Gene expression differences in skin fibroblasts in identical twins discordant for type 1 diabetes.
Clinical studies suggest metabolic memory to hyperglycemia. We tested whether diabetes leads to persistent systematic in vitro gene expression alterations in patients with type 1 diabetes (T1D) compared with their monozygotic, nondiabetic twins. Microarray gene expression was determined in skin fibroblasts (SFs) of five twin pairs cultured in high glucose (HG) for ∼6 weeks. The Exploratory Visual Analysis System tested group differences in gene expression levels within KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways. An overabundance of differentially expressed genes was found in eight pathways: arachidonic acid metabolism (P = 0.003849), transforming growth factor-β signaling (P = 0.009167), glutathione metabolism (P = 0.01281), glycosylphosphatidylinositol anchor (P = 0.01949), adherens junction (P = 0.03134), dorsal-ventral axis formation (P = 0.03695), proteasome (P = 0.04327), and complement and coagulation cascade (P = 0.04666). Several genes involved in epigenetic mechanisms were also differentially expressed. All differentially expressed pathways and all the epigenetically relevant differentially expressed genes have previously been related to HG in vitro or to diabetes and its complications in animal and human studies. However, this is the first in vitro study demonstrating diabetes-relevant gene expression differences between T1D-discordant identical twins. These SF gene expression differences, persistent despite the HG in vitro conditions, likely reflect "metabolic memory", and discordant identical twins thus represent an excellent model for studying diabetic epigenetic processes in humans.
Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA. caram001@umn.edu
M Luiza
ML
Caramori
Youngki
Y
Kim
Jason H
JH
Moore
Stephen S
SS
Rich
Josyf C
JC
Mychaleckyj
Nobuaki
N
Kikyo
Michael
M
Mauer
D000328:Adult; D016718:Arachidonic Acid / Q000378:metabolism; D002199:Capillary Permeability; D002478:Cells, Cultured; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000378:metabolism; D004200:Diseases in Twins; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D020869:Gene Expression Profiling; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D015398:Signal Transduction; D012867:Skin / Q000166:cytology; D016212:Transforming Growth Factor beta / Q000502:physiology; D014430:Twins, Monozygotic
D016212:Transforming Growth Factor beta; D016718:Arachidonic Acid; D005978:Glutathione