Metabolism
The main interest of the group is to understand the various mechanisms regulating metabolism and insulin sensitivity at whole body level as well as specifically in skeletal muscle. We are interested in molecular and genetic mechanisms contributing to type 2 diabetes (T2D) and related traits.
We are interested in the regulation of metabolism and especially in the molecular mechanisms regulating in¬sulin action in human skeletal muscle. As a main research model, we are using primary muscle cell cultures, established from muscle biopsies obtained from clinically carefully characterized volunteers. We analyse mechanisms predisposing and leading to insulin resistance, and seek novel ways to improve insulin action. We have a variety of in vitro methods to study cell metabolism at our disposal.
Finland-United States Investigation of NIDDM Genetics (FUSION) is an international multi-organizational collaborative project, the main goal of which is to identify genetic risk factors that predispose to T2D and related intermediate traits. We collaborate closely with the FUSION study, with the head of the group, Docent Heikki Koistinen being one of the FUSION PIs. As an example how research questions and collaborations converge in a fruitful fashion, we have identified a missense variant p.P50T/AKT2 as part of the ongoing genetic analyses of FUSION – and METSIM-studies (Metabolic Syndrome in Men – study). This variant is specific for Finns, very rare in non-Finnish Europeans and it predisposes to insulin resistance and type 2 diabetes. We have established an internationally unique and largest collection of primary muscle cell cultures from carriers of the Finnish p.P50T/AKT2 variant and have demonstrated a large scale impairment in insulin signaling in myotubes from variant carriers (Mäkinen et al. 2023).
Selected publications
Mäkinen S, Datta N, Rangarajan S, Nguyen YH, Olkkonen VM, Latva-Rasku A, Nuutila P, Laakso M, Koistinen HA: Finnish-specific AKT2 gene variant leads to impaired insulin signalling in myotubes. Journal of Molecular Endocrinology. 2023 Jan 4;70(2):e210285. doi: 10.1530/JME-21-0285. Print 2023 Feb 1. PMID: 36409629
Öhman T, Teppo J, Datta N, Mäkinen S, Varjosalo M, Koistinen HA: Skeletal muscle proteomes reveal downregulation of mitochondrial proteins in transition from prediabetes into type 2 diabetes. iScience 2021 Jun 10;24(7):102712. doi: 10.1016/j.isci.2021.102712. eCollection 2021 Jul 23. PMID: 34235411
Mäkinen S, Datta N, Nguyen YH, Kyrylenko P, Laakso M, Koistinen HA: Simvastatin profoundly impairs energy metabolism in primary human muscle cells. Endocrine Connections, 9(11):1103-1113, 2020, doi: 10.1530/EC-20-0444. PMID: 33295884
Taylor DL , Scott LJ , Jackson AU, Narisu N , Hemani G , Erdos MR , Chines PS , Swift A , Idol J , Didion JP , Welch RP , Kinnunen L , Saramies J , Lakka TA , Laakso M , Tuomilehto J , Parker SCJ, Koistinen HA , Smith GD , Boehnke M , Birney E , Collins FS : Integrative analysis of gene expression, DNA methylation, physiological traits, and genetic variation in human skeletal muscle. Proc Natl Acad Sci U S A. 16(22):10883-10888. 2019 May 10. pii: 201814263. doi: 10.1073/pnas.1814263116. [Epub ahead of print] PMID: 31076557
Latva-Rasku A, Honka MJ, Stančáková A, Koistinen HA, Kuusisto J, Guan L, Manning AK, Stringham H, Gloyn AL, Lindgren CM, the T2D-GENES Consortium, Collins FS, Mohlke KL, Scott LJ, Karjalainen T, Nummenmaa L, Boehnke M, Nuutila P, Laakso M: A Partial Loss-of-Function Variant in AKT2 is Associated with Reduced Insulin-Mediated Glucose Uptake in Multiple Insulin Sensitive Tissues: a Genotype-Based Callback Positron Emission Tomography Study. Diabetes 2018 Feb;67(2):334-342. doi: 10.2337/db17-1142. Epub 2017 Nov 15.PMID:29141982
Scott LJ*, Erdos MR*, Huyghe JR*, Welch RP*, Beck AT, Wolford BN, Chines PS, Didion JP, Narisu N, Stringham HM, Taylor DL, Jackson AU, Vadlamudi S, Bonnycastle LL, Kinnunen L, Saramies J, Sundvall J, D’Oliveira Albanus R, Kiseleva A, Hensley J, Crawford GE, Jiang H, Wen X, Watanabe RM, Lakka TA, Mohlke KL, Laakso M, Tuomilehto J, Koistinen HA, Boehnke M*, Collins FS*, Parker SCJ*: The genetic regulatory signature of type 2 diabetes in human skeletal muscle. Nature Communications. Jun 29;7:11764, 2016. doi: 10.1038/ncomms11764. PMID: 27353450
