CELLULAR NEUROCIENCE | NEURONAL SIGNALING | CARDIOVASCULAR RESEARCH | METABOLISM | LIPID SIGNALING AND HOMEOSTASIS | ENDOCRINOLOGY | CELLULAR PHYSIOLOGY | TARGETED GENE-EXPRESSION ANALYSIS | MEMBRANE BIOLOGY | TELOMERE RESEARCH
Heikki Koistinen, M.D., Dr.Med.Sci., Docent, Head
Neeta Datta Sengupta, Ph.D.
Selina Mäkinen, M.Sc.
Petro Kyrylenko, M.Sc.
In 2014, the primary focus of research activity in the group was on the regulation of glucose and fatty acid metabolism in skeletal muscle. To this end, the team established a collection of primary human muscle cells from clinically characterized subjects from different glucose tolerance phenotypes, including normal glucose tolerance (NGT), impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and type 2 diabetes (T2D). A variety of biochemical and functional analyses with these collections are currently ongoing.
In FUSION (Finnish United States Investigation on NIDDM Genetics) Tissue Biopsy study we collected muscle, adipose and skin samples from a cohort of >300 clinically characterized Finnish people across all glucose tolerance stages. Sampling was performed in 2009–2013. Analysis of the skeletal muscle transcriptome by RNA sequencing of vastus lateralis muscle biopsies from 279 subjects was completed in 2014. With these patient materials, we performed dense genotyping and imputation, as well as constructed and sequenced strand-specific mRNAseq libraries. Using expression quantitative trait loci (eQTL), we identified >8000 genes, some of which appear to be disease-state specific. Multiple eQTLs are in high linkage disequilibrium with genomewide association studies single nucleotide polymorphisms for T2D, pinpointing genes as candidates for a role in T2D risk. Further analyses of FUSION Tissue Biopsy samples are currently ongoing.
Figure. Human myotubes after seven days of differentiation. For immunocytochemistry, cells were stained with DNA binding dye DAPI to show nuclei (blue) and muscle-specific antibody desmin (red) to show the myotubes. The photograph was taken at 20X magnification using a Leica fluorescence microscope.
As a part of a large international collaboration, whole-exome sequencing data from peripheral blood DNA of >17,000 persons was analysed. The presence of detectable somatic mutations rose in frequency with advancing age, with prevalence being highest in age group of people >90 years of age. The highest proportion of somatic mutations occurred in three genes: DNMT3A, TET2, and ASXL1, and the presence of a variant increased not only the risk of hematological malignancy, but increased allcause mortality and the risk of cardiovascular disease, as well.
Heikki Koistinen, M.D., Dr.Med.Sci., Docent
Tel: +358 2941 25706
Jaiswal S, Fontanillas P, Flannick J, Manning A, Grauman PV, Mar BG, M.D., Lindsley RC, Mermel CH, Burtt N, Chavez A, Higgins JM, Moltchanov V, Kuo FC, Kluk MJ, Henderson B, Kinnunen L, Koistinen HA, Ladenvall C, Getz G, Correa A, Banahan BF, Gabriel S, Kathiresan S, Stringham HM, McCarthy MI, on behalf of T2D-GENES; Boehnke M, on behalf of GoT2D; Altshuler D, on behalf of SIGMA T2D, Tuomilehto J, Haiman C, Groop L, Atzmon G, Wilson JG, Neuberg D, Altshuler D, Ebert BL. Age-related clonal hematopoiesis associated with adverse outcomes. New Engl J Med. 2014; 25;371:2488–98.
Mäkinen S, Skrobuk P, Nguyen YH, Koistinen H. Insuliiniresistenssin mekanismit. Duodecim 2013; 129:2115–22.
Koistinen H: Plasman copeptiini – kliinikon monitoimityökalu? Duodecim 2012; 128:1541-9.
Koistinen H: Metformiinin käyttöönn liittyvä maitohappoasidoosi ei ole harvinaisuus. Suomen Lääkärilehti 2012; 67:2742-2744.
Koistinen H, Holmberg V, Palojärvi V: Kolmesti sokkiin kolmessa vuodessa – kolmas kerta toden sanoo. Duodecim 2012; 128:105.
Robciuc MR, Skrobuk P, Anisimov A, Olkkonen VM, Alitalo K, Eckel RH, Koistinen HA, Jauhiainen M, Ehnholm C: Angiopoietin-like 4 mediates peroxisome proliferator-activated receptor delta effect on lipoprotein lipase-dependent fatty acid uptake but not on beta-oxidation in myotubes. PLosOne 2012; 7:e46212.
Skrobuk P, von Kraemer S, Semenova MM, Zitting A, Koistinen HA: Acute exposure to resveratrol inhibits AMPK activity in human skeletal muscle cells. Diabetologia 2012; 55:3051-60.