski, Blazej; Zozulinska-Ziolkiewicz, Dorota; Jaremek, Jesse D.; Cano, Antonio; Chedraui, Peter; Goulis, Dimitrios G.; Lopes, Patrice; Mishra, Gita; Mueck, Alfred; Rees, Margaret; Senturk, Levent M.; Simoncini, Tommaso; Stevenson, John C.; Stute, Petra; Tuomikoski, Pauliina; Paschou, Stavroula A.; Anagnostis, Panagiotis; Lambrinoudaki, Irene (2018)
    Introduction: Whether menopause increases the risk of type 2 diabetes mellitus (T2DM) independently of ageing has been a matter of debate. Controversy also exists about the benefits and risks of menopausal hormone therapy (MHT) in women with T2DM. Aims: To summarise the evidence on 1) the effect of menopause on metabolic parameters and the risk of T2DM, 2) the effect of T2DM on age at menopause, 3) the effect of MHT on the risk of T2DM, and 4) the management of postmenopausal women with T2DM. Materials and methods: Literature review and consensus of experts' opinions. Results and conclusion: Metabolic changes during the menopausal transition include an increase in and the central redistribution of adipose tissue, as well as a decrease in energy expenditure. In addition, there is impairment of insulin secretion and insulin sensitivity and an increase in the risk of T2DM. MHT has a favourable effect on glucose metabolism, both in women with and in women without T2DM, while it may delay the onset of T2DM. MHT in women with T2DM should be administered according to their risk of cardiovascular disease (CVD). In women with T2DM and low CVD risk, oral oestrogens may be preferred, while transdermal 17 beta-oestradiol is preferred for women with T2DM and coexistent CVD risk factors, such as obesity. In any case, a progestogen with neutral effects on glucose metabolism should be used, such as progesterone, dydrogesterone or transdermal norethisterone. Postmenopausal women with T2DM should be managed primarily with lifestyle intervention, including diet and exercise. Most of them will eventually require pharmacological therapy. The selection of antidiabetic medications should be based on the patient's specific characteristics and comorbidities, as well on the metabolic, cardiovascular and bone effects of the medications.
  • Ganel, Liron; Chen, Lei; Christ, Ryan; Vangipurapu, Jagadish; Young, Erica; Das, Indraniel; Kanchi, Krishna; Larson, David; Regier, Allison; Abel, Haley; Kang, Chul Joo; Scott, Alexandra; Havulinna, Aki; Chiang, Charleston W. K.; Service, Susan; Freimer, Nelson; Palotie, Aarno; Ripatti, Samuli; Kuusisto, Johanna; Boehnke, Michael; Laakso, Markku; Locke, Adam; Stitziel, Nathan O.; Hall, Ira M. (2021)
    Background Mitochondrial genome copy number (MT-CN) varies among humans and across tissues and is highly heritable, but its causes and consequences are not well understood. When measured by bulk DNA sequencing in blood, MT-CN may reflect a combination of the number of mitochondria per cell and cell-type composition. Here, we studied MT-CN variation in blood-derived DNA from 19184 Finnish individuals using a combination of genome (N = 4163) and exome sequencing (N = 19034) data as well as imputed genotypes (N = 17718). Results We identified two loci significantly associated with MT-CN variation: a common variant at the MYB-HBS1L locus (P = 1.6 x 10(-8)), which has previously been associated with numerous hematological parameters; and a burden of rare variants in the TMBIM1 gene (P = 3.0 x 10(-8)), which has been reported to protect against non-alcoholic fatty liver disease. We also found that MT-CN is strongly associated with insulin levels (P = 2.0 x 10(-21)) and other metabolic syndrome (metS)-related traits. Using a Mendelian randomization framework, we show evidence that MT-CN measured in blood is causally related to insulin levels. We then applied an MT-CN polygenic risk score (PRS) derived from Finnish data to the UK Biobank, where the association between the PRS and metS traits was replicated. Adjusting for cell counts largely eliminated these signals, suggesting that MT-CN affects metS via cell-type composition. Conclusion These results suggest that measurements of MT-CN in blood-derived DNA partially reflect differences in cell-type composition and that these differences are causally linked to insulin and related traits.
