Tarja Kokkola - Academia.edu (original) (raw)

Papers by Tarja Kokkola

We investigated the processes underlying glycemic deterioration in type 2 diabetes (T2D). Researc... more We investigated the processes underlying glycemic deterioration in type 2 diabetes (T2D). Research Design and Methods 732 recently diagnosed T2D patients from the IMI-DIRECT study were extensively phenotyped over three years, including measures of insulin sensitivity (OGIS), β-cell glucose sensitivity (GS) and insulin clearance (CLIm) from mixed meal tests, liver enzymes, lipid profiles, and baseline

Multiple Sclerosis and Related Disorders

PLOS Medicine

Characterization of the pathophysiological determinants of diarrheagenic Escherichia coli infecti... more Characterization of the pathophysiological determinants of diarrheagenic Escherichia coli infection using a challenge model in healthy adults

F1000Research

GR24 is a synthetic strigolactone analog, demonstrated to regulate the development of plants and ... more GR24 is a synthetic strigolactone analog, demonstrated to regulate the development of plants and arbuscular mycorrhizal fungi. GR24 possesses anti-cancer and anti-apoptotic properties, enhances insulin sensitivity and mitochondrial biogenesis in skeletal myotubes, inhibits adipogenesis, decreases inflammation in adipocytes and macrophages and downregulates the expression of hepatic gluconeogenic enzymes. Transcription factor Nrf2 (Nuclear factor (erythroid-derived 2)-like 2) is a master regulator of antioxidant response, regulating a multitude of genes involved in cellular stress responses and anti-inflammatory pathways, thus maintaining cellular redox homeostasis. Nrf2 activation reduces the deleterious effects of mitochondrial toxins and has multiple roles in promoting mitochondrial function and dynamics. We studied the role of GR24 on gene expression in rat L6 skeletal muscle cells which were differentiated into myotubes. The myotubes were treated with GR24 and analyzed by microa...

Genetic variants identified by genome-wide association studies can contribute to disease risk by ... more Genetic variants identified by genome-wide association studies can contribute to disease risk by altering the production and abundance of mRNA, proteins and other molecules. However, the interplay between molecular intermediaries that define the pathway from genetic variation to disease is not well understood. Here, we evaluated the shared genetic regulation of mRNA molecules, proteins and metabolites derived from whole blood from 3,029 human donors. We find abundant allelic heterogeneity, where multiple variants regulate a particular molecular phenotype, and pleiotropy, where a single variant was associated with multiple molecular phenotypes over multiple genomic regions. We find varying proportions of shared genetic regulation across phenotypes, highest between expression and proteins (66.6%). We were able to recapitulate a substantial proportion of gene expression genetic regulation in a diverse set of 44 tissues, with a median of 88% shared associations for blood expression and ...

Type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD) often co-occur. Defining caus... more Type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD) often co-occur. Defining causal pathways underlying this relationship may help optimize the prevention and treatment of both diseases. Thus, we assessed the strength and magnitude of the putative causal pathways linking dysglycemia and fatty liver, using a combination of causal inference methods. Measures of glycemia, insulin dynamics, magnetic resonance imaging (MRI)-derived abdominal and liver fat content, serological biomarkers, lifestyle, and anthropometry were obtained in participants from the IMI DIRECT cohorts (n=795 with new onset T2D and 2234 individuals free from diabetes). UK Biobank (n=3641) was used for modelling and replication purposes. Bayesian networks were employed to infer causal pathways, with causal validation using two-sample Mendelian randomization. Bayesian networks fitted to IMI DIRECT data identified higher basal insulin secretion rate (BasalISR) and MRI-derived excess visceral fat (VAT) ac...

Journal of Breath Research

Background: Non-alcoholic fatty liver disease (NAFLD) is highly prevalent and causes serious heal... more Background: Non-alcoholic fatty liver disease (NAFLD) is highly prevalent and causes serious health complications in type 2 diabetes (T2D) and beyond. Early diagnosis of NAFLD is important, as this can help prevent irreversible damage to the liver and ultimately hepatocellular carcinomas. Methods and Findings: Utilizing the baseline data from the IMI DIRECT participants (n=1514) we sought to expand etiological understanding and develop a diagnostic tool for NAFLD using machine learning. Multi-omic (genetic, transcriptomic, proteomic, and metabolomic) and clinical (liver enzymes and other serological biomarkers, anthropometry, and 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% or >=5%). 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...