Fuchsberger C, Flannick J, Teslovich TM, Mahajan A, Agarwala V, Gaulton KJ, Ma C, Fontanillas P, Moutsianas L, McCarthy DJ, Rivas MA, Perry JR, Sim X, Blackwell TW, Robertson NR, Rayner NW, Cingolani P, Locke AE, Tajes JF, Highland HM, Dupuis J, Chines PS, Lindgren CM, Hartl C, Jackson AU, Chen H, Huyghe JR, van de Bunt M, Pearson RD, Kumar A, Müller-Nurasyid M, Grarup N, Stringham HM, Gamazon ER, Lee J, Chen Y, Scott RA, Below JE, Chen P, Huang J, Go MJ, Stitzel ML, Pasko D, Parker SC, Varga TV, Green T, Beer NL, Day-Williams AG, Ferreira T, Fingerlin T, Horikoshi M, Hu C, Huh I, Ikram MK, Kim BJ, Kim Y, Kim YJ, Kwon MS, Lee J, Lee S, Lin KH, Maxwell TJ, Nagai Y, Wang X, Welch RP, Yoon J, Zhang W, Barzilai N, Voight BF, Han BG, Jenkinson CP, Kuulasmaa T, Kuusisto J, Manning A, Ng MC, Palmer ND, Balkau B, Stančáková A, Abboud HE, Boeing H, Giedraitis V, Prabhakaran D, Gottesman O, Scott J, Carey J, Kwan P, Grant G, Smith JD, Neale BM, Purcell S, Butterworth AS, Howson JM, Lee HM, Lu Y, Kwak SH, Zhao W, Danesh J, Lam VK, Park KS, Saleheen D, So WY, Tam CH, Afzal U, Aguilar D, Arya R, Aung T, Chan E, Navarro C, Cheng CY, Palli D, Correa A, Curran JE, Rybin D, Farook VS, Fowler SP, Freedman BI, Griswold M, Hale DE, Hicks PJ, Khor CC, Kumar S, Lehne B, Thuillier D, Lim WY, Liu J, van der Schouw YT, Loh M, Musani SK, Puppala S, Scott WR, Yengo L, Tan ST, Taylor HA Jr, Thameem F, Wilson G, Wong TY, Njølstad PR, Levy JC, Mangino M, Bonnycastle LL, Schwarzmayr T, Fadista J, Surdulescu GL, Herder C, Groves CJ, Wieland T, Bork-Jensen J, Brandslund I, Christensen C, Koistinen HA, Doney AS, Kinnunen L, Esko T, Farmer AJ, Hakaste L, Hodgkiss D, Kravic J, Lyssenko V, Hollensted M, Jørgensen ME, Jørgensen T, Ladenvall C, Justesen JM, Käräjämäki A, Kriebel J, Rathmann W, Lannfelt L, Lauritzen T, Narisu N, Linneberg A, Melander O, Milani L, Neville M, Orho-Melander M, Qi L, Qi Q, Roden M, Rolandsson O, Swift A, Rosengren AH, Stirrups K, Wood AR, Mihailov E, Blancher C, Carneiro MO, Maguire J, Poplin R, Shakir K, Fennell T, DePristo M, Hrabé de Angelis M, Deloukas P, Gjesing AP, Jun G, Nilsson P, Murphy J, Onofrio R, Thorand B, Hansen T, Meisinger C, Hu FB, Isomaa B, Karpe F, Liang L, Peters A, Huth C, O’Rahilly SP, Palmer CN, Pedersen O, Rauramaa R, Tuomilehto J, Salomaa V, Watanabe RM, Syvänen AC, Bergman RN, Bharadwaj D, Bottinger EP, Cho YS, Chandak GR, Chan JC, Chia KS, Daly MJ, Ebrahim SB, Langenberg C, Elliott P, Jablonski KA, Lehman DM, Jia W, Ma RC, Pollin TI, Sandhu M, Tandon N, Froguel P, Barroso I, Teo YY, Zeggini E, Loos RJ, Small KS, Ried JS, DeFronzo RA, Grallert H, Glaser B, Metspalu A, Wareham NJ, Walker M, Banks E, Gieger C, Ingelsson E, Im HK, Illig T, Franks PW, Buck G, Trakalo J, Buck D, Prokopenko I, Mägi R, Lind L, Farjoun Y, Owen KR, Gloyn AL, Strauch K, Tuomi T, Kooner JS, Lee JY, Park T, Donnelly P, Morris AD, Hattersley AT, Bowden DW, Collins FS, Atzmon G, Chambers JC, Spector TD, Laakso M, Strom TM, Bell GI, Blangero J, Duggirala R, Tai ES, McVean G, Hanis CL, Wilson JG, Seielstad M, Frayling TM, Meigs JB, Cox NJ, Sladek R, Lander ES, Gabriel S, Burtt NP, Mohlke KL, Meitinger T, Groop L, Abecasis G, Florez JC, Scott LJ, Morris AP, Kang HM, Boehnke M, Altshuler D, McCarthy MI: The genetic architecture of type 2 diabetes. Nature, Jul 11, 536(7614):41-47, 2016. doi: 10.1038/nature18642. PMID: 27398621
Skrobuk P, von Kraemer S, Semenova MM, Zitting A, Koistinen HA: Acute exposure to resveratrol inhibits AMPK activity in human skeletal muscle cells. Diabetologia 55:3051-60, 2012. DOI 10.1007/s00125-012-2691-1.
Bouzakri K, Zachrisson A, Al-Khalili L, Zhang BB, Koistinen HA, Krook A, Zierath JR : siRNA based gene silencing reveals specialized roles of IRS1/Akt2 and IRS-2/Akt1 in glucose and lipid metabolism in human skeletal muscle. Cell Metabolism 4 :89-96, 2006
Koistinen HA, Galuska D, Chibalin AV, Yang J, Zierath JR, Holman GD, Wallberg-Henriksson H: AICAR (5 amino-imidazole carboxamide riboside) increases glucose transport and cell-surface GLUT4 content in skeletal muscle from Type 2 diabetic subjects. Diabetes 52:1066-1072, 2003
External funding
Finnish Cultural Foundation
HUS-VATR
Jalmari and Rauha Ahokas Foundation
Medical Society of Finland
Medicinska understödsföreningen Liv och Hälsa r.f