  • Kivimaki, Mika; Vahtera, Jussi; Tabak, Adam G.; Halonen, Jaana I.; Vineis, Paolo; Pentti, Jaana; Pahkala, Katja; Rovio, Suvi; Viikari, Jorma; Kahonen, Mika; Juonala, Markus; Ferrie, Jane E.; Stringhini, Silvia; Raitakari, Olli T. (2018)
    Background Neighbourhood socioeconomic disadvantage has been linked to increased diabetes risk, but little is known about differences in risk factors in childhood and adulthood in those with high and low neighbourhood socioeconomic disadvantage, or about the association between long-term neighbourhood socioeconomic disadvantage and incidence of diabetes in adulthood. We used data from the prospective, population-based Young Finns Study to address these questions. Methods We did a nationwide population-based cohort study in Finland using data from The Young Finns Study, which included 3467 participants aged 6-18 years followed up for over 30 years via eight repeated biomedical examinations and linkage to electronic health records. Participants were also linked to national grid data on neighbourhood disadvantage via their residential address from age 6-48 years. We used these data to examine differences in ten risk factors (dietary habits, physical activity, daily smoking, body-mass index, systolic blood pressure, fasting HDL cholesterol, fasting triglycerides, fasting plasma glucose, fasting serum insulin, and homoeostasis model assessment insulin sensitivity) from childhood (6-21 years) to adulthood (22-48 years) among individuals with high (>= 0.5 SD above the national mean) and low (0.5 SD below the national mean) neighbourhood socioeconomic disadvantage, and the association of cumulative neighbourhood socioeconomic disadvantage with six cardiometabolic risk factors (obesity, high waist circumference, fatty liver, hypertension, carotid plaque, and left ventricle mass index) and diabetes by middle age (22-48 years). We used logistic and linear regression analyses to assess the effects of neighbourhood disadvantage on cardiometabolic and diabetes risk, controlling for potential confounders (age, sex, and individual socioeconomic disadvantage). Findings We included data for 3002 individuals with risk factor assessment in childhood and adulthood. Of whom, 2048 underwent a clinical examination during the last follow-up at age 33-48 years. Differences in risk factors by neighbourhood socioeconomic disadvantage at the beginning of follow-up were small, but large differences emerged over the follow-up. High neighbourhood socioeconomic disadvantage was characterised by decreased fruit and vegetable intake as early as age 6 years, decreased physical activity, and increased prevalence of daily smoking from adolescence (12 years) onwards, and decreased homoeostasis model assessment insulin sensitivity and increased fasting glucose and insulin concentration from early adulthood (27 years; all p Interpretation Living in socioeconomically disadvantaged areas can shape health in childhood and adulthood. Neighbourhood socioeconomic disadvantage is associated with differences in health risks across the life course, including detrimental lifestyle factors from childhood and adolescence onwards and worse glucose metabolism from early adulthood. By middle age, cumulative neighbourhood socioeconomic disadvantage is associated with increased cardiometabolic risk factors and increased incidence of diabetes. Copyright (C) The Author(s). Published by Elsevier Ltd.
