Insulin Signaling in Human Adipocytes a Systems Biology Approach

................................................................................................. 2 SAMMANFATTNING PÅ SVENSKA .............................................................. 4 ABBREVIATIONS ......................................................................................... 6 LIST OF ORIGINAL PAPERS .......................................................................... 8 PAPERS NOT INCLUDED IN THESIS ............................................................ 10 INTRODUCTION ........................................................................................ 12 THE ADIPOSE TISSUE AND THE ADIPOCYTE ........................................................... 12 GLUCOSE HOMEOSTASIS.................................................................................. 13 Insulin .................................................................................................... 14 Models of Glucose Homeostasis ............................................................ 14 TYPE 2 DIABETES ...................................................................................... 16 Genetics and epigenetics ....................................................................... 17 Obesity .................................................................................................. 17 Insulin sensitivity in obesity ................................................................... 18 MODELS OF TYPE 2 DIABETES ........................................................................... 18 INSULIN RESISTANCE AND POSSIBLE CAUSES ........................................... 20 Inflammation ......................................................................................... 20 Limitation of the Size of Adipocytes ...................................................... 20 FROM INSULIN RESISTANCE TO TYPE 2 DIABETES .................................................. 22 NORMAL INSULIN SIGNALING IN HUMAN ADIPOCYTES ........................... 24 THE INSULIN RECEPTOR ................................................................................... 24 INSULIN RECEPTOR SUBSTRATE 1 ...................................................................... 25 INTERNALIZATION OF INSULIN BOUND INSULIN RECEPTOR IS NECESSARY FOR EARLY INSULIN SIGNALING (PAPER I) ........................................................................... 28 SIGNALING DOWNSTREAM OF IRS1 ................................................................... 32 Mammalian Target of Rapamycin ........................................................ 32 Glucose uptake in adipocytes ................................................................ 33 MODELS OF INSULIN SIGNALING ........................................................................ 36 THE INSULIN SIGNALING NETWORK IN TYPE 2 DIABETES ......................... 38 Role of IR in Type 2 Diabetes ................................................................. 38 Role of IRS1 in Type 2 Diabetes ............................................................. 40 The Insulin signaling network downstream of IRS1 in type 2 diabetes . 42 A NETWORK ANALYSIS OF INSULIN SIGNALING NORMALLY AND IN TYPE 2 DIABETES (PAPER III) .............................................................................................................. 44 HIERACHICAL MODELLING AS A LINK BETWEEN THE IN VITRO AND IN VIVO SITUATION (PAPER II)..................................................................................................... 48 METHODS ................................................................................................ 52 BIOLOGICAL METHODS .................................................................................... 52 MATHEMATICAL MODELS ARE POTENT TOOLS FOR ANALYZING AND UNDERSTANDING COMPLEX BIOLOGICAL SYSTEMS ........................................................................ 53 MODEL CONSTRUCTION ................................................................................... 54 PREPARING SIGNALING DATA FOR MODELING ..................................................... 57 UNKNOWN PARAMETERS ................................................................................ 58 PARAMETER OPTIMIZATION ............................................................................. 58 CORE PREDICTIONS (PAPER I) ........................................................................... 60 CONCLUSIONS .......................................................................................... 64 FUTURE PERSPECTIVES ............................................................................. 66 ACKNOWLEDGEMENTS / TACK ................................................................. 68 REFERENCES ............................................................................................. 70