Diabetologia

Aims/hypothesis It is well established that physical activity, abdominal ectopic fat and glycaemi... more Aims/hypothesis It is well established that physical activity, abdominal ectopic fat and glycaemic regulation are related but the underlying structure of these relationships is unclear. The previously proposed twin-cycle hypothesis (TC) provides a mechanistic basis for impairment in glycaemic control through the interactions of substrate availability, substrate metabolism and abdominal ectopic fat accumulation. Here, we hypothesise that the effect of physical activity in glucose regulation is mediated by the twin-cycle. We aimed to examine this notion in the Innovative Medicines Initiative Diabetes Research on Patient Stratification (IMI DIRECT) Consortium cohorts comprised of participants with normal or impaired glucose regulation (cohort 1: N ≤ 920) or with recently diagnosed type 2 diabetes (cohort 2: N ≤ 435). Methods We defined a structural equation model that describes the TC and fitted this within the IMI DIRECT dataset. A second model, twin-cycle plus physical activity (TC-P...

Bioorganic & Medicinal Chemistry

Sirtuins (SIRT1-SIRT7) are an evolutionary conserved family of NAD +-dependent protein deacylases... more Sirtuins (SIRT1-SIRT7) are an evolutionary conserved family of NAD +-dependent protein deacylases regulating the acylation state of ε-N-lysine residues of proteins thereby controlling key biological processes. Numerous studies have found association of the aberrant enzymatic activity of SIRTs with various diseases like diabetes, cancer and neurodegenerative disorders. Previously, we have shown that substituted 2-alkyl-chroman-4-one/ chromone derivatives can serve as selective inhibitors of SIRT2 possessing an antiproliferative effect in two human cancer cell lines. In this study, we have explored the bioisosteric replacement of the chroman-4-one/ chromone core structure with different less lipophilic bicyclic scaffolds to overcome problems associated to poor physiochemical properties due to a highly lipophilic substitution pattern required for achieve a good inhibitory effect. Various new derivatives based on the quinolin-4(1H)-one scaffold, bicyclic secondary sulfonamides or saccharins were synthesized and evaluated for their SIRT inhibitory effect. Among the evaluated scaffolds, the benzothiadiazine-1,1-dioxide-based compounds showed the highest SIRT2 inhibitory activity. Molecular modeling studies gave insight into the binding mode of the new scaffold-replacement analogues.

Biochemical and biophysical research communications, Jan 5, 2018

Obesity is characterized by excess fat accumulation in white adipose tissue, which triggers chron... more Obesity is characterized by excess fat accumulation in white adipose tissue, which triggers chronic low-grade inflammation through secretion of pro-inflammatory factors by the enlarged adipocytes and infiltrated macrophages. This affects glucose and lipid metabolism in adipose tissue, inducing type 2 diabetes. NAD-dependent deacetylase SIRT1 is known to inhibit adipogenesis through the regulation of the key adipogenic transcription factors, PPARγ and C/EBPα. SIRT1 activators such as resveratrol inhibit adipogenesis and exert anti-inflammatory responses in the adipose tissue. We aimed to investigate the role of two SIRT1 activating plant-derived compounds, strigolactone analog GR24 and pinosylvin, in adipogenesis and inflammation of murine adipocytes. 3T3-L1 preadipocytes were differentiated into adipocytes and were treated with GR24 and pinosylvin. Resveratrol was used as a reference treatment. The effects of these compounds on adipogenesis and inflammation were explored by differen...