  • Matinolli, Hanna-Maria; Hovi, Petteri; Levälahti, Esko; Kaseva, Nina; Silveira, Patricia P.; Hemiö, Katri; Järvenpää, Anna-Liisa; Eriksson, Johan G.; Andersson, Sture; Lindström, Jaana; Männistö, Satu; Kajantie, Eero (2017)
    Epidemiological studies and animal models suggest that early postnatal nutrition and growth can influence adult health. However, few human studies have objective recordings of early nutrient intake. We studied whether nutrient intake and growth during the first 9 weeks after preterm birth with very low birth weight (VLBW,
  • Cederberg, Henna; Gylling, Helena; Miettinen, Tatu A.; Paananen, Jussi; Vangipurapu, Jagadish; Pihlajamaki, Jussi; Kuulasmaa, Teemu; Stancakova, Alena; Smith, Ulf; Kuusisto, Johanna; Laakso, Markku (2013)
  • Pinola, Pekka; Puukka, Katri; Piltonen, Terhi T.; Puurunen, Johanna; Vanky, Eszter; Sundström-Poromaa, Inger; Stener-Victorin, Elisabet; Hirschberg, Angelica Linden; Ravn, Pernille; Andersen, Marianne Skovsager; Glintborg, Dorte; Mellembakken, Jan Roar; Ruokonen, Aimo; Tapanainen, Juha; Morin-Papunen, Laure C. (2017)
    Objective: To compare the metabolic profiles of normo- and hyperandrogenic women with polycystic ovary syndrome (PCOS) with those of control women at different ages during reproductive life. Design: Case-control study. Setting: Not applicable. Patient(s): In all, 1,550 women with normoandrogenic (n = 686) or hyperandrogenic (n = 842) PCOS and 447 control women were divided into three age groups: <30, 30-39, and > 39 years). Interventions(s): None. Main Outcome Measure(s): Body mass index (BMI), waist circumference, blood pressure, glucose, insulin, cholesterol, lipoproteins, triglycerides and high-sensitivity C-reactive protein. Result(s): Both normo- and hyperandrogenic women with PCOS were more obese, especially abdominally. They had increased serum levels of insulin (fasting and in oral glucose tolerance tests), triglycerides, low-density lipoprotein, and total cholesterol, higher blood pressure, and lower high-density lipoprotein levels independently from BMI compared with the control population as early as from young adulthood until menopause. The prevalence of metabolic syndrome was two-to fivefold higher in women with PCOS compared with control women, depending on age and phenotype, and the highest prevalence was observed in hyperandrogenic women with PCOS at late reproductive age. Conclusion(s): When evaluating metabolic risks in women with PCOS, androgenic status, especially abdominal obesity and age, should be taken into account, which would allow tailored management of the syndrome from early adulthood on. (C) 2016 by American Society for Reproductive Medicine.
  • Salonen, Minna K.; Wasenius, Niko; Kajantie, Eero; Lano, Aulikki; Lahti, Jari; Heinonen, Kati; Räikkönen, Katri; Eriksson, Johan G. (2015)
    Objective Low physical activity (PA) is a major risk factor for cardiovascular and metabolic disorders in all age groups. We measured intensity and volume of PA and examined the associations between PA and the metabolic syndrome (MS), its components and body composition among young Finnish adults. Research Design and Methods The study comprises 991 men and women born 1985-86, who participated in a clinical study during the years 2009-11 which included assessments of metabolism, body composition and PA. Objectively measured (SenseWear Armband) five-day PA data was available from 737 participants and was expressed in metabolic equivalents of task (MET). Results The prevalence of MS ranged between 8-10%. Higher total mean volume (MET-hours) or intensity (MET) were negatively associated with the risk of MS and separate components of MS, while the time spent at sedentary level of PA was positively associated with MS. Conclusions MS was prevalent in approximately every tenth of the young adults at the age of 24 years. Higher total mean intensity and volume rates as well as longer duration spent at moderate and vigorous PA level had a beneficial impact on the risk of MS. Longer time spent at the sedentary level of PA increased the risk of MS.
