Apoptotic, regenerative, and immune-related signaling in human islets from type 2 diabetes individuals.
Islet dysfunction is a primary cause of developing type 2 diabetes mellitus (T2DM). Events leading to islet failure are still poorly defined due to the complexity of the disease and scarcity of human T2DM islets. The aim of the present study was to identify cellular mechanisms involved in the T2DM pathophysiology by protein profiling islets obtained from T2DM individuals and age- and weight-matched controls using liquid chromatography Fourier transform ion cyclotron resonance mass spectrometry and surface enhanced laser desorption/ionization time-of-flight mass spectrometry. In T2DM islets, multiple differentially expressed proteins correlated with insulin secretion. When these T2DM islet proteins were analyzed for differential pathway activation, three of the five most activated pathways were pathways of cell arrest and apoptosis (p53, caspase, stress-activated), one represented immune-response (Fas), and the most activated pathway was connected with proliferation and regeneration (E2F). Among the inactivated pathways, three out of five were pathways of proliferation and regeneration (insulin, PRL, PDGF). The present study is the first to report differential activation of specific pathways during T2DM islet deterioration. The information about alterations in pathway signaling patterns may open new ways to develop strategies aimed at restoring islet cell function and survival.
Department of Medical Cell Biology, Uppsala University, 75123 Uppsala, Sweden.
Hanna K
HK
Nyblom
Marco
M
Bugliani
Eva
E
Fung
Ugo
U
Boggi
Roman
R
Zubarev
Piero
P
Marchetti
Peter
P
Bergsten
D000368:Aged; D017209:Apoptosis; D016022:Case-Control Studies; D049109:Cell Proliferation; D003924:Diabetes Mellitus, Type 2 / Q000473:pathology*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007109:Immunity; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D011506:Proteins / Q000032:analysis; D040901:Proteomics; D012038:Regeneration; D015398:Signal Transduction / Q000502:physiology*
D007328:Insulin; D011506:Proteins