International journal of pharmaceutics, Jan 10, 2018

l-Type amino acid transporter 1 (LAT1) is a sodium-independent exchanger transporting large neura... more l-Type amino acid transporter 1 (LAT1) is a sodium-independent exchanger transporting large neural amino acids and several amino-acid mimicking drugs across the cell membranes. LAT1 is highly expressed at the blood brain barrier (BBB) and in numerous cancer cells and is therefore a potential drug target. However, structural features affecting the ability to bind to LAT1 and the cellular translocation by LAT1 are unclear. In the present study we determined the binding to and transport through human LAT1 of several compounds into the human breast adenocarcinoma cells (MCF-7). We show that the meta-conjugation of l-phenylalanine increases binding to human LAT1 compared to para-conjugation or aliphatic amino acid moiety. Furthermore, large, rigid and aromatic meta-substituted l-phenylalanine derivative enabled selective and efficient LAT1-mediated cellular uptake. Our results also demonstrates that in addition to binding studies, it is of utmost importance to determine the cellular accu...

Biochemical and Biophysical Research Communications

Simvastatin induces insulin resistance in L6 skeletal muscle myotubes by suppressing insulin sign... more Simvastatin induces insulin resistance in L6 skeletal muscle myotubes by suppressing insulin signaling, GLUT4 expression and GSK-3ß phosphorylation Yaluri N Elsevier BV info:eu-repo/semantics/article

Page 1. KUOPION YLIOPISTON JULKAISUJA С LUONNONTIETEET JA YMPÄRISTÖTIETEET 161 KUOPIO UNIVERSITY ... more Page 1. KUOPION YLIOPISTON JULKAISUJA С LUONNONTIETEET JA YMPÄRISTÖTIETEET 161 KUOPIO UNIVERSITY PUBLICATIONS С NATURAL AND ENVIRONMENTAL SCIENCES 161 TARJA KOKKOLA Mapping the ...

Biochemical and Biophysical Research Communications, Sep 1, 1998

Most established effects of physiological melatonin con-A yeast functional colorimetric assay was... more Most established effects of physiological melatonin con-A yeast functional colorimetric assay was employed centrations are mediated via high-affinity cell membrane to test the effects of site-directed point mutations on receptors which belong to the superfamily of G proteinthe function of the human Mel 1a melatonin receptor. coupled receptors (GPCRs) (2, 3). Seven mutants were created in transmembrane do-Recent cloning of genes encoding several melatonin mains III, V, and VII of the receptor to test the rhodopreceptors has revealed so far three melatonin receptor sin-based model of melatonin recognition. Two musubtypes, two of which have been found in mammals tants in transmembrane domains III and VI were cre-(for reviews, see 2, 3). Though melatonin receptors form ated to investigate the mechanisms of G protein a new subfamily within the GPCR superfamily, they activation in the melatonin receptor. Mutations in have conserved the most important features of GPCRs, transmembrane domain V either potentiated agonist such as seven transmembrane helices (TM I-TM VII) efficiencies (H195A) or totally abolished all responses connected by intra-and extracellular loops. to tested compounds (V192T/H195A). Mutation N124A Elucidation of the primary structures of melatonin in the conserved NRY motif in the end of transmembrane domain III seriously impaired receptor activa-receptors has allowed construction of a three-dimention. Several mutants were found to have decreased sional rhodopsin-based model for melatonin recogniability to activate functional responses, reflecting the tion at its receptor (4). According to this model, melatoimportance of these residues for receptor function. nin is recognized by specific amino acid residues in a These data also suggest that activation of the receptor binding pocket formed by the TM helices. The amino involves interaction of the 5-methoxy group of melatoacids suggested to interact with melatonin are highly nin with the conserved histidine H195 in transmemconserved in all so far cloned melatonin receptors but brane domain V. ᭧ 1998 Academic Press are not present in other GPCRs. Testing of the relevance of this model should increase our understanding on how melatonin is recognized at the molecular level. To begin to address this issue, we mutated five amino Melatonin is the major hormonal product of the pineal acid residues proposed to participate in melatonin recgland, providing the chemical expression of darkness. ognition in the human Mel 1a receptor. Melatonin is secreted during the hours of darkness to A general view of GPCR function is that these recepadjust circadian and circannual rhythms. The synthesis tors exist in equilibrium between the active and inacof melatonin is synchronized by the daily light-dark cycle tive state (5). As agonist binding stabilizes the active through a neural pathway originating from the eyes (1). conformation of the receptor, the intracellular parts of the receptor, especially the second and the third intracellular loop and possibly also the C-terminal tail, are