  • Mardinoglu, Adil; Stancakova, Alena; Lotta, Luca A.; Kuusisto, Johanna; Boren, Jan; Bluher, Matthias; Wareham, Nicholas J.; Ferrannini, Ele; Groop, Per Henrik; Laakso, Markku; Langenberg, Claudia; Smith, Ulf (2017)
  • Sahebekhtiari, Navid; Saraswat, Mayank; Joenväärä, Sakari; Jokinen, Riikka; Lovric, Alen; Kaye, Sanna; Mardinoglu, Adil; Rissanen, Aila; Kaprio, Jaakko; Renkonen, Risto; Pietiläinen, Kirsi H. (2019)
    Purpose The purpose of this study is to elucidate the effect of excess body weight and liver fat on the plasma proteome without interference from genetic variation. Experimental Design The effect of excess body weight is assessed in young, healthy monozygotic twins from pairs discordant for body mass index (intrapair difference (Delta) in BMI > 3 kg m(-2), n = 26) with untargeted LC-MS proteomics quantification. The effect of liver fat is interrogated via subgroup analysis of the BMI-discordant twin cohort: liver fat discordant pairs (Delta liver fat > 2%, n = 12) and liver fat concordant pairs (Delta liver fat <2%, n = 14), measured by magnetic resonance spectroscopy. Results Seventy-five proteins are differentially expressed, with significant enrichment for complement and inflammatory response pathways in the heavier co-twins. The complement dysregulation is found in obesity in both the liver fat subgroups. The complement and inflammatory proteins are significantly associated with adiposity measures, insulin resistance and impaired lipids. Conclusions and Clinical Relevance The early pathophysiological mechanisms in obesity are incompletely understood. It is shown that aberrant complement regulation in plasma is present in very early stages of clinically healthy obese persons, independently of liver fat and in the absence of genetic variation that typically confounds human studies.
  • Atabaki-Pasdar, Naeimeh; Ohlsson, Mattias; Vinuela, Ana; Frau, Francesca; Pomares-Millan, Hugo; Haid, Mark; Jones, Angus G.; Thomas, E. Louise; Koivula, Robert W.; Kurbasic, Azra; Mutie, Pascal M.; Fitipaldi, Hugo; Fernandez, Juan; Dawed, Adem Y.; Giordano, Giuseppe N.; Forgie, Ian M.; McDonald, Timothy J.; Rutters, Femke; Cederberg, Henna; Chabanova, Elizaveta; Dale, Matilda; Masi, Federico De; Thomas, Cecilia Engel; Allin, Kristine H.; Hansen, Tue H.; Heggie, Alison; Hong, Mun-Gwan; Elders, Petra J. M.; Kennedy, Gwen; Kokkola, Tarja; Pedersen, Helle Krogh; Mahajan, Anubha; McEvoy, Donna; Pattou, Francois; Raverdy, Violeta; Haussler, Ragna S.; Sharma, Sapna; Thomsen, Henrik S.; Vangipurapu, Jagadish; Vestergaard, Henrik; 't Hart, Leen M.; Adamski, Jerzy; Musholt, Petra B.; Brage, Soren; Brunak, Soren; Dermitzakis, Emmanouil; Frost, Gary; Hansen, Torben; Laakso, Markku; Pedersen, Oluf; Ridderstrale, Martin; Ruetten, Hartmut; Hattersley, Andrew T.; Walker, Mark; Beulens, Joline W. J.; Mari, Andrea; Schwenk, Jochen M.; Gupta, Ramneek; McCarthy, Mark I.; Pearson, Ewan R.; Bell, Jimmy D.; Pavo, Imre; Franks, Paul W. (2020)
    Background Non-alcoholic fatty liver disease (NAFLD) is highly prevalent and causes serious health complications in individuals with and without type 2 diabetes (T2D). Early diagnosis of NAFLD is important, as this can help prevent irreversible damage to the liver and, ultimately, hepatocellular carcinomas. We sought to expand etiological understanding and develop a diagnostic tool for NAFLD using machine learning. Methods and findings We utilized the baseline data from IMI DIRECT, a multicenter prospective cohort study of 3,029 European-ancestry adults recently diagnosed with T2D (n= 795) or at high risk of developing the disease (n= 2,234). Multi-omics (genetic, transcriptomic, proteomic, and metabolomic) and clinical (liver enzymes and other serological biomarkers, anthropometry, measures of beta-cell function, insulin sensitivity, and lifestyle) data comprised the key input variables. The models were trained on MRI-image-derived liver fat content (= 5%) available for 1,514 participants. We applied LASSO (least absolute shrinkage and selection operator) to select features from the different layers of omics data and random forest analysis to develop the models. The prediction models included clinical and omics variables separately or in combination. A model including all omics and clinical variables yielded a cross-validated receiver operating characteristic area under the curve (ROCAUC) of 0.84 (95% CI 0.82, 0.86;p = 5%) rather than a continuous one. Conclusions In this study, we developed several models with different combinations of clinical and omics data and identified biological features that appear to be associated with liver fat accumulation. In general, the clinical variables showed better prediction ability than the complex omics variables. However, the combination of omics and clinical variables yielded the highest accuracy. We have incorporated the developed clinical models into a web interface (see:) and made it available to the community.
  • Arora, Tulika; Velagapudi, Vidya; Pournaras, Dimitri J.; Welbourn, Richard; le Roux, Carel W.; Oresic, Matej; Backhed, Fredrik (2015)
    Roux-en-Y gastric bypass (RYGB) is an effective method to attain sustained weight loss and diabetes remission. We aimed to elucidate early changes in the plasma metabolome and lipidome after RYGB. Plasma samples from 16 insulin-resistant morbidly obese subjects, of whom 14 had diabetes, were subjected to global metabolomics and lipidomics analysis at pre-surgery and 4 and 42 days after RYGB. Metabolites and lipid species were compared between time points and between subjects who were in remission and not in remission from diabetes 2 years after surgery. We found that the variables that were most discriminatory between time points were decanoic acid and octanoic acid, which were elevated 42 days after surgery, and sphingomyelins (18:1/21:0 and 18:1/23:3), which were at their lowest level 42 days after surgery. Insulin levels were lower at 4 and 42 days after surgery compared with pre-surgery levels. At 4 days after surgery, insulin levels correlated positively with metabolites of branched chain and aromatic amino acid metabolism and negatively with triglycerides with long-chain fatty acids. Of the 14 subjects with diabetes prior to surgery, 7 were in remission 2 years after surgery. The subjects in remission displayed higher pre-surgery levels of tricarboxylic acid cycle intermediates and triglycerides with long-chain fatty acids compared with subjects not in remission. Thus, metabolic alterations are induced soon after surgery and subjects with diabetes remission differ in the metabolic profiles at pre- and early post-surgery time points compared to patients not in remission.
  • Holster, Savanne; Lindqvist, Carl Mårten; Repsilber, Dirk; Salonen, Anne; de Vos, Willem M.; König, Julia; Brummer, Robert J. (2019)
    OBJECTIVES: Fecal microbiota transfer (FMT) is suggested as a potential treatment for patients with irritable bowel syndrome (IBS). We aimed to study the effect of allogenic and autologous FMT on IBS symptoms, visceral sensitivity, and compositional changes in fecal and mucosa-adherent microbiota. METHODS: Seventeen patients with IBS were randomized either to receive fecal material from a healthy donor (allogenic) or to receive their own fecal material (autologous). The fecal material was administered into the cecum by whole colonoscopy after bowel cleansing. RESULTS: No significant differences were found between the allogenic and the autologous FMT regarding symptom scores. However, symptom scores of patients receiving allogenic fecal material significantly decreased after FMT compared with baseline (P = 0.02), which was not the case in the autologous group (P=0.16). Visceral sensitivity was not affected except for a small beneficial effect on urge scores in the autologous group (P <0.05). While both fecal and mucosa-adherent microbiota of some patients shifted to their respective donor's fecal microbiota, some patients showed no relevant microbial changes after allogenic FMT. Large compositional shifts in fecal and mucosa-adherent microbiota also occurred in the autologous group. CONCLUSIONS: This study showed that a single FMT by colonoscopy may have beneficial effects in IBS; however, the allogenic fecal material was not superior to the autologous fecal material. This suggests that bowel cleansing prior to the colonoscopy and/or processing of the fecal material as part of the FMT routine contribute to symptoms and gut microbiota composition changes in IBS.
  • Scott, Laura J.; Erdos, Michael R.; Huyghe, Jeroen R.; Welch, Ryan P.; Beck, Andrew T.; Wolford, Brooke N.; Chines, Peter S.; Didion, John P.; Narisu, Narisu; Stringham, Heather M.; Taylor, D. Leland; Jackson, Anne U.; Vadlamudi, Swarooparani; Bonnycastle, Lori L.; Kinnunen, Leena; Saramies, Jouko; Sundvall, Jouko; Albanus, Ricardo D'Oliveira; Kiseleva, Anna; Hensley, John; Crawford, Gregory E.; Jiang, Hui; Wen, Xiaoquan; Watanabe, Richard M.; Lakka, Timo A.; Mohlke, Karen L.; Laakso, Markku; Tuomilehto, Jaakko; Koistinen, Heikki Allan; Boehnke, Michael; Collins, Francis S.; Parker, Stephen C. J. (2016)
    Type 2 diabetes (T2D) results from the combined effects of genetic and environmental factors on multiple tissues over time. Of the 4100 variants associated with T2D and related traits in genome-wide association studies (GWAS), >90% occur in non-coding regions, suggesting a strong regulatory component to T2D risk. Here to understand how T2D status, metabolic traits and genetic variation influence gene expression, we analyse skeletal muscle biopsies from 271 well-phenotyped Finnish participants with glucose tolerance ranging from normal to newly diagnosed T2D. We perform high-depth strand-specific mRNA-sequencing and dense genotyping. Computational integration of these data with epigenome data, including ATAC-seq on skeletal muscle, and transcriptome data across diverse tissues reveals that the tissue-specific genetic regulatory architecture of skeletal muscle is highly enriched in muscle stretch/super enhancers, including some that overlap T2D GWAS variants. In one such example, T2D risk alleles residing in a muscle stretch/super enhancer are linked to increased expression and alternative splicing of muscle-specific isoforms of ANK1.
  • Liimatta, Jani; Jääskeläinen, Jarmo; Karvonen, Anne M.; Remes, Sami; Voutilainen, Raimo; Pekkanen, Juha (2020)
    Context: Adrenarche is a gradual process, but its programming is unknown. Objective: The objective of this article is to examine the trajectory of dehydroepiandrosterone sulfate (DHEAS) from age 1 to 6 years and the associations of early growth with DHEAS concentration by age 6 years. Design and participants: Longitudinal data from a population sample of 78 children (43 girls) with serum samples for DHEAS and insulin-like growth factor 1 (IGF-1) measurements available at ages 1 and 6 years. Main outcome measure: Serum DHEAS concentration at age 6 years. Results: DHEAS concentration at age 1 year correlated with DHEAS concentration at age 6 years (r = 0.594, P <.001). DHEAS levels at age 6 years increased with tertiles of DHEAS at age 1 year (medians (mu g/dL); 4.2, 14.4, 22.6; P <.001) and with those of greater increase in length by age 1 year (6.0, 11.7, 16.4; P = .047), and decreased with Wailes of birth length (17.7, 13.3, 7.1; P = .042). In a regression model including birth size, biochemical covariates at age 1 year, and growth measures by age 6 years, higher DHEAS concentration at age 1 year was an independent determinant of falling into the highest DHEAS tertile at age 6 years. Conclusions: Higher serum DHEAS concentrations already at age 1 year are associated with those at age 6 years. Also, shorter birth length and rapid catch-up growth in length by age 1 year are associated with higher DHEAS concentrations at age 6 years. These results corroborate the early origin of adrenarche and strongly suggest that part of adrenarchal programming already takes place by the end of infancy. (C) Endocrine Society 2020.
  • Gilijamse, Pim W.; Hartstra, Annick V.; Levin, Evgeni; Wortelboer, Koen; Serlie, Mireille J.; Ackermans, Mariette T.; Herrema, Hilde; Nederveen, Aart J.; Imangaliyev, Sultan; Aalvink, Steven; Sommer, Morton; Levels, Han; Stroes, Erik S. G.; Groen, Albert K.; Kemper, Marleen; de Vos, Willem M.; Nieuwdorp, Max; Prodan, Andrei (2020)
    Dysbiosis of the intestinal microbiota has been implicated in insulin resistance, although evidence regarding causality in humans is scarce. We performed a phase I/II dose-finding and safety study on the effect of oral intake of the anaerobic butyrogenic strain Anaerobutyricum soehngenii on glucose metabolism in 24 subjects with metabolic syndrome. We found that treatment with A. soehngenii was safe and observed a significant correlation between the measured fecal abundance of administered A. soehngenii and improvement in peripheral insulin sensitivity after 4 weeks of treatment. This was accompanied by an altered microbiota composition and a change in bile acid metabolism. Finally, we show that metabolic response upon administration of A. soehngenii (defined as improved insulin sensitivity 4 weeks after A. soehngenii intake) is dependent on microbiota composition at baseline. These data in humans are promising, but additional studies are needed to reproduce our findings and to investigate long-term effects, as well as other modes of delivery.
  • Rappou, Elisabeth; Jukarainen, Sakari; Rinnankoski-Tuikka, Rita; Kaye, Sanna M.; Heinonen, Sini; Hakkarainen, Antti; Lundbom, Jesper; Lundbom, Nina; Saunavaara, Virva; Rissanen, Aila; Virtanen, Kirsi A.; Pirinen, Eija; Pietilainen, Kirsi H. (2016)
    Context: Sirtuins (SIRTs) and poly(ADP-ribose) polymerases (PARPs) are 2 important nicotinamide adenine dinucleotide (NAD)(+)-dependent enzyme families with opposing metabolic effects. Energy shortage increases NAD(+) biosynthesis and SIRT activity but reduces PARP activity in animals. Effects of energy balance on these pathways in humans are unknown. Objective: We compared NAD(+)/SIRT pathway expressions and PARP activities in sc adipose tissue (SAT) between lean and obese subjects and investigated their change in the obese subjects during a 12-month weight loss. Design, Setting and Participants: SAT biopsies were obtained from 19 clinically healthy obese subjects (mean +/- SE body mass index, 34.6 +/- 2.7 kg/m(2)) during a weight-loss intervention (0, 5, and 12 mo) and from 19 lean reference subjects (body mass index, 22.7 +/- 1.1 kg/m(2)) at baseline. Main Outcome Measures: SAT mRNA expressions of SIRTs 1-7 and the rate-limiting gene in NAD(+) biosynthesis, nicotinamide phosphoribosyltransferase (NAMPT) were measured by Affymetrix, and total PARP activity by ELISA kit. Results: SIRT1, SIRT3, SIRT7, and NAMPT expressions were significantly lower, whereas total PARP activity was increased in obese compared with lean subjects. SIRT1 and NAMPT expressions increased in obese subjects between 0 and 5 months, after a mean weight loss of 11.7%. In subjects who continued to lose weight between 5 and 12 months, SIRT1 expression increased progressively, whereas in subjects with weight regain, SIRT1 reverted to baseline levels. PARP activity significantly decreased in all subjects upon weight loss. Conclusions: Calorie restriction is an attractive strategy to improve the NAD(+)/SIRT pathway and decrease PARPs in SAT in human